Informing the Selection of Screening Hit Series with in Silico Absorption, Distribution, Metabolism, Excretion, and Toxicity Profiles.

PubMed

Sanders, John M; Beshore, Douglas C; Culberson, J Christopher; Fells, James I; Imbriglio, Jason E; Gunaydin, Hakan; Haidle, Andrew M; Labroli, Marc; Mattioni, Brian E; Sciammetta, Nunzio; Shipe, William D; Sheridan, Robert P; Suen, Linda M; Verras, Andreas; Walji, Abbas; Joshi, Elizabeth M; Bueters, Tjerk

2017-08-24

High-throughput screening (HTS) has enabled millions of compounds to be assessed for biological activity, but challenges remain in the prioritization of hit series. While biological, absorption, distribution, metabolism, excretion, and toxicity (ADMET), purity, and structural data are routinely used to select chemical matter for further follow-up, the scarcity of historical ADMET data for screening hits limits our understanding of early hit compounds. Herein, we describe a process that utilizes a battery of in-house quantitative structure-activity relationship (QSAR) models to generate in silico ADMET profiles for hit series to enable more complete characterizations of HTS chemical matter. These profiles allow teams to quickly assess hit series for desirable ADMET properties or suspected liabilities that may require significant optimization. Accordingly, these in silico data can direct ADMET experimentation and profoundly impact the progression of hit series. Several prospective examples are presented to substantiate the value of this approach.

Absorption, Distribution and Excretion of Four Forms of Titanium Dioxide Pigment in the Rat.

PubMed

Farrell, Thomas P; Magnuson, Berna

2017-08-01

Titanium dioxide (TiO 2 ) is a white color additive that has a long history of global approval and use in food. There is, however, considerable confusion regarding the applicability of the biological effects of novel, engineered, nano-sized forms of TiO 2 developed for nonpigmentary applications to the safety of oral exposure to food grade TiO 2 pigment. The objective of this study was to assess the absorption, distribution, and routes of excretion in rats after oral exposure to food grade TiO 2 . Four different grades of TiO 2 (200 ppm) or control (0 ppm) diets were fed to rats for 7 consecutive days, followed by control diet only for 1, 24, or 72 h. Concentrations of titanium in liver, kidney and muscle were mainly below the limit of detection (<0.1 to < 0.2 mg/kg wet weight); tissue concentrations of titanium above the LOD were in the range of 0.1 to 0.3 mg/kg wet weight for all groups. Whole blood concentrations of titanium were <0.04 mg/L for all groups. Urinary excretion of titanium was equivalent to <2% daily dose/L of urine for all groups and was generally below the limit of quantification (<0.04 mg/L). Feces represented the predominant route of excretion. These results demonstrate that there is no accumulation of titanium in tissues following consumption of diets containing 200 ppm food grade TiO 2 . No differences in systemic absorption of the 4 forms of TiO 2 were observed indicating that the bioavailability of TiO 2 is consistently low for the range of particle sizes and morphologies examined in this study. © 2017 Institute of Food Technologists®.

Pharmacokinetics, Distribution, Metabolism, and Excretion of Omadacycline following a Single Intravenous or Oral Dose of 14C-Omadacycline in Rats

PubMed Central

Lin, Wen; Flarakos, Jimmy; Du, Yancy; Hu, Wenyu; He, Handan; Mangold, James; Tanaka, S. Ken

2016-01-01

ABSTRACT The absorption, distribution, metabolism, and excretion (ADME) of omadacycline, a first-in-class aminomethylcycline antibiotic with a broad spectrum of activity against Gram-positive, Gram-negative, anaerobic, and atypical bacteria, were evaluated in rats. Tissue distribution was investigated by quantitative whole-body autoradiography in male Long-Evans Hooded (LEH) rats. Following an intravenous (i.v.) dose of 5 mg/kg of body weight, radioactivity widely and rapidly distributed into most tissues. The highest tissue-to-blood concentration ratios (t/b) were observed in bone mineral, thyroid gland, and Harderian gland at 24 h post-i.v. dose. There was no evidence of stable accumulation in uveal tract tissue, suggesting the absence of a stable binding interaction with melanin. Following a 90 mg/kg oral dose in LEH rats, the highest t/b were observed in bone mineral, Harderian gland, liver, spleen, and salivary gland. The plasma protein binding levels were 26% in the rat and 15% to 21% in other species. Omadacycline plasma clearance was 1.2 liters/h/kg, and its half-life was 4.6 h; the steady-state volume of distribution (Vss) was 6.89 liters/kg. Major circulating components in plasma were intact omadacycline and its epimer. Consistent with observations in human, approximately 80% of the dose was excreted into the feces as unchanged omadacycline after i.v. administration. Fecal excretion was primarily the result of biliary excretion (∼40%) and direct gastrointestinal secretion (∼30%). However, urinary excretion (∼30%) was equally prominent after i.v. dosing. PMID:27821446

Maternally-Mediated Effects on Development*

EPA Science Inventory

In standard Segment II mammalian bioassays for developmental toxicity, it is the pregnant animal that is exposed to the test article, so in this sense, all in utero developmental toxicity is mediated by the mother. This will include absorption, distribution, metabolism and excret...

Pharmacokinetics, tissue distribution, and excretion of zinc oxide nanoparticles

PubMed Central

Baek, Miri; Chung, Hae-Eun; Yu, Jin; Lee, Jung-A; Kim, Tae-Hyun; Oh, Jae-Min; Lee, Won-Jae; Paek, Seung-Min; Lee, Jong Kwon; Jeong, Jayoung; Choy, Jin-Ho; Choi, Soo-Jin

2012-01-01

Background This study explored the pharmacokinetics, tissue distribution, and excretion profile of zinc oxide (ZnO) nanoparticles with respect to their particle size in rats. Methods Two ZnO nanoparticles of different size (20 nm and 70 nm) were orally administered to male and female rats, respectively. The area under the plasma concentration-time curve, tissue distribution, excretion, and the fate of the nanoparticles in organs were analyzed. Results The plasma zinc concentration of both sizes of ZnO nanoparticles increased during the 24 hours after administration in a dose-dependent manner. They were mainly distributed to organs such as the liver, lung, and kidney within 72 hours without any significant difference being found according to particle size or rat gender. Elimination kinetics showed that a small amount of ZnO nanoparticles was excreted via the urine, while most of nanoparticles were excreted via the feces. Transmission electron microscopy and x-ray absorption spectroscopy studies in the tissues showed no noticeable ZnO nanoparticles, while new Zn-S bonds were observed in tissues. Conclusion ZnO nanoparticles of different size were not easily absorbed into the bloodstream via the gastrointestinal tract after a single oral dose. The liver, lung, and kidney could be possible target organs for accumulation and toxicity of ZnO nanoparticles was independent of particle size or gender. ZnO nanoparticles appear to be absorbed in the organs in an ionic form rather than in a particulate form due to newly formed Zn-S bonds. The nanoparticles were mainly excreted via the feces, and smaller particles were cleared more rapidly than the larger ones. ZnO nanoparticles at a concentration below 300 mg/kg were distributed in tissues and excreted within 24 hours. These findings provide crucial information on possible acute and chronic toxicity of ZnO nanoparticles in potential target organs. PMID:22811602

Fluoride metabolism.

PubMed

Buzalaf, Marília Afonso Rabelo; Whitford, Gary Milton

2011-01-01

Knowledge of all aspects of fluoride metabolism is essential for comprehending the biological effects of this ion in humans as well as to drive the prevention (and treatment) of fluoride toxicity. Several aspects of fluoride metabolism - including gastric absorption, distribution and renal excretion - are pH-dependent because the coefficient of permeability of lipid bilayer membranes to hydrogen fluoride (HF) is 1 million times higher than that of F(-). This means that fluoride readily crosses cell membranes as HF, in response to a pH gradient between adjacent body fluid compartments. After ingestion, plasma fluoride levels increase rapidly due to the rapid absorption from the stomach, an event that is pH-dependent and distinguishes fluoride from other halogens and most other substances. The majority of fluoride not absorbed from the stomach will be absorbed from the small intestine. In this case, absorption is not pH-dependent. Fluoride not absorbed will be excreted in feces. Peak plasma fluoride concentrations are reached within 20-60 min following ingestion. The levels start declining thereafter due to two main reasons: uptake in calcified tissues and excretion in urine. Plasma fluoride levels are not homeostatically regulated and vary according to the levels of intake, deposition in hard tissues and excretion of fluoride. Many factors can modify the metabolism and effects of fluoride in the organism, such as chronic and acute acid-base disturbances, hematocrit, altitude, physical activity, circadian rhythm and hormones, nutritional status, diet, and genetic predisposition. These will be discussed in detail in this review. Copyright © 2011 S. Karger AG, Basel.

SUITABILITY OF USING IN VITRO AND COMPUTATIONALLY ESTIMATED PARAMETERS IN SIMPLIFIED PHARMACOKINETIC MODELS

EPA Science Inventory

A challenge in PBPK model development is estimating the parameters for absorption, distribution, metabolism, and excretion of the parent compound and metabolites of interest. One approach to reduce the number of parameters has been to simplify pharmacokinetic models by lumping p...

Comparison of Laboratory Measured BCFs, BMFs, and BSAFs to Field Measured BAFs, BMFs, and BSAFs

EPA Science Inventory

A series of workshops on bioaccumulation science and issues have been held since 2005, and the foci of these past workshops were1) Bioaccumulation Data Sources, 2) In Vitro/ADME (absorption, distribution, metabolism, and excretion) in Bioaccumulation Assessments, and 3) Bioaccumu...

Human and Rat ABC Transporter Efflux of Bisphenol A and Bisphenol A Glucuronide: Interspecies Comparison and Implications for Pharmacokinetic Assessment

EPA Science Inventory

Significant interspecies differences exist between human and rodent with respect to absorption, distribution, and excretion of bisphenol A (BPA) and its primary metabolite, BPA-glucuronide (BPA-G). ATP-Binding Cassette (ABC) transporter enzymes play important roles in these physi...

Absorption of ferulic acid from low-alcohol beer.

PubMed

Bourne, L; Paganga, G; Baxter, D; Hughes, P; Rice-Evans, C

2000-03-01

Flavonoids and monophenolic compounds have been well-described over recent years for their properties as antioxidants and scavengers of reactive oxygen and nitrogen species. A number of epidemiological studies implicate a role for flavonoids in reducing the risk of coronary heart disease. In particular, the focus has been on flavonol-rich fruit and vegetables and flavonoid-rich beverages, especially tea and red wine. Mechanisms of protection are unclear since the absorption, distribution, metabolism and elimination of dietary phenolics have not yet been extensively investigated. Here we report the bioavailability of ferulic acid, 4-hydroxy-3-methoxy-cinnamic acid, the major hydroxycinnamate in beer. Studies of the pharmacokinetics of urinary excretion of ferulic acid from low alcohol beer consumption in humans have been undertaken. The results show that ferulic acid is absorbed with a peak time for maximal excretion of ca. 8 h and the mean cumulative amount excreted is 5.8 +/- 3.2 mg. These findings are consistent with the uptake of ferulic acid from dietary sources, such as tomatoes, and suggest that ferulic acid is more bioavailable than individual dietary flavonoids and phenolics so far studied.

Absorption, Distribution and Excretion of 14C-Probimane in Mice Bearing Lewis Lung Carcinoma

PubMed Central

Lu, Da-Yong; Chen, Rui-Ting; Lu, Ting-Ren; Wu, Hong-Ying; Qu, Rong-Xin; Che, Jin-Yu; Xu, Bin

2010-01-01

Spontaneous neoplasm metastasis, a fatalist pathological feature of cancer, is a long-evolving, multi-steps process that can now only be treated or controlled by drugs or immuno-modulators. Probimane (Pro), as a representative of the well-known class of antimetastatic agents ‘Bisdioxopiperazine compounds (Biz)’, is systematically studied for its absorption, distribution and excretion in mice bearing Lewis lung carcinoma by a radioactivity-detective method in this investigation. It is found that the 14C-Pro concentrations in different normal organs of mice at 2 hrs are very high and dramatically declined at 24 and 48 hrs. However, Pro concentrations in metastatic foci are slightly changed at the same time. Almost no change of Pro concentrations is observed in pulmonary metastatic nodules within 48 hrs. This evidence can be used to explain the characteristics of good metastatic inhibition by Biz compounds. The radioactivity in brain is relatively low because Pro can hardly penetrate into the blood-brain-barrier to eliminate brain tumors. The excretion of 14C-Pro is observed at the same ratios from both urine and feces and also at constant rates. These data are much useful for better understanding of the general pharmacological characters and possible antimetastatic mechanisms of actions of probimane and other Biz compounds from a new perspective and research angles. PMID:21179357

Evaluation of in vitro absorption, distribution, metabolism, and excretion (ADME) properties of mitragynine, 7-hydroxymitragynine, and mitraphylline

USDA-ARS?s Scientific Manuscript database

Mitragyna speciosa (Kratom) is a popular herb in Southeast Asia which is traditionally used to treat withdrawal symptoms associated with opiate addiction. Mitragynine, 7-hydroxymitragynine and mitraphylline are reported to be the central nervous system (CNS) active alkaloids which bind to the opiat...

Identification of Absorption, Distribution, Metabolism, and Excretion (ADME) Genes Relevant to Steatosis Using a Systems Biology Approach

EPA Science Inventory

Ensuring chemical safety and sustainability form a main priority of the U.S. Environmental Protection Agency. This entails efforts on multiple fronts to characterize the potential hazard posed by chemicals currently in use and those to be commercialized in the future. The use of ...

Challenges and opportunities in absorption, distribution, metabolism, and excretion studies of therapeutic biologics.

PubMed

Xu, Xin; Vugmeyster, Yulia

2012-12-01

With the advancement of biotechnology in the last two decades, optimized and novel modalities and platforms of biologic moieties have emerged rapidly in drug discovery pipelines. In addition, new technologies for delivering therapeutic biologics (e.g., needle-free devices, nanoparticle complexes), as well as novel approaches for disease treatments (e.g., stem cell therapy, individualized medicine), continue to be developed. While pharmacokinetic studies are routinely carried out for therapeutic biologics, experiments that elucidate underlying mechanisms for clearance and biodistribution or identify key factors that govern absorption, distribution, metabolism, and excretion (ADME) of biologics often are not thoroughly conducted. Realizing the importance of biologics as therapeutic agents, pharmaceutical industry has recently begun to move the research focus from small molecules only to a blended portfolio consisting of both small molecules and biologics. This trend brings many opportunities for scientists working in the drug disposition research field. In anticipation of these opportunities and associated challenges, this review highlights impact of ADME studies on clinical and commercial success of biologics, with a particular focus on emerging applications and technologies and linkage with mechanistic pharmacokinetic/pharmacodynamic modeling and biomarker research.

Absorption of Orally Administered Hyaluronan.

PubMed

Kimura, Mamoru; Maeshima, Takuya; Kubota, Takumi; Kurihara, Hitoshi; Masuda, Yasunobu; Nomura, Yoshihiro

2016-12-01

Hyaluronan (HA) has been utilized as a supplement. However, the absorption of orally administrated HA remains controversial. The degradation and absorption of HA in the intestine were investigated in this study. HA excretion into the feces, degradation in the intestinal tract, absorption through the large intestine, and translocation to the blood and skin were examined. HA administered orally was not detected in rat feces. HA was degraded by cecal content, but not by artificial gastric juice and intestinal juice. Oligosaccharide HA passed through excised large intestine sacs. Furthermore, disaccharides, tetrasaccharides, and polysaccharides HA were distributed to the skin of rats following oral administration of high molecular weight HA (300 kDa). The results of the study suggest that orally administered HA is degraded to oligosaccharides by intestinal bacteria, and oligosaccharide HA is absorbed in the large intestine and is subsequently distributed throughout the tissues, including the skin.

Absorption, Distribution, Metabolism, and Excretion of [14C]-Volixibat in Healthy Men: Phase 1 Open-Label Study.

PubMed

Siebers, Nicholas; Palmer, Melissa; Silberg, Debra G; Jennings, Lee; Bliss, Caleb; Martin, Patrick T

2018-02-01

Volixibat is a potent inhibitor of the apical sodium-dependent bile acid transporter in development for the treatment of nonalcoholic steatohepatitis. This phase 1, open-label study investigated the absorption, distribution, metabolism, and excretion of [ 14 C]-volixibat in heathy men. Eligible men (n = 8) aged 18-50 years (body mass index 18.0-30.0 kg/m 2 ; weight >50 kg) received a single oral dose of [ 14 C]-volixibat 50 mg containing ~5.95 µCi radioactivity. The primary objectives were to assess the pharmacokinetics of [ 14 C]-volixibat and to determine the total radioactivity in whole blood, plasma, urine, and feces at pre-selected time points over 6 days. The secondary objectives were to characterize metabolites and to assess the safety and tolerability. Low concentrations of volixibat (range 0-0.179 ng/mL) were detected in plasma up to 8 h following administration; the pharmacokinetic parameters could not be calculated. No radioactivity was observed in plasma or whole blood. The percentage (mean ± standard deviation) of total radioactivity in urine was 0.01 ± 0.007%. The vast majority (92.3 ± 5.25%) of volixibat was recovered in feces (69.2 ± 33.1% within 24 h). Unchanged volixibat was the only radioactive component detected in feces. Adverse events were mild in severity and mostly gastrointestinal. Changes in laboratory values were not clinically meaningful. Following oral administration, [ 14 C]-volixibat was excreted unchanged from the parent compound almost exclusively via fecal excretion, indicating that the drug is minimally absorbed. Consistent with other studies, adverse events were primarily gastrointestinal in nature. ClinicalTrials.gov identifier NCT02571192.

Breast Cancer Resistance Protein (ABCG2) Determines Distribution of Genistein Phase II Metabolites: Reevaluation of the Roles of ABCG2 in the Disposition of Genistein

PubMed Central

Yang, Zhen; Zhu, Wei; Gao, Song; Yin, Taijun; Jiang, Wen

2012-01-01

It was recently proposed that the improved oral bioavailability of genistein aglycone and conjugates in Bcrp1(−/−) mice is mainly due to increased intestinal absorption of aglycone and subsequent elevated exposure to conjugation enzymes. Here we tested this proposed mechanism and found that intestinal absorption of genistein aglycone did not increase in Bcrp1(−/−) mice compared with wild-type mice using an in situ mouse intestinal perfusion model and that inhibition of breast cancer resistance protein (BCRP) in Caco-2 cells also did not significantly increase permeability or intracellular concentration of aglycone. Separately, we showed that 5- to 10-fold increases in exposures of conjugates and somewhat lower fold increases (<2-fold) in exposures of aglycone were apparent after both oral and intraperitoneal administration in Bcrp1(−/−) mice. In contrast, the intestinal and biliary excretion of genistein conjugates significantly decreased in Bcrp1(−/−) mice without corresponding changes in aglycone excretion. Likewise, inhibition of BCRP functions in Caco-2 cells altered polarized excretion of genistein conjugates by increasing their basolateral excretion. We further found that genistein glucuronides could be hydrolyzed back to genistein, whereas sulfates were stable in blood. Because genistein glucuronidation rates were 110% (liver) and 50% (colon) higher and genistein sulfation rates were 40% (liver) and 42% (colon) lower in Bcrp1(−/−) mice, the changes in genistein exposures are not mainly due to changes in enzyme activities. In conclusion, improved bioavailability of genistein and increased plasma area under the curve of its conjugates in Bcrp1(−/−) mice is due to altered distribution of genistein conjugates to the systemic circulation. PMID:22736306

Important drug-nutrient interactions in the elderly.

PubMed

Thomas, J A; Burns, R A

1998-09-01

Several drug-nutrient interactions can occur, but their prevalence may be accentuated in the elderly. Geriatric patients may experience age-related changes in the pharmacokinetics of a drug-absorption, distribution, metabolism and excretion. When drug-nutrient interactions occur, they usually affect absorptive processes more frequently. Specific transporter systems facilitate the absorption of many drugs. Little is known about how these transporter systems are affected by aging. Co-existing disease states in the elderly may exaggerate the action of a drug and represent a confounding factor in drug-nutrient interactions. While several different drug-nutrient interactions are important in the elderly, those affecting the cardiovascular system warrant special attention.

Absorption, distribution, metabolism, and excretion of decursin and decursinol angelate from Angelica gigas Nakai.

PubMed

Kim, Kang Min; Kim, Myo Jeong; Kang, Jae Seon

2009-12-01

The pharmacokinetics of decursin and decursinol angelate (D/DA) was investigated in male SD rats following oral and intravenous administration. D/DA and metabolites obtained from in vitro samples were evaluated by LC/MS. The level of D/DA and metabolized decursinol in the blood following oral and intravenous administration declined according to first-order kinetics, with T1/2 values of 56.67, 58.01 and 57.22 h, respectively, being observed after administration of a dose of 2 mg/kg body weight. The large intestine was the major site of disposition following oral administration. These data indicate that D/DA is rapidly absorbed from the gastrointestinal tract. In in vitro experiment utilizing liver microsomal protein, the major metabolic reaction of D/DA occurred to change decursinol. The cumulative biliary, urinary, and fecal excretion of D/DA in bile duct-cannulated rats was 36.10+/-2.9, 25.35+/-3.8, and 34.20+/-3.2%, respectively, at 72 h after administration. These results indicate that the absorption of D/DA is almost complete, and that its metabolites are primarily excreted into feces through the bile. These results indicate that D/DA is subject to enterohepatic circulation.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boyd, G.S.; Merrick, M.V.; Monks, R.

Four selenium-labeled free bile acids and four selenium-labeled conjugated bile acids, labeled with Se-75 at the C-19, C-22, C-23, or C-24 position, have been synthesized and their absorption and excretion compared with that of (24-14C)cholic acid, following both oral and intravenous administration. All but one of the compounds is absorbed and excreted in bile to a significant extent. One compound, SeHCAT, has been selected for particular study. It is quantitatively absorbed from the gut at the same rate as cholic acid, and both are excreted into the bile at the same rate. It remains almost entirely confined to the enterohepaticmore » circulation (the gut, liver, and biliary tree) and excretion is exclusively fecal. Whole-body retention, measured for 41 days, and tissue distributions suggest that the absorbed radiation dose would be small compared with that in many established tests. Such a compound offers the possibility of a simple, novel, and aesthetically acceptable method of investigating small-bowel disease. It therefore merits further investigation.« less

Absorption, Distribution, and Excretion of 14C-APX001 after Single-Dose Administration to Rats and Monkeys

PubMed Central

Mansbach, Robert; Shaw, Karen J; Hodges, Michael R; Coleman, Samantha; Fitzsimmons, Michael E

2017-01-01

Abstract Background APX001 is a small-molecule therapeutic agent in clinical development for the treatment of invasive fungal infections (IFI). Methods The absorption, distribution and excretion profiles of [14C]APX001-derived radioactivity were determined in rats (albino and pigmented) and monkeys. Rats (some implanted with bile duct cannulae) were administered a single 100 mg/kg oral dose or a 30 mg/kg intravenous (IV) dose. Monkeys were administered a single 6 mg/kg IV dose. Samples of blood, urine, feces and bile, as well as carcasses, were collected through 168 hours after dosing. Samples were analyzed for total radioactivity content by liquid scintillation counting, and carcasses were analyzed by quantitative whole-body autoradiography. Results [14C]APX001-derived radioactivity was rapidly and extensively absorbed and extensively distributed to most tissues for both routes of administration in both species. In rats, tissues with the highest radioactivity Cmax values included bile, abdominal fat, reproductive fat, subcutaneous fat, and liver, but radioactivity was also detected in tissues associated with IFI, including lung, brain and eye. In monkeys, the highest Cmax values were in bile, urine, uveal tract, bone marrow, abdominal fat, liver, and kidney cortex. Liver and kidney were the tissues with highest radioactivity, but as in the rat, radioactivity was also detected in lung, brain and eye tissues. In pigmented rats, radiocarbon was densely distributed into pigmented tissue and more slowly cleared than from other tissues. Mean recovery of radioactivity in rats was approximately 95–100%. In bile duct-intact rats, >90% of radioactivity was recovered in feces. In cannulated rats, biliary excretion of radioactivity was the major route of elimination and accounted for 88.8% of the dose, whereas urinary and fecal excretion of radioactivity was minor and accounted for 2.56% and 5.42% of the dose, respectively. In monkeys, the overall recovery of radioactivity was 87.6%, and was eliminated in feces (49.8% of dose) and to a lesser extent in urine (20.6% of dose). Conclusion Together, the results indicate that APX001-related radioactivity is extensively distributed to major tissues (including tissues relevant to IFI) in both rats and monkeys and cleared primarily by biliary/fecal excretion. Disclosures R. Mansbach, Amplyx Pharmaceuticals Inc.: Consultant, Consulting fee; K. J. Shaw, Amplyx Pharmaceuticals Inc.: Employee, Salary; M. R. Hodges, Amplyx Pharmaceuticals: Employee, Salary; S. Coleman, Covance Laboratories: Employee, Salary; M. E. Fitzsimmons, Covance Laboratories: Employee, Salary

Pre-clinical Characterization of Absorption, Distribution, Metabolism and Excretion Properties of TAK-063.

PubMed

Tohyama, Kimio; Sudo, Miyako; Morohashi, Akio; Kato, Suguru; Takahashi, Junzo; Tagawa, Yoshihiko

2018-06-01

TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine. TAK-063 can also cross the blood-brain barrier. TAK-063 was metabolized mainly by CYP2C8 and CYP3A4/5, while incubation with human liver microsomes produced the major human metabolite, M-I as well as several unknown minor metabolites. Metabolism of TAK-063 to M-I occurs through hydroxylation of the mono-substituted pyrazole moiety. In vitro, TAK-063 was observed to inhibit CYP2C8, CYP2C19 and P-gp with IC 50 values of 8.4, 12 and 7.13 μM, respectively. TAK-063 was primarily excreted in the faeces in rats and dogs with M-I as a predominant component. The pre-clinical data from these ADME studies demonstrate a favourable pharmacokinetic profile for TAK-063 with good brain distribution supporting the feasibility of targeting central nervous system regions involved in schizophrenia pathophysiology. TAK-063 has recently been investigated in a phase 2 clinical trial (NCT02477020). © 2018 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Thallium Toxicity: The Problem; An Analytical Approach; An Antidotal Study

DTIC Science & Technology

1993-05-15

of DMPS to significantly decrease the TI content in 4 target organs suggests it would not be useful in the treatment of T1 poisoning. Accoion For B y...would not be useful in the treatment of Ti poisoning. TABLE OF CONTENTS PAGE ACKNOWLEDGEMENTS ...................................... vii INTRODUCTION...6 PRODUCTION AND USES .............................. 7 ABSORPTION, DISTRIBUTION, EXCRETION ................. 8 MOLECULAR BASIS OF

The method of radioactive tracer for measuring the amount of inorganic nanoparticles in biological samples

NASA Astrophysics Data System (ADS)

Buzulukov, Yu; Antsiferova, A.; Demin, V. A.; Demin, V. F.; Kashkarov, P.

2015-11-01

The method to measure the mass of inorganic nanoparticles in biological (or any other samples) using nanoparticles labeled with radioactive tracers is developed and applied to practice. The tracers are produced in original nanoparticles by radioactive activation of some of their atomic nuclei. The method of radioactive tracers demonstrates a sensitivity, specificity and accuracy equal or better than popular methods of optical and mass spectrometry, or electron microscopy and has some specific advantages. The method can be used for study of absorption, distribution, metabolism and excretion in living organism, as well as in ecological and fundamental research. It was used in practice to study absorption, distribution, metabolism and excretion of nanoparticles of Ag, Au, Se, ZnO, TiO2 as well as to study transportation of silver nanoparticles through the barriers of blood-brain, placenta and milk gland of rats. Brief descriptions of data obtained in experiments with application of this method included in the article. The method was certified in Russian Federation standard system GOST-R and recommended by the Russian Federation regulation authority ROSPOTREBNADZOR for measuring of toxicokinetic and organotropy parameters of nanoparticles.

THE USE OF Y$sup 91$ AS AN INERT INDICATOR IN INTESTINAL ABSORPTION TESTS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Maisterrena, J.A.; Murphy, C.A.; Tovar, E.

The use of Y/sup 91/ as an inert-indicator in the studies of the intestinal absorption of I/sup 131/-labeled substances is reported, emphasis being given to its clinical advantages. The Y/sup 91/ is not absorbed in the gastrointestinal tract, since recovery in the feces in 22 cases was 96 plus or minus 6.7% (S.D.) of the amount given. The Y/sup 91/ and the I/sup 131/-labeled substances are homogeneously distributed throughout any given stool sample but their rate of excretion is not always parallel. A close correlation was found between the amount of I/sup 131/ excreted as obtained from the complete fecalmore » collection method and that of Y/sup 91/-indicator method in a group of 20 subjects under special supervision. The value of the Y/sup 91/ inert-indicator method where the completeness of the stool collection is doubtful is shown in 23 cases. (auth)« less

Gastrointestinal absorption of americium-241 by orally exposed swine: comparison of experimental results with predictions of metabolic models.

PubMed

Eisele, G R; Bernard, S R; Nestor, C W

1987-10-01

Two groups of 11-week-old swine (40 miniature and 40 domestic swine) received a single oral administration of 1.9 X 10(8) Bq (5.2 mCi) of 241Am citrate, and groups of eight animals, four of each type, were killed and sampled at 1, 2, 4, 8, 16, 24, 48, 72, and 96 h and 30 days later. Uptake and excretion patterns of the radioactivity appeared to occur in three phases: rapid uptake, rapid excretion, and then a slower excretion. All animals were systematically dissected, and the eviscerated carcasses were autoclaved for separation of bone and muscle. The predominant site of deposition was bone, and autoclaving had little effect on releasing 241Am from either bone or muscle. The maximum fractional gastrointestinal absorption of 1.1 X 10(-3) occurred 8 h after radionuclide administration. The tissue distribution data suggest partitions of 50, 20, and 30%, for bone, liver, and other soft tissues, respectively. Two metabolic models were evaluated: a modified Mewhinney-Griffith model and the ICRP 30 model to compare the biological data with model predictions. All models underestimated the actual early time data, but the fits to the experimental results were better at later times.

Dietary raw versus retrograded resistant starch enhances apparent but not true magnesium absorption in rats.

PubMed

Heijnen, M L; van den Berg, G J; Beynen, A C

1996-09-01

Dietary raw (RS2) vs. retrograded resistant starch (RS3) raises apparent magnesium absorption in rats. The mechanism proposed is that RS2 enhances magnesium avaibility for absorption; it does this by increasing ileal solubility of magnesium due to a reduction in pH as a consequence of RS2 fermentation in the gut. The mechanism implies that dietary RS2 vs. RS3 would raise true magnesium absorption and stimulate reabsorption of endogenous magnesium, leading to a lower fecal excretion of endogenous magnesium. Dietary lactulose vs. glucose raises apparent magnesium absorption, and the mechanism proposed is similar to that for the stimulatory effect of RS2 vs. RS3. Thus, we measured in rats fed RS3, RS2, glucose or lactulose true magnesium absorption on the basis of the retention of the orally and intraperitoneally administered radiotracer 28Mg. Feeding rats RS2 instead of RS3 significantly enhanced apparent but not true magnesium absorption, because RS2 lowered fecal excretion of endogenous magnesium. When compared with dietary glucose, lactulose significantly raised both apparent and true magnesium absorption, but did not affect fecal excretion of endogenous magnesium. It is suggested that the proposed mechanism by which RS2 and lactulose would enhance magnesium absorption is disproved by the present data.

Pharmacokinetics, bioavailability, tissue distribution and excretion of tangeretin in rat.

PubMed

Hung, Wei-Lun; Chang, Wei-Shan; Lu, Wen-Chien; Wei, Guor-Jien; Wang, Yu; Ho, Chi-Tang; Hwang, Lucy Sun

2018-04-01

Tangeretin, 4',5,6,7,8-pentamethoxyflavone, is one of the major polymethoxyflavones (PMFs) existing in citrus fruits, particularly in the peels of sweet oranges and mandarins. Tangeretin has been reported to possess several beneficial bioactivities including anti-inflammatory, anti-proliferative and neuroprotective effects. To achieve a thorough understanding of the biological actions of tangeretin in vivo, our current study is designed to investigate the pharmacokinetics, bioavailability, distribution and excretion of tangeretin in rats. After oral administration of 50 mg/kg bw tangeretin to rats, the C max , T max and t 1/2 were 0.87 ± 0.33 μg/mL, 340.00 ± 48.99 min and 342.43 ± 71.27 min, respectively. Based on the area under the curves (AUC) of oral and intravenous administration of tangeretin, calculated absolute oral bioavailability was 27.11%. During tissue distribution, maximum concentrations of tangeretin in the vital organs occurred at 4 or 8 h after oral administration. The highest accumulation of tangeretin was found in the kidney, lung and liver, followed by spleen and heart. In the gastrointestinal tract, maximum concentrations of tangeretin in the stomach and small intestine were found at 4 h, while in the cecum, colon and rectum, tangeretin reached the maximum concentrations at 12 h. Tangeretin excreted in the urine and feces was recovered within 48 h after oral administration, concentrations were only 0.0026% and 7.54%, respectively. These results suggest that tangeretin was mainly eliminated as metabolites. In conclusion, our study provides useful information regarding absorption, distribution, as well as excretion of tangeretin, which will provide a good base for studying the mechanism of its biological effects. Copyright © 2017. Published by Elsevier B.V.

Biokinetics of food additive silica nanoparticles and their interactions with food components.

PubMed

Lee, Jeong-A; Kim, Mi-Kyung; Song, Jae Ho; Jo, Mi-Rae; Yu, Jin; Kim, Kyoung-Min; Kim, Young-Rok; Oh, Jae-Min; Choi, Soo-Jin

2017-02-01

Nanomaterials have been widely utilized in the food industry in production, packaging, sensors, nutrient delivery systems, and food additives. However, research on the interactions between food-grade nanoparticles and biomolecules as well as their potential toxicity is limited. In the present study, the in vivo solubility, oral absorption, tissue distribution, and excretion kinetics of one of the most extensively used food additives, silica (SiO 2 ) were evaluated with respect to particle size (nano vs bulk) following single-dose oral administration to rats. Intestinal transport mechanism was investigated using a 3D culture system, in vitro model of human intestinal follicle-associated epithelium (FAE). The effect of the presence of food components, such as sugar and protein, on the oral absorption of nanoparticles was also evaluated with focus on their interactions. The results obtained demonstrated that the oral absorption of nanoparticles (3.94±0.38%) was greater than that of bulk materials (2.95±0.37%), possibly due to intestinal transport by microfold (M) cells. On the other hand, particle size was found to have no significant effect on in vivo dissolution property, biodistribution, or excretion kinetics. Oral absorption profile of silica nanoparticles was highly dependent on the presence of sugar or protein, showing rapid absorption rate in glucose, presumably due to their surface interaction on nanoparticles. These findings will be useful for predicting the potential toxicity of food-grade nanoparticles and for understanding biological interactions. Copyright © 2016 Elsevier B.V. All rights reserved.

Structure–activity relationships for biodistribution, pharmacokinetics, and excretion of atomically precise nanoclusters in a murine model†

PubMed Central

Wong, O. Andrea; Hansen, Ryan J.; Ni, Thomas W.; Heinecke, Christine L.; Compel, W. Scott; Gustafson, Daniel L.

2013-01-01

The absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic (PK) properties of inorganic nanoparticles with hydrodynamic diameters between 2 and 20 nm are presently unpredictable. It is unclear whether unpredictable in vivo properties and effects arise from a subset of molecules in a nanomaterials preparation, or if the ADME/PK properties are ensemble properties of an entire preparation. Here we characterize the ADME/PK properties of atomically precise preparations of ligand protected gold nanoclusters in a murine model system. We constructed atomistic models and tested in vivo properties for five well defined compounds, based on crystallographically resolved Au25(SR)18 and Au102(SR)44 nanoclusters with different (SR) ligand shells. To rationalize unexpected distribution and excretion properties observed for several clusters in this study and others, we defined a set of atomistic structure–activity relationships (SAR) for nanoparticles, which includes previously investigated parameters such as particle hydrodynamic diameter and net charge, and new parameters such as hydrophobic surface area and surface charge density. Overall we find that small changes in particle formulation can provoke dramatic yet potentially predictable changes in ADME/PK. PMID:24057086

Metabolic mechanisms of drug-nutrient interactions.

PubMed

Hathcock, J N

1985-01-01

Metabolic mechanisms of nutrition and drug interactions include 1) the effects of diet on drug metabolism and action and 2) the effects of drugs on nutritional processes. The type, amount, and timing of foods consumed influence drug dissolution, absorption, distribution, metabolism, and excretion. High-fat meals enhance the absorption of griseofulvin and some other drugs. Milk and other sources of calcium inhibit absorption of tetracycline. High-fat meals increase plasma concentrations of free fatty acids and thereby displace many drugs from binding sites on plasma albumin. High-protein diets increase the activity of the mixed-function oxidase system and enhance the metabolism of numerous drugs. High-electrolyte intakes increase excretion of lithium and also diminish the action of diuretic agents. Bile acid sequestrants and some laxatives decrease lipid digestion and absorption, as well as absorption of the fat-soluble vitamins. Numerous drugs, including tetracycline and cholestyramine, bind iron and decrease its absorption. Coumarins inhibit the function of vitamin K. Phenobarbital and other anticonvulsants are inducers of cytochrome P-450 and the mixed-function oxidase system. Long-term treatment with these inducers can cause excessive metabolism and deficiency of vitamin D. Prooxidant drugs such as chloroquine, drugs detoxified by conjugation with glutathione, and alcohol can deplete reduced glutathione with consequent effects on amino acid transport and the redox status of cells. Acid-forming foods acidify the urine and increase the loss of alkaline drugs such as the amphetamines. Base-forming drugs increase the loss of acidic drugs such as barbiturates. The range of metabolic interactions of drugs and nutrients includes the full scope of physiological processes to which drugs and nutrients are subject.

Drug advertising in medical journals

PubMed Central

Morgan, A. H.; Jeffers, T. A.; Petrie, J. C.; Walker, W.

1976-01-01

1 One hundred different drug advertisements from each of seven leading medical journals have been assessed. 2 Information about drug interactions, adverse reactions, mode of action, absorption, distribution, metabolism, excretion and cost was seldom provided in UK journals. 3 A requirement should exist that drug advertisements include such clinically important information. Only a few pharmaceutical companies are attempting to educate doctors through their marketing and promotional material in advertisements in medical journals. PMID:22216530

Ethnopharmacology, phytochemistry, and biological activities of Cymbopogon citratus (DC.) Stapf extracts.

PubMed

Ekpenyong, Christopher E; Akpan, Ernest; Nyoh, Azah

2015-05-01

Cymbopogon citratus is a widely distributed perennial herb belonging to the Poaceae family and has been extensively consumed for its medicinal, cosmetic, and nutritional effects for centuries. A large number of reports have been published describing the pharmacological, biological, and therapeutic actions of this herb. In this review, we summarized the literatures on related studies (up to January, 2014) that highlighted the pharmacologic and biological effects of the major phytochemicals isolated from C. citratus extracts and its essential oil. The components of the essential oils found in C. citratus have a similar pharmacokinetic properties, including absorption, distribution, metabolism, and excretion. They are quickly absorbed following oral, pulmonary, and dermal administration. Based on the published reports, it can also be inferred that, after absorption from the small intestine, some phytochemicals in C. citratus can undergo oxidation, glucuronidation, sulfation, and/or O-methylation. Excretion is through urine, feces and/or expired volatiles. The biotransformation reactions of C. citratus bioactive constituents are essential for its relatively safe consumption and therapeutic applications. The data available so far warrant further studies evaluating C. citratus pharmacokinetics. Reliable pharmacokinetic data in humans would be critical for a better understanding of the the systemic handling of C. citratus. Copyright © 2015 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

P-gp is involved in the intestinal absorption and biliary excretion of afatinib in vitro and in rats.

PubMed

Zhang, Yan; Wang, Changyuan; Liu, Zhihao; Meng, Qiang; Huo, Xiaokui; Liu, Qi; Sun, Pengyuan; Yang, Xiaobo; Sun, Huijun; Ma, Xiaodong; Liu, Kexin

2018-04-01

Afatinib is an irreversible multi-targeted TKI, used in the treatment with EGFR mutated non-small cell lung cancer (NSCLC). The purpose of this study is to explore the molecular pharmacokinetic mechanism underlying the effect of P-gp inhibitors on the intestinal absorption and biliary excretion and to understand how P-gp inhibitors affect afatinib pharmacokinetics. Pharmacokinetics in vivo, in situ intestinal perfusion, perfused rat liver in situ, Caco-2 cells, P-gp ATPase activity, sandwich-cultured rat hepatocytes (SCRH) and transfected-cell transport were used in the evaluation. P-gp inhibitor verapamil (Ver) markedly increased the plasma concentrations and significantly decreased the biliary excretion of afatinib in vivo. Ver increased the intestinal absorption and decreased biliary excretion of afatinib in situ single-pass intestinal perfusion studies and in situ perfused rat liver, respectively. The accumulation of afatinib in Caco-2 cells was enhanced by Ver and Cyclosporin A (CsA). The biliary excretion index (BEI) of afatinib in SCRH was decreased by Ver and CsA, respectively. The net efflux ratio of afatinib was 2.3 across vector-/MDR1-MDCKII cell monolayers and was decreased by P-gp inhibitor. The activity of P-gp ATPase was induced by afatinib and the K m and V max were 1.05μM and 59.88nmol ATP/mg hP-gp/min, respectively. At least partly P-gp is involved in increasing the intestinal absorption and decreasing the biliary excretion of afatinib in rats. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Absorption, excretion and retention of 51Cr from labelled Cr-(III)-picolinate in rats.

PubMed

Kottwitz, Karin; Laschinsky, Niels; Fischer, Roland; Nielsen, Peter

2009-04-01

The bioavailability of chromium from Cr-picolinate (CrPic(3)) and Cr-chloride (CrCl(3)) was studied in rats using (51)Cr-labelled compounds and whole-body-counting. The intestinal absorption of Cr was twice as high from CrPic(3) (1.16% vs 0.55%) than from CrCl(3), however most of the absorbed (51)Cr from CrPic(3) was excreted into the urine within 24 h. After i.v. or i.p. injection, the whole-body retention curves fitted well to a multiexponential function, demonstrating that plasma chromium is in equilibrium with three pools. For CrPic(3), a large pool exists with a very rapid exchange (T (1/2) = <0.5 days), suggesting that CrPic(3) is absorbed as intact molecule, from which the main part is directly excreted by the kidney before degradation of the chromium complex in the liver can occur. CrCl(3) is less well absorbed but the rapid exchange pool is much smaller, resulting in even higher Cr concentrations in tissue such as muscle and fat. However, 1-3 days after application, the relative distribution of (51)Cr from both compounds was similar in all tissues studied, indicating that both compounds contribute to the same storage pool. In summary, the bioavailability of CrPic(3) in rats is not superior compared to CrCl(3).

Absorption and distribution of orally administered jojoba wax in mice.

PubMed

Yaron, A; Samoiloff, V; Benzioni, A

1982-03-01

The liquid wax obtained from the seeds of the arid-land shrub jojoba (Simmondsia chinensis) is finding increasing use in skin treatment preparations. The fate of this wax upon reaching the digestive tract was studied. 14C-Labeled wax was administered intragastrically to mice, and the distribution of the label in the body was determined as a function of time. Most of the wax was excreted, but a small amount was absorbed, as was indicated by the distribution of label in the internal organs and the epididymal fat. The label was incorporated into the body lipids and was found to diminish with time.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kramer, L.

The effect of drugs such as glucocorticoids and thyroid extract on calcium metabolism is unknown. However, several other medications affect the excretion and intestinal absorption of calcium. A controlled study was carried out to investigate these aspects. Urinary calcium was determined for 3 months during the long-term intake of the antituberculous drug isoniazid (INH) and of the antibiotic tetracycline. The effect of the diuretics furosemide and hydrochlorothiazide, of several aluminum-containing antacids, of thyroid extract and of corticosteroids was also studied. Metabolic balances of calcium, phosphorus, magnesium and zinc were determined, as well as the intestinal absorption of calcium using Camore » 47. Plasma levels, urinary and fecal excretions of Ca 47 were determined. All drugs tested increased urinary calcium except for the diuretic hydrochlorothiazide. Regarding the effect of corticosteroids: the intestinal absorption of calcium was unchanged after the short-term use and was very high after long-term use. The studies have shown that several commonly used drugs induce an increase in urinary calcium excretion which may contribute to calcium loss, if this increase persists for prolonged periods of time. Urinary excretions of phosphorus, magnesium and zinc increased in some of the studies.« less

Sterol balance and cholesterol absorption in inbred strains of rabbits hypo- or hyperresponsive to dietary cholesterol.

PubMed

Beynen, A C; Meijer, G W; Lemmens, A G; Glatz, J F; Versluis, A; Katan, M B; Van Zutphen, L F

1989-06-01

In 2 inbred strains of rabbits with high or low response of plasma cholesterol to dietary cholesterol, excretion of steroids in the feces and efficiency of cholesterol absorption were determined. Rates of whole-body cholesterol synthesis, measured as fecal excretion of bile acids and neutral steroids minus cholesterol intake, were similar in hypo- and hyperresponders fed a low-cholesterol (8 mumol/100 g) diet. Transfer of the rabbits to a high-cholesterol (182 mumol/100 g) diet caused an increase in fecal bile acid excretion in hypo- but not in hyperresponders. Dietary cholesterol did not affect neutral steroid excretion in either rabbit strain. Hyperresponders tended to accumulate more cholesterol in their body than did hyporesponders. After the rabbits were switched back from the high- to the low-cholesterol diet, rates of whole-body cholesterol synthesis were significantly higher in the hypo- than in the hyperresponders. With the use of the simultaneous oral administration of [3H]cholesterol and beta-[14C]sitosterol, hyperresponders were found to absorb significantly higher percentages of cholesterol than hyporesponders. It is concluded that the differences in stimulation of bile acid excretion after cholesterol feeding and the efficiency of cholesterol absorption are important determinants of the phenomenon of hypo- and hyperresponsiveness in the 2 inbred rabbit strains.

Influence of a low- and a high-oxalate vegetarian diet on intestinal oxalate absorption and urinary excretion.

PubMed

Thomas, E; von Unruh, G E; Hesse, A

2008-09-01

To compare quantitatively the effect of a low- and a high-oxalate vegetarian diet on intestinal oxalate absorption and urinary excretion. Eight healthy volunteers (three men and five women, mean age 28.6+/-6.3) were studied. Each volunteer performed the [(13)C(2)]oxalate absorption test thrice on a low-oxalate mixed diet, thrice on a low-oxalate vegetarian diet and thrice on a high-oxalate vegetarian diet. For each test, the volunteers had to adhere to an identical diet and collect their 24-h urines. In the morning of the second day, a capsule containing [(13)C(2)]oxalate was ingested. On the low-oxalate vegetarian diet, mean intestinal oxalate absorption and urinary oxalate excretion increased significantly to 15.8+/-2.9% (P=0.012) and 0.414+/-0.126 mmol/day (P=0.012), compared to the mixed diet. On the high-oxalate vegetarian diet, oxalate absorption (12.5+/-4.6%, P=0.161) and urinary excretion (0.340+/-0.077 mmol/day, P=0.093) did not change significantly, compared to the mixed diet. A vegetarian diet can only be recommended for calcium oxalate stone patients, if the diet (1) contains the recommended amounts of divalent cations such as calcium and its timing of ingestion to a meal rich in oxalate is considered and (2) excludes foodstuffs with a high content of nutritional factors, such as phytic acid, which are able to chelate calcium.

Disposition and metabolism of 2-bromo-4,6-dinitroaniline in the male F344 rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chopade, H.M.; Matthews, H.B.

1986-01-01

The disposition of (/sup 14/C)-2-bromo-4,6-dinitroaniline (BDNA) was studied in male F344 rats following oral or intravenous (iv) administration. The gastrointestinal absorption of BDNA was nearly complete and was not affected by dose in the range (10-100 ..mu..mol/kg body weight) studied. Following either oral or iv administration, BDNA was rapidly distributed throughout the tissues and showed no marked affinity for any particular tissue. Clearance of (/sup 14/C)BDNA-derived radioactivity from various tissues was rapid and was best described by two-component decay curves. The whole-body half-life of BDNA was approximately 7 h. Within 72 h, clearance of (/sup 14/C)BDNA-derived radioactivity from the bodymore » was 98% complete. (/sup 14/C)BDNA was rapidly cleared by metabolism to 13 metabolites, which were excreted in urine (62%) and feces (33%). Most (66%) of the urinary radioactivity was excreted in the form of sulfate conjugates of two metabolites of BDNA; excretion of unmetabolized BDNA was minimal (less than 2%). Biliary excretion of (/sup 14/C)BDNA was significant; however, some of this BDNA-derived radioactivity underwent enterohepatic circulation and was subsequently excreted in urine. Results of this study indicate that, if metabolism is a detoxification process, the rapid metabolism and excretion of this compound should minimize the likelihood of chronic toxicity from repeated exposure to BDNA beyond that predicted by data from acute or short-term exposures.« less

Sub-Chronic Oral Exposure to Iridium (III) Chloride Hydrate in Female Wistar Rats: Distribution and Excretion of the Metal

PubMed Central

Iavicoli, Ivo; Fontana, Luca; Bergamaschi, Antonio; Conti, Marcelo Enrique; Pino, Anna; Mattei, Daniela; Bocca, Beatrice; Alimonti, Alessandro

2012-01-01

Iridium tissue distribution and excretion in female Wistar rats following oral exposure to iridium (III) chloride hydrate in drinking water (from 1 to 1000 ng/ml) in a sub-chronic oral study were determined. Samples of urine, feces, blood and organs (kidneys, liver, lung, spleen and brain) were collected at the end of exposure. The most prominent fractions of iridium were retained in kidney and spleen; smaller amounts were found in lungs, liver and brain. Iridium brain levels were lower than those observed in other tissues but this finding can support the hypothesis of iridium capability to cross the blood brain barrier. The iridium kidney levels rose significantly with the administered dose. At the highest dose, important amounts of the metal were found in serum, urine and feces. Iridium was predominantly excreted via feces with a significant linear correlation with the ingested dose, which is likely due to low intestinal absorption of the metal. However, at the higher doses iridium was also eliminated through urine. These findings may be useful to help in the understanding of the adverse health effects, particularly on the immune system, of iridium dispersed in the environment as well as in identifying appropriate biological indices of iridium exposure. PMID:22942873

Toxicokinetics of short-chain chlorinated paraffins in Sprague-Dawley rats following single oral administration.

PubMed

Geng, Ningbo; Zhang, Haijun; Xing, Liguo; Gao, Yuan; Zhang, Baoqin; Wang, Feidi; Ren, Xiaoqian; Chen, Jiping

2016-02-01

Short-chain chlorinated paraffins (SCCPs) have attracted considerable attention for their characteristic of persistent organic pollutants. However, very limited information is available for their toxicokinetic characteristics, limiting the evaluation of their health risks. In this study, we performed a toxicokinetics study to explore the absorption and excretion processes of SCCPs (a mixture of C10-, C11-, C12- and C13-CPs) after a single oral administration to the Sprague-Dawley rats. The toxicokinetic results showed that peak blood concentration of total SCCPs was attained at 2.8 day with Cmax value of 2.3 mg L(-1). The half-lives of total SCCPs in blood for the absorption t1/2 (ka), distribution t1/2 (α) and elimination phases t1/2 (β) were calculated to be 1.0, 1.7 and 6.6 days, respectively. During the 28 days post-dosing, about 27.9% and 3.5% of orally administrated SCCPs were excreted through feces and urine without metabolism, respectively. Congener group abundance profiles indicate a relative increase of Cl5-SCCPs in blood and urine in the elimination stage, and a higher accumulation of Cl8-10-SCCPs in feces. The distribution discrepancies of SCCPs congener groups in blood and excreta were more dependent on chlorine contents than on carbon chain lengths. Copyright © 2015 Elsevier Ltd. All rights reserved.

Absorption, tissue distribution and excretion of radiolabelled compounds in rats after administration of [14C]-L-alpha-glycerylphosphorylcholine.

PubMed

Abbiati, G; Fossati, T; Lachmann, G; Bergamaschi, M; Castiglioni, C

1993-01-01

The kinetics and metabolism of L-alpha-glycerylphosphoryl-choline (alpha-GPC) were investigated in male and female rats after i.v. (10 mg/kg) and oral doses (100-300 mg/kg). alpha-GPC was labelled with [14C]-glycerol ([14G]-GPC) or [14C]-choline ([14C]-GPC). Different kinetic and metabolic profiles were observed after i.v. and oral administration. It is assumed that alpha-GPC is hydrolyzed by phosphodiesterases in the gut mucosa. The different labelled metabolites have different kinetic properties of absorption, distribution and clearance, leading to different blood concentration-time curves of total radioactivity. Both labelled compounds gave a wide distribution of radioactivity, particularly concentrated in the liver, kidney, lung and spleen compared to blood. Brain concentrations of [14C]-GPC were comparable to ([14G]-GPC) or lower than ([14C]-GPC) total blood radioactivity. The metabolite profile in the perfused brain showed a small amount of choline and two unknown metabolites, probably the same as in blood. In addition, choline was incorporated into brain phospholipids in increasing amounts within 24 h of dosing. In all cases renal and fecal excretion of radioactivity was low and comparable for [14G]-GPC and [14C]-GPC. Mostly the administered radioactivity was exhaled as 14CO2, this degradation being faster and more pronounced for the glycerol-labelled metabolites than for the choline-labelled metabolites for both routes of administration. In all cases the results were the same for male and female rats.

Bile pigment pharmacokinetics and absorption in the rat: therapeutic potential for enteral administration

PubMed Central

Bulmer, AC; Coombes, JS; Blanchfield, JT; Toth, I; Fassett, RG; Taylor, SM

2011-01-01

BACKGROUND AND PURPOSE Bilirubin and biliverdin possess antioxidant and anti-inflammatory properties and their exogenous administration protects against the effects of inflammation and trauma in experimental models. Despite the therapeutic potential of bile pigments, little is known about their in vivo parenteral or enteral absorption after exogenous administration. This study investigated the absorption and pharmacokinetics of bile pigments after i.v., i.p. and intraduodenal (i.d.) administration in addition to their metabolism and routes of excretion. EXPERIMENTAL APPROACH Anaesthetized Wistar rats had their bile duct, jugular and portal veins cannulated. Bile pigments were infused and their circulating concentrations/biliary excretion were measured over 180 min. KEY RESULTS After i.v. administration of unconjugated bilirubin, biliverdin and bilirubin ditaurate, their plasma concentrations decreased exponentially over time. Subsequently, native and metabolized compounds appeared in the bile. When administered i.p., their absolute bioavailabilities equalled 14.0, 16.1 and 33.1%, respectively, and correspondingly 38, 28 and 34% of the same bile pigment doses were excreted in the bile. Administration of unconjugated bilirubin and bilirubin ditaurate i.d. increased their portal and systemic concentrations and their systemic bioavailability equalled 1.0 and 2.0%, respectively. Correspondingly, 2.7 and 4.6%, of the doses were excreted in the bile. Biliverdin was rapidly metabolized and these products were absorbed and excreted via the urine and bile. CONCLUSIONS AND IMPLICATIONS Bile pigment absorption from the peritoneal and duodenal cavities demonstrate new routes of administration for the treatment of inflammatory and traumatic pathology. Oral biliverdin administration may lead to the production of active metabolite that protect from inflammation/complement activation. PMID:21486273

Absorption, Distribution, Metabolism, and Excretion of 14C-RDX Following Oral Administration to Minipigs

DTIC Science & Technology

2010-08-02

ELEMENT NUMBER 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 6. AUTHOR(S) 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING... ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) 11. SPONSOR/MONITOR’S REPORT... Covance Laboratories Inc. 3301 Kinsman Boulevard Madison, WI 53704-2595 Covance 7273-121 U.S. Army Center for Health Promotion and Preventive Medicine

United States Air Force Summer Faculty Research Program (1987). Program Management Report.

DTIC Science & Technology

1987-12-01

lllllll~hEEEI ,II .2 I. 1.25u 11111 1 1 MICROCOP RESOLUTION TES CHART 1% 0., :: nb- l q1 120 I iI UNITED STATES AIR FORCE SUMMER FACULTY RESEARCH...certain chemical compound , its pharmacological properties and the pathways of metabolism, absorption, distribution and excretion must be investigated, the...criteria can be recommended for personnel who handle or are otherwise in contact with such compounds . 5.0. r ,r,. -,&5 N The Toxic Hazards Division

eUnaG: a new ligand-inducible fluorescent reporter to detect drug transporter activity in live cells

PubMed Central

Yeh, Johannes T.-H.; Nam, Kwangho; Yeh, Joshua T.-H.; Perrimon, Norbert

2017-01-01

The absorption, distribution, metabolism and excretion (ADME) of metabolites and toxic organic solutes are orchestrated by the ATP-binding cassette (ABC) transporters and the organic solute carrier family (SLC) proteins. A large number of ABC and SLC transpoters exist; however, only a small number have been well characterized. To facilitate the analysis of these transporters, which is important for drug safety and physiological studies, we developed a sensitive genetically encoded bilirubin (BR)-inducible fluorescence sensor (eUnaG) to detect transporter-coupled influx/efflux of organic compounds. This sensor can be used in live cells to measure transporter activity, as excretion of BR depends on ABC and SLC transporters. Applying eUnaG in functional RNAi screens, we characterize l(2)03659 as a Drosophila multidrug resistant-associated ABC transporter. PMID:28176814

Reduced vertebral bone density in hypercalciuric nephrolithiasis

NASA Technical Reports Server (NTRS)

Pietschmann, F.; Breslau, N. A.; Pak, C. Y.

1992-01-01

Dual-energy x-ray absorptiometry and single-photon absorptiometry were used to determine bone density at the lumbar spine and radial shaft in 62 patients with absorptive hypercalciuria, 27 patients with fasting hypercalciuria, and 31 nonhypercalciuric stone formers. Lumbar bone density was significantly lower in patients with absorptive (-10%) as well as in those with fasting hypercalciuria (-12%), with 74 and 92% of patients displaying values below the normal mean, whereas only 48% of the nonhypercalciuric stone formers had bone density values below the normal mean. In contrast, radial bone density was similar in all three groups of renal stone formers investigated. The comparison of urinary chemistry in patients with absorptive hypercalciuria and low normal bone density compared to those with high normal bone density showed a significantly increased 24 h urinary calcium excretion on random diet and a trend toward a higher 24 h urinary uric acid excretion and a higher body mass index in patients with low normal bone density. Moreover, among the patients with absorptive hypercalciuria we found a statistically significant correlation between the spinal bone density and the 24 h sodium and sulfate excretion and the urinary pH. These results gave evidence for an additional role of environmental factors (sodium and animal proteins) in the pathogenesis of bone loss in absorptive hypercalciuria. In conclusion, our data suggest an osteopenia of trabecular-rich bone tissues in patients with fasting and absorptive hypercalciurias.

Measurements of Deposition, Lung Surface Area and Lung Fluid for Simulation of Inhaled Compounds.

PubMed

Fröhlich, Eleonore; Mercuri, Annalisa; Wu, Shengqian; Salar-Behzadi, Sharareh

2016-01-01

Modern strategies in drug development employ in silico techniques in the design of compounds as well as estimations of pharmacokinetics, pharmacodynamics and toxicity parameters. The quality of the results depends on software algorithm, data library and input data. Compared to simulations of absorption, distribution, metabolism, excretion, and toxicity of oral drug compounds, relatively few studies report predictions of pharmacokinetics and pharmacodynamics of inhaled substances. For calculation of the drug concentration at the absorption site, the pulmonary epithelium, physiological parameters such as lung surface and distribution volume (lung lining fluid) have to be known. These parameters can only be determined by invasive techniques and by postmortem studies. Very different values have been reported in the literature. This review addresses the state of software programs for simulation of orally inhaled substances and focuses on problems in the determination of particle deposition, lung surface and of lung lining fluid. The different surface areas for deposition and for drug absorption are difficult to include directly into the simulations. As drug levels are influenced by multiple parameters the role of single parameters in the simulations cannot be identified easily.

Alkali absorption and citrate excretion in calcium nephrolithiasis

NASA Technical Reports Server (NTRS)

Sakhaee, K.; Williams, R. H.; Oh, M. S.; Padalino, P.; Adams-Huet, B.; Whitson, P.; Pak, C. Y.

1993-01-01

The role of net gastrointestinal (GI) alkali absorption in the development of hypocitraturia was investigated. The net GI absorption of alkali was estimated from the difference between simple urinary cations (Ca, Mg, Na, and K) and anions (Cl and P). In 131 normal subjects, the 24 h urinary citrate was positively correlated with the net GI absorption of alkali (r = 0.49, p < 0.001). In 11 patients with distal renal tubular acidosis (RTA), urinary citrate excretion was subnormal relative to net GI alkali absorption, with data from most patients residing outside the 95% confidence ellipse described for normal subjects. However, the normal relationship between urinary citrate and net absorbed alkali was maintained in 11 patients with chronic diarrheal syndrome (CDS) and in 124 stone-forming patients devoid of RTA or CDS, half of whom had "idiopathic" hypocitraturia. The 18 stone-forming patients without RTA or CDS received potassium citrate (30-60 mEq/day). Both urinary citrate and net GI alkali absorption increased, yielding a significantly positive correlation (r = 0.62, p < 0.0001), with the slope indistinguishable from that of normal subjects. Thus, urinary citrate was normally dependent on the net GI absorption of alkali. This dependence was less marked in RTA, confirming the renal origin of hypocitraturia. However, the normal dependence was maintained in CDS and in idiopathic hypocitraturia, suggesting that reduced citrate excretion was largely dietary in origin as a result of low net alkali absorption (from a probable relative deficiency of vegetables and fruits or a relative excess of animal proteins).

ADDME – Avoiding Drug Development Mistakes Early: central nervous system drug discovery perspective

PubMed Central

Tsaioun, Katya; Bottlaender, Michel; Mabondzo, Aloise

2009-01-01

The advent of early absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening has increased the attrition rate of weak drug candidates early in the drug-discovery process, and decreased the proportion of compounds failing in clinical trials for ADMET reasons. This paper reviews the history of ADMET screening and its place in pharmaceutical development, and central nervous system drug discovery in particular. Assays that have been developed in response to specific needs and improvements in technology that result in higher throughput and greater accuracy of prediction of human mechanisms of absorption and toxicity are discussed. The paper concludes with the authors' forecast of new models that will better predict human efficacy and toxicity. PMID:19534730

Do we still need to collect stool? Evaluation of visualized fatty acid absorption: experimental studies using rats.

PubMed

Chiba, T; Ohi, R

1998-01-01

Short-gut syndrome is likely to impair enteric fat utilization. This study was undertaken to develop a clinical test of lipid absorption without fecal collection. The absorption of enterally fed radioactive long-chain fatty acid, beta-methyl-p-(123I)-iodophenylpentadecanoic acid was investigated with continuous chyle collection in rats. The changes in excretion and time-dependent biodistribution of radioactivity of the enterally fed agent were assessed in normal control animals. Similarly, sequential urinary excretion and biodistribution were studied along with scintigraphy using sham-operated and short-gut animals. Approximately 64% of the enterally fed radioactivity was recovered in the collected chyle (24 hours). A comparison of normal control, sham-operated, and short-gut animals showed significantly less urinary and greater fecal excretions of radioactivity in short-gut animals. With the use of sequential scintigraphy, the small intestine, whole-body soft tissues, and urinary bladder were well visualized in sham-operated animals, whereas the large intestine and feces were demonstrated earlier in short-gut animals. Our results suggest that enteral feeding of the agent might be feasible for determining lipid absorption from the the dynamic changes of radioactivity in visualized abdominal organs and in urine.

Relative lipophilicities and structural-pharmacological considerations of various angiotensin-converting enzyme (ACE) inhibitors.

PubMed

Ranadive, S A; Chen, A X; Serajuddin, A T

1992-11-01

Lipophilicities of seven structurally diverse angiotensin-converting enzyme (ACE) inhibitors, viz., captopril, zofenoprilat, enalaprilat, ramiprilat, lisinopril, fosinoprilat, and ceronapril (SQ29852), were compared by determining their octanol-water distribution coefficients (D) under physiological pH conditions. The distribution co-efficients of zofenopril, enalapril, ramipril and fosinopril, which are the prodrug forms of zofenoprilat, enalaprilat, ramiprilat, and fosinoprilat, respectively, were also determined. Attempts were made to correlate lipophilicities with the reported data for oral absorption, protein binding, ACE inhibitory activity, propensity for biliary excretion, and penetration across the blood-brain barrier for these therapeutic entities. Better absorption of prodrugs compared to their respective active forms is in agreement with their greater lipophilicities. Captopril, lisinopril, and ceronapril are orally well absorbed despite their low lipophilicities, suggesting involvement of other factors such as a carrier-mediated transport process. Of all the compounds studied, the two most lipophilic ACE inhibitors, fosinoprilat and zofenoprilat, exhibit a rank-order correlation with respect to biliary excretion. This may explain the dual routes of elimination (renal and hepatic) observed with fosinoprilat in humans. The more lipophilic compounds also exhibit higher protein binding. Both the lipophilicity and a carrier-mediated process may be involved in penetration of some of these drugs into brain. For structurally similar compounds, in vitro ACE inhibitory activity increased with the increase in lipophilicity. However, no clear correlation between lipophilicity and ACE inhibitory activity emerged when different types of inhibitors are compared, possibly because their interactions with enzymes are primarily ionic in nature.

Translational value of liquid chromatography coupled with tandem mass spectrometry-based quantitative proteomics for in vitro-in vivo extrapolation of drug metabolism and transport and considerations in selecting appropriate techniques.

PubMed

Al Feteisi, Hajar; Achour, Brahim; Rostami-Hodjegan, Amin; Barber, Jill

2015-01-01

Drug-metabolizing enzymes and transporters play an important role in drug absorption, distribution, metabolism and excretion and, consequently, they influence drug efficacy and toxicity. Quantification of drug-metabolizing enzymes and transporters in various tissues is therefore essential for comprehensive elucidation of drug absorption, distribution, metabolism and excretion. Recent advances in liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) have improved the quantification of pharmacologically relevant proteins. This report presents an overview of mass spectrometry-based methods currently used for the quantification of drug-metabolizing enzymes and drug transporters, mainly focusing on applications and cost associated with various quantitative strategies based on stable isotope-labeled standards (absolute quantification peptide standards, quantification concatemers, protein standards for absolute quantification) and label-free analysis. In mass spectrometry, there is no simple relationship between signal intensity and analyte concentration. Proteomic strategies are therefore complex and several factors need to be considered when selecting the most appropriate method for an intended application, including the number of proteins and samples. Quantitative strategies require appropriate mass spectrometry platforms, yet choice is often limited by the availability of appropriate instrumentation. Quantitative proteomics research requires specialist practical skills and there is a pressing need to dedicate more effort and investment to training personnel in this area. Large-scale multicenter collaborations are also needed to standardize quantitative strategies in order to improve physiologically based pharmacokinetic models.

[Effect of green tea (matcha) on gastrointestinal tract absorption of polychlorinated biphenyls, polychlorinated dibenzofurans and polychlorinated dibenzo-p-dioxins in rats].

PubMed

Morita, K; Matsueda, T; Iida, T

1997-05-01

This paper presents the liver distribution and fecal excretion of polychlorinated biphenyls (PCB), polychlorinated dibenzofurans (PCDF) congeners and polychlorinated dibenzo-p-dioxins (PCDD) congeners, in male rats fed with powdered green tea (matcha). The rats were given a treatment diet containing 10% matcha for the first five days. Then, the animals were administered 4 g of 10% matcha diet containing 0.5 ml of the casual rice-bran oil of Yusho that had occurred in the Southwest part of Japan in 1968 and kept on the same diet for another five days. The fecal excretion of PCB, PCDF and PCDD in the group fed with 10% matcha were 4.4, 2.4-9.1 and 2.5-4.7 times higher (p < 0.01), respectively, than that in the control group. The liver distribution of PCB, PCDF and PCDD in the same groups were 79%, 20-75% and 26-67% of the control group, respectively. These findings suggest that administration of matcha is useful as a treatment of Yusho patients exposed to PCB, PCDF and PCDD.

The fractional urinary fluoride excretion of adults consuming naturally and artificially fluoridated water and the influence of water hardness: a randomized trial.

PubMed

Villa, A; Cabezas, L; Anabalón, M; Rugg-Gunn, A

2009-09-01

To assess whether there was any significant difference in the average fractional urinary fluoride excretion (FUFE) values among adults consuming (NaF) fluoridated Ca-free water (reference water), naturally fluoridated hard water and an artificially (H2SiF6) fluoridated soft water. Sixty adult females (N=20 for each treatment) participated in this randomized, double-blind trial. The experimental design of this study provided an indirect estimation of the fluoride absorption in different types of water through the assessment of the fractional urinary fluoride excretion of volunteers. Average daily FUFE values (daily amount of fluoride excreted in urine/daily total fluoride intake) were not significantly different between the three treatments (Kruskal-Wallis; p = 0.62). The average 24-hour FUFE value (n=60) was 0.69; 95% C.I. 0.65-0.73. The results of this study suggest that the absorption of fluoride is not affected by water hardness.

An improved methodology of asymmetric flow field flow fractionation hyphenated with inductively coupled mass spectrometry for the determination of size distribution of gold nanoparticles in dietary supplements.

PubMed

Mudalige, Thilak K; Qu, Haiou; Linder, Sean W

2015-11-13

Engineered nanoparticles are available in large numbers of commercial products claiming various health benefits. Nanoparticle absorption, distribution, metabolism, excretion, and toxicity in a biological system are dependent on particle size, thus the determination of size and size distribution is essential for full characterization. Number based average size and size distribution is a major parameter for full characterization of the nanoparticle. In the case of polydispersed samples, large numbers of particles are needed to obtain accurate size distribution data. Herein, we report a rapid methodology, demonstrating improved nanoparticle recovery and excellent size resolution, for the characterization of gold nanoparticles in dietary supplements using asymmetric flow field flow fractionation coupled with visible absorption spectrometry and inductively coupled plasma mass spectrometry. A linear relationship between gold nanoparticle size and retention times was observed, and used for characterization of unknown samples. The particle size results from unknown samples were compared to results from traditional size analysis by transmission electron microscopy, and found to have less than a 5% deviation in size for unknown product over the size range from 7 to 30 nm. Published by Elsevier B.V.

The influence of Parachlorella beyerinckii CK-5 on the absorption and excretion of methylmercury (MeHg) in mice.

PubMed

Uchikawa, Takuya; Yasutake, Akira; Kumamoto, Yoshimitsu; Maruyama, Isao; Kumamoto, Shoichiro; Ando, Yotaro

2010-02-01

Chlorella (Parachlorella beyerinckii CK-5), previously identified as Chlorella vulgaris CK-5, is a unicellular green algae that has for many years been used as a nutritional supplement. In order to investigate the effects of methylmercury (MeHg) detoxification by Chlorella, we examined the absorption and excretion of MeHg in mice. Female C57BL/6N mice were randomly divided into three groups of five, and were housed in metabolism cages. Mice were orally administered MeHg chloride at doses of 5 mg (4 mg Hg)/kg body weight with or without 100 mg/mouse of P. beyerinckii powder (BP), and were assigned to either a MeHg group or MeHg + BP group, accordingly. Twenty-four hr after oral administration, feces and urine were collected, and blood, liver, and kidney samples were obtained. Total mercury contents in the samples obtained were determined using an atomic absorption method. The amounts of Hg excreted in feces and urine of the MeHg + BP group were increased nearly 1.9 and 2.2-fold compared with those of the MeHg group. On the other hand, blood and organ Hg levels were not significantly different between two groups. These results suggest that the intake of BP may induce the excretion of Hg both in feces and urine, although it does not affect MeHg absorption from the gastrointestinal tract. The effect of BP on the tissue mercury accumulation may become evident in a long-term experiment.

Pharmacokinetic properties and drug interactions of apigenin, a natural flavone.

PubMed

Tang, Ding; Chen, Keli; Huang, Luqi; Li, Juan

2017-03-01

Apigenin, a natural flavone, is widely distributed in plants such as celery, parsley and chamomile. It is present principally as glycosylated in nature. Higher intake of apigenin could reduce the risk of chronic diseases. It has gained particular interest in recent years as a beneficial, health-promoting agent with low intrinsic toxicity. Areas covered: This review summarizes and the absorption, distribution, metabolism and excretion (ADME) properties of apigenin, and drug-drug interaction of apigenin. Expert opinion: Since apigenin is a bioactive plant flavone and is widely distributed in common food, its consumption through the diet is recommended. Apigenin-enriched drugs are better for some chronic diseases, but may affect animal and human health if present in the daily diet. Dietary or therapeutic apigenin has value as a good cellular regulator in cancer, especially cancers of the gastrointestinal tract. Due to apigenin's limitations on absorption and bioavailability, novel carriers would need to be developed to enhance the oral bioavailability of apigenin. Further research about its ADME properties and drug-drug interactions are needed before apigenin can be brought to clinical trials.

Promises of Machine Learning Approaches in Prediction of Absorption of Compounds.

PubMed

Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar

2018-01-01

The Machine Learning (ML) is one of the fastest developing techniques in the prediction and evaluation of important pharmacokinetic properties such as absorption, distribution, metabolism and excretion. The availability of a large number of robust validation techniques for prediction models devoted to pharmacokinetics has significantly enhanced the trust and authenticity in ML approaches. There is a series of prediction models generated and used for rapid screening of compounds on the basis of absorption in last one decade. Prediction of absorption of compounds using ML models has great potential across the pharmaceutical industry as a non-animal alternative to predict absorption. However, these prediction models still have to go far ahead to develop the confidence similar to conventional experimental methods for estimation of drug absorption. Some of the general concerns are selection of appropriate ML methods and validation techniques in addition to selecting relevant descriptors and authentic data sets for the generation of prediction models. The current review explores published models of ML for the prediction of absorption using physicochemical properties as descriptors and their important conclusions. In addition, some critical challenges in acceptance of ML models for absorption are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Starch blockers--their effect on calorie absorption from a high-starch meal.

PubMed

Bo-Linn, G W; Santa Ana, C A; Morawski, S G; Fordtran, J S

1982-12-02

It has been known for more than 25 years that certain plant foods, such as kidney beans and wheat, contain a substance that inhibits the activity of salivary and pancreatic amylase. More recently, this antiamylase has been purified and marketed for use in weight control under the generic name "starch blockers." Although this approach to weight control is highly popular, it has never been shown whether starch-blocker tablets actually reduce the absorption of calories from starch. Using a one-day calorie-balance technique and a high-starch (100 g) meal (spaghetti, tomato sauce, and bread), we measured the excretion of fecal calories after normal subjects had taken either placebo or starch-blocker tablets. If the starch-blocker tablets had prevented the digestion of starch, fecal calorie excretion should have increased by 400 kcal. However, fecal calorie excretion was the same on the two test days (mean +/- S.E.M., 80 +/- 4 as compared with 78 +/- 2). We conclude that starch-blocker tablets do not inhibit the digestion and absorption of starch calories in human beings.

Importance of the regiospecific distribution of long-chain saturated fatty acids on gut comfort, fat and calcium absorption in infants.

PubMed

Petit, Valérie; Sandoz, Laurence; Garcia-Rodenas, Clara L

2017-06-01

Gastrointestinal tolerance and fat and calcium (Ca) absorption are different between breast-fed (BF) and formula-fed (FF) infants. Certain components and/or structural particularities in human milk (HM), can contribute to favorable outcomes in BF infants. In HM, the long-chain saturated fatty acid (LCSFA) palmitic acid has a different stereospecific distribution (sn-2 position) compared to most infant formula (IF) (primarily sn-1, 3 positions), which may contribute to unfavorable outcomes. Evidence suggests palmitic acid is important in the formation of stool FA-mineral (or FA-Ca) soaps, associated with harder stools in FF infants. Partial replacement by structured palmitic acid-rich triacylglycerols (TAGs) promotes palmitic acid absorption. However, evidence for stool softening, improved fat absorption and reduced Ca excretion in stools is inconsistent. IFs with less palmitic acid can improve fat and Ca absorption, and stool consistency. The presence of other LCSFAs (myristic and stearic acids) in sn-1, 3 positions may also contribute to reduced absorption of fat and Ca, and stool hardness, in FF infants. Nevertheless, little attention has been given to modifying these other LCSFAs in IF. We review literature comparing the effect of HM and IF with different lipid compositions on stool patterns and/or fat and Ca absorption in healthy, term infants. Based on available data, we estimate a maximum level for sn-1, 3 LCSFAs of 13% of TAGs, under which fat and Ca absorption and stool consistency are improved. IF designed according to this threshold could efficiently improve nutrient absorption and stool patterns in healthy infants who cannot be breast-fed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Urinary excretion of polyethylene glycol 3350 during colonoscopy preparation.

PubMed

Rothfuss, K S; Bode, J C; Stange, E F; Parlesak, A

2006-02-01

Whole gut lavage with a polyethylene glycol electrolyte solution (PEG) is a common bowel cleansing method for diagnostic and therapeutic colon interventions. Absorption of orally administered PEG from the gastrointestinal tract in healthy human beings is generally considered to be poor. In patients with inflammatory bowel disease (IBD), intestinal permeability and PEG absorption were previously reported to be higher than in normal subjects. In the current study, we investigated the absorption of PEG 3350 in patients undergoing routine gut lavage. Urine specimens were collected for 8 hours in 24 patients undergoing bowel cleansing with PEG 3350 for colonoscopy. The urinary excretion of PEG 3350, measured by size exclusion chromatography, ranged between 0.01 and 0.51 % of the ingested amount, corresponding to 5.8 and 896 mg in absolute amounts, respectively. Mean PEG excretion in patients with impaired mucosa such as inflammation or ulceration of the intestine (0.24 % +/- 0.19, n = 11) was not significantly higher (p = 0.173) compared to that in subjects with macroscopically normal intestinal mucosa (0.13 % +/- 0.13, n = 13). The results indicate that intestinal absorption of PEG 3350 is higher than previously assumed and underlies a strong inter-individual variation. Inflammatory changes of the intestine do not necessarily lead to a significantly higher permeability of PEG.

[In vitro absorption mechanism of strychnine and the transport interaction with liquiritin in Caco-2 cell monolayer model].

PubMed

Wang, Jun-jun; Liao, Xiao-huan; Ye, Min; Chen, Yong

2010-09-01

To study the effect of liquiritin (Liq) on the transport of strychnine (Str) in Caco-2 cell monolayer model, the transport parameters of Str, such as apparent permeability coefficient (P app (B-->A) and P app (A-->B)) and cumulative transport amount (TRcum), were determined and comparatively analyzed when Str was used solely and co-used with Liq. The effect of drug concentrations, conveying times, P-glycoprotein (P-gp) inhibitor verapamil and conveying liquor pH values on the transport of Str were also investigated. The results indicated that the absorption of Str in Caco-2 cell monolayer model was well and the passive transference was the main intestinal absorption mechanism of Str in the Caco-2 monolayer model, along with the excretion action mediated by P-gp. Liq enhanced the absorption of Str. Meanwhile, conveying liquor pH value had significant influence on the excretion transport of Str.

Magnesium, zinc, arsenic, selenium and platinum urinary excretion from cancer patients of Antofagasta region, Chile: multi-metal approach

PubMed Central

Pizarro, I; Rivera, L; Ávila, J; Cortés, P

2016-01-01

Objectives To evaluate the short-term 24 h urinary excretion of platinum, arsenic, selenium, magnesium and zinc in patients with lung cancer and with cancer other than lungs treated with cisplatin or/and carboplatin from Antofagasta, Chile. Design Urine measurements of Pt and Se were made by inductively coupled plasma optical emission spectrometry, As by hydride-generation atomic absorption spectrometry and Mg and Zn by means of flame furnace atomic absorption spectrometry. Setting All samples were provided by the Oncological Centre of Antofagasta Regional Hospital (Region of Antofagasta, Chile). Participants Ninety 24-h urine samples from cancer patients after the infusion of Pt-base drugs and 10 24-h urine samples from cancer patients not treated with metal-base drugs. Main outcome measures Concentrations of Pt, Se, As, Zn and Mg coming from 24-h urine samples. Results Pt excreted was not significantly different between patients with lung and other cancers treated with cisplatin. The excretion of Mg, Zn and Se was greater than As. Then, Pt favours the excretion of essential elements. For lung and other types of cancers treated with drugs without Pt, excretion of Mg, Zn and Se was also greater than that of As, suggesting antagonism Mg-Zn-Se–anti-cancer drug relationship. Conclusions The amounts of Mg, Zn and Se excreted were greater than for As either with or without Pt-containing drugs, suggesting antagonist Mg-Zn-Se–anti-cancer drug relationships. The excretion of As, Mg, Zn and Se is induced by Pt. Knowledge obtained can contribute to understanding the arsenic cancer mechanism and the As-Mg-Zn-Se-Pt inter-element association for lung cancer and other types of cancer. PMID:27757244

Maturation of the renal response to hypertonic sodium chloride loading in rats: micropuncture and clearance studies.

PubMed Central

Baker, J T; Solomon, S

1976-01-01

1. The ability of maturing rats to excrete a sodium load was studied by micropuncture and clearance procedures. 2. During control conditions, no change of glomerular filtration rate or sodium excretion was observed for the time period of the entire procedure (P greater than 0-20). During the infusion of hypertonic (4%) sodium chloride, fractional sodium excretion was 0-08 +/- 0-01 in rats 21-30 days old and 0-14 +/- 0-01 (P less than 0-01) in adults. However, the depression of proximal tubular water re-absorption was equal in both groups (P greater than 0-20). 3. Proximal glomerulotubular balance for water re-absorption was similar in all groups (P less than 0-20). Since end proximal tubular water excretion and depression of fractional water excretion were the same in all animals, differences of urinary sodium excretion during development are probably due to differences of function of segments beyond the proximal tubule during development. 4. Fractional potassium excretion was reduced in young rats (0-17 +/- 0-04) during hypertonic sodium chloride infusion, compared to adults (0-24 +/- 0-01, P less than 0-05). 5. Passage time of fast green through cortical segments in seconds is prolonged in young rats during control conditions. Similar decreases of passage time were seen in all groups during hypertonic sodium chloride infusion. No segmental differences of passage time were seen during developmental. 6. No difference in the relationship between fractional sodium and water excretion was seen during development of the renal response to hypertonic sodium chloride infusion. Thus, altered sensitivity to sodium chloride osmotic diuresis does not exist during maturation in rats. PMID:945839

Free and protein-bound cobalamin absorption in healthy middle-aged and older subjects.

PubMed

van Asselt, D Z; van den Broek, W J; Lamers, C B; Corstens, F H; Hoefnagels, W H

1996-08-01

To study free- and protein-bound cobalamin absorption and the correlation with atrophic gastritis in healthy middle-aged and older subjects. A cross-sectional study. Fifty-two healthy subjects, aged 26 to 87 years, apparently free from conditions known to influence the cobalamin status. Middle-aged subjects were defined as those younger than 65 years of age (median age 57 years) and older subjects as those 65 years and older (median age 75 years). Protein-bound cobalamin absorption was assessed by 48-hour urinary excretion method following oral administration of scrambled egg yolk, labeled in vivo with 57 Co-cobalamin by injecting a hen with 57 Co-cyanocobalamin. The percentage of 57 Co-cobalamin bound to protein was 65%. Free cobalamin absorption was assessed by 48-hour urinary excretion method following oral administration of crystalline 57 Co-cyanocobalamin. Plasma cobalamin, folate and fasting plasma gastrin, and pepsinogen A and C concentrations were determined. The median urinary excretion of egg yolk 57 Co-cobalamin in middle-aged subjects was 12.3% (25th and 75th percentiles 10.5%-14.5%) compared with 11.7% (25th and 75th percentiles 9.8%-13.6%) in older subjects (P = .283). The median urinary excretion after administration of free 57 Co-cobalamin in middle-aged subjects was 25.7% (25th and 75th percentiles 20.6%-30.7%) compared with 27.9% (25th and 75th percentiles 21.4%-34.5%) in older subjects (P = .694). Neither egg yolk nor free 57 Co-cobalamin excretion correlated with age. A ratio of pepsinogen A to pepsinogen C less than 1.6, indicating atrophic gastritis, was found in 13 subjects. Within the atrophic gastritis group, 11 subjects had a pepsinogen A concentration greater than or equal to 17 micrograms/L, indicating mild to moderate atrophic gastritis, and two subjects had a pepsinogen A concentration less than 17 micrograms/L, indicating severe atrophic gastritis or gastric atrophy. All subjects had normal fasting plasma gastrin concentrations. Free and egg yolk 57 Co-cobalamin excretions were not reduced in the atrophic gastritis group when compared with the non-atrophic gastritis group. Median plasma cobalamin concentration was not significantly lower in older subjects (P = .205). Nonetheless, plasma cobalamin concentration correlated negatively with age (r = -.36; P = .008). We demonstrated no significant difference in either free or protein-bound cobalamin absorption between healthy middle-aged and older adults. In addition, no alteration in cobalamin absorption was found in subjects identified as having mild to moderate atrophic gastritis. Therefore, based on our results, the high prevalence of low cobalamin levels in older people cannot be explained by either the aging process or mild to moderate atrophic gastritis.

Measurements of Deposition, Lung Surface Area and Lung Fluid for Simulation of Inhaled Compounds

PubMed Central

Fröhlich, Eleonore; Mercuri, Annalisa; Wu, Shengqian; Salar-Behzadi, Sharareh

2016-01-01

Modern strategies in drug development employ in silico techniques in the design of compounds as well as estimations of pharmacokinetics, pharmacodynamics and toxicity parameters. The quality of the results depends on software algorithm, data library and input data. Compared to simulations of absorption, distribution, metabolism, excretion, and toxicity of oral drug compounds, relatively few studies report predictions of pharmacokinetics and pharmacodynamics of inhaled substances. For calculation of the drug concentration at the absorption site, the pulmonary epithelium, physiological parameters such as lung surface and distribution volume (lung lining fluid) have to be known. These parameters can only be determined by invasive techniques and by postmortem studies. Very different values have been reported in the literature. This review addresses the state of software programs for simulation of orally inhaled substances and focuses on problems in the determination of particle deposition, lung surface and of lung lining fluid. The different surface areas for deposition and for drug absorption are difficult to include directly into the simulations. As drug levels are influenced by multiple parameters the role of single parameters in the simulations cannot be identified easily. PMID:27445817

Updated bioavailability and 48 h excretion profile of flavan-3-ols from green tea in humans.

PubMed

Calani, Luca; Del Rio, Daniele; Luisa Callegari, Maria; Morelli, Lorenzo; Brighenti, Furio

2012-08-01

Green tea is a popular beverage, prepared with infusion of unfermented dried leaves of Camellia sinensis, and is one of the most relevant sources of polyphenolic compounds in the human diet. This study reports green tea flavan-3-ol absorption, metabolism and complete urinary excretion up to 48 h in 20 healthy volunteers. Urinary and tea samples were analysed by high-performance liquid chromatography coupled with tandem mass spectrometry. Green tea contained monomeric flavan-3-ols and proanthocyanidins with a total polyphenol content of 728 μmol. A total of 41 metabolites were identified in urines, all present in conjugated forms. Among these, six colonic metabolites of green tea flavan-3-ols were identified for the first time after green tea consumption in humans. The average 48 h bioavailability was close to 62%, major contributors being microbial metabolites. Some volunteer showed a 100% absorption/excretion, whereas some others were unable to efficiently absorb/excrete this class of flavonoids. This suggests that colonic ring fission metabolism could be relevant in the putative bioactivity of green tea polyphenols.

Interplay of biopharmaceutics, biopharmaceutics drug disposition and salivary excretion classification systems

PubMed Central

Idkaidek, Nasir M.

2013-01-01

The aim of this commentary is to investigate the interplay of Biopharmaceutics Classification System (BCS), Biopharmaceutics Drug Disposition Classification System (BDDCS) and Salivary Excretion Classification System (SECS). BCS first classified drugs based on permeability and solubility for the purpose of predicting oral drug absorption. Then BDDCS linked permeability with hepatic metabolism and classified drugs based on metabolism and solubility for the purpose of predicting oral drug disposition. On the other hand, SECS classified drugs based on permeability and protein binding for the purpose of predicting the salivary excretion of drugs. The role of metabolism, rather than permeability, on salivary excretion is investigated and the results are not in agreement with BDDCS. Conclusion The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion based on permeability (not metabolism) and protein binding. PMID:24493977

Control of potassium excretion: a Paleolithic perspective.

PubMed

Halperin, Mitchell L; Cheema-Dhadli, Surinder; Lin, Shih-Hua; Kamel, Kamel S

2006-07-01

Regulation of potassium (K) excretion was examined in an experimental setting that reflects the dietary conditions for humans in Paleolithic times (high, episodic intake of K with organic anions; low intake of NaCl), because this is when major control mechanisms were likely to have developed. The major control of K secretion in this setting is to regulate the number of luminal K channels in the cortical collecting duct. Following a KCl load, the K concentration in the medullary interstitial compartment rose; the likely source of this medullary K was its absorption by the H/K-ATPase in the inner medullary collecting duct. As a result of the higher medullary K concentration, the absorption of Na and Cl was inhibited in the loop of Henle, and this led to an increased distal delivery of a sufficient quantity of Na to raise K excretion markedly, while avoiding a large natriuresis. In addition, because K in the diet was accompanied by 'future' bicarbonate, a role for bicarbonate in the control of K secretion via 'selecting' whether aldosterone would be a NaCl-conserving or a kaliuretic hormone is discussed. This way of examining the control of K excretion provides new insights into clinical disorders with an abnormal plasma K concentration secondary to altered K excretion, and also into the pathophysiology of calcium-containing kidney stones.

Prediction of Human Intestinal Absorption of Compounds Using Artificial Intelligence Techniques.

PubMed

Kumar, Rajnish; Sharma, Anju; Siddiqui, Mohammed Haris; Tiwari, Rajesh Kumar

2017-01-01

Information about Pharmacokinetics of compounds is an essential component of drug design and development. Modeling the pharmacokinetic properties require identification of the factors effecting absorption, distribution, metabolism and excretion of compounds. There have been continuous attempts in the prediction of intestinal absorption of compounds using various Artificial intelligence methods in the effort to reduce the attrition rate of drug candidates entering to preclinical and clinical trials. Currently, there are large numbers of individual predictive models available for absorption using machine learning approaches. Six Artificial intelligence methods namely, Support vector machine, k- nearest neighbor, Probabilistic neural network, Artificial neural network, Partial least square and Linear discriminant analysis were used for prediction of absorption of compounds. Prediction accuracy of Support vector machine, k- nearest neighbor, Probabilistic neural network, Artificial neural network, Partial least square and Linear discriminant analysis for prediction of intestinal absorption of compounds was found to be 91.54%, 88.33%, 84.30%, 86.51%, 79.07% and 80.08% respectively. Comparative analysis of all the six prediction models suggested that Support vector machine with Radial basis function based kernel is comparatively better for binary classification of compounds using human intestinal absorption and may be useful at preliminary stages of drug design and development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

[Influence of mineral water on absorption of oral alendronate in rats].

PubMed

Akagi, Yuuki; Sakaue, Tomoyuki; Yoneyama, Eiji; Aoyama, Takao

2011-01-01

Alendronate, an oral bisphosphonate (e.g., Fosamax(®)), is effective in the treatment of osteoporosis, and the Fosamax(®) package insert advises that the bioavailability is reduced when taken with mineral water containing high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards regarding the water used when taking alendronate are unclear. In this study, the influence of mineral water on the absorption of oral alendronate was investigated based on urinary excretion of its unchanged form in rats. Alendronate was diluted in each water sample and administered orally (0.7 mg/kg) to male Wistar rats after 24-hour fast. Urine samples were collected until 24 h after dosing. Urine samples were alkalinized, and alendronate in urine was precipitated as a calcium salt, followed by loading on an anion exchange cartridge. Eluted alendronate was derivatized with 9-fluorenylmethoxycarbonyl (Fmoc) chloride and determined by HPLC with fluorescent detection. Cumulative urinary excretion recoveries of alendronate were calculated from the amounts of urinary excretion. Alendronate was rapidly excreted in the first 6 h, and similar elimination rate constants were seen (from 0.28 to 0.45 h(-1/2)) among the water samples. Cumulative urinary excretion recoveries with tap water, evian(®) and 100% deep ocean water were 0.98±0.17%, 0.80±0.18% and 1.01±0.16% (mean±S.E., n=4). Those with Contrex(®) (0.33±0.07%) were significantly lower when compared with ultrapure water (1.56±0.35%, p<0.01). These findings suggest that the absorption of alendronate decreases based on the calcium concentration of mineral water. In conclusion, mineral water containing high levels of calcium is not recommended when alendronate is taken.

A combination of a dairy product fermented by lactobacilli and galactooligosaccharides shows additive effects on mineral balances in growing rats with hypochlorhydria induced by a proton pump inhibitor.

PubMed

Takasugi, Satoshi; Ashida, Kinya; Maruyama, Suyaka; Matsukiyo, Yukari; Kaneko, Tetsuo; Yamaji, Taketo

2013-06-01

This study aimed to investigate the effects of a combination of a dairy product fermented by lactobacilli (DFL) and galactooligosaccharides (GOS) on mineral balances in growing rats with hypochlorhydria induced by a proton pump inhibitor (PPI). Three-week-old male rats were assigned to receive one of six diets: a control diet, control diets containing 1.6 or 5.0 % GOS, a DFL diet and DFL diets containing 1.6 or 5.0 % GOS for 9 days. From day 5 of the feeding period, half of the rats fed with control diets were subcutaneously administered with saline, whereas the remaining rats were administered with PPI for 5 days. Calcium (Ca), phosphorus (P), magnesium (Mg), iron (Fe) and zinc (Zn) balances were determined from days 6 to 9. PPI administration significantly decreased the apparent absorption of Ca and Fe and increased urinary P excretion, resulting in decreased Ca, Fe and P retention. GOS dose-dependently increased the apparent absorption of Ca, Mg and Fe and urinary Mg excretion and decreased urinary P excretion. DFL significantly increased the apparent absorption of Ca and Mg and urinary Mg excretion. The combination of DFL and GOS additively affected these parameters, resulting in increased Ca, P and Fe retention, and it further increased the apparent absorption and retention of Zn at 5.0 % GOS. In conclusion, the combination of DFL and GOS improves Ca, P and Fe retention in an additive manner and increases the Zn retention in growing rats with hypochlorhydria induced by PPI.

Docking-based Screening of Ficus religiosa Phytochemicals as Inhibitors of Human Histamine H2 Receptor.

PubMed

Chaudhary, Amit; Yadav, Birendra Singh; Singh, Swati; Maurya, Pramod Kumar; Mishra, Alok; Srivastva, Shweta; Varadwaj, Pritish Kumar; Singh, Nand Kumar; Mani, Ashutosh

2017-10-01

Ficus religiosa L. is generally known as Peepal and belongs to family Moraceae . The tree is a source of many compounds having high medicinal value. In gastrointestinal tract, histamine H2 receptors have key role in histamine-stimulated gastric acid secretion. Their over stimulation causes its excessive production which is responsible for gastric ulcer. This study aims to screen the range of phytochemicals present in F. religiosa for binding with human histamine H2 and identify therapeutics for a gastric ulcer from the plant. In this work, a 3D-structure of human histamine H2 receptor was modeled by using homology modeling and the predicted model was validated using PROCHECK. Docking studies were also performed to assess binding affinities between modeled receptor and 34 compounds. Molecular dynamics simulations were done to identify most stable receptor-ligand complexes. Absorption, distribution, metabolism, excretion, and screening was done to evaluate pharmacokinetic properties of compounds. The results suggest that seven ligands, namely, germacrene, bergaptol, lanosterol, Ergost-5-en-3beta-ol, α-amyrin acetate, bergapten, and γ-cadinene showed better binding affinities. Among seven phytochemicals, lanosterol and α-amyrin acetate were found to have greater stability during simulation studies. These two compounds may be a suitable therapeutic agent against histamine H2 receptor. This study was performed to screen antiulcer compounds from F. religiosa . Molecular modeling, molecular docking and MD simulation studies were performed with selected phytochemicals from F. religiosa . The analysis suggests that Lanosterol and α-amyrin may be a suitable therapeutic agent against histamine H2 receptor. This study facilitates initiation of the herbal drug discovery process for the antiulcer activity. Abbreviations used: ADMET: Absorption, distribution, metabolism, excretion and toxicity, DOPE: Discrete Optimized Potential Energy, OPLS: Optimized potential for liquid simulations, RMSD: Root-mean-square deviation, HOA: Human oral absorption, MW: Molecular weight, SP: Standard-precision, XP: Extra-precision, GPCRs: G protein-coupled receptors, SASA: Solvent accessible surface area, Rg: Radius of gyration, NHB: Number of hydrogen bond.

In vitro investigation of intestinal transport mechanism of silicon, supplied as orthosilicic acid-vanillin complex.

PubMed

Sergent, Thérèse; Croizet, Karine; Schneider, Yves-Jacques

2017-02-01

Silicon (Si) is one of the most abundant trace elements in the body. Although pharmacokinetics data described its absorption from the diet and its body excretion, the mechanisms involved in the uptake and transport of Si across the gut wall have not been established. Caco-2 cells were used as a well-accepted in vitro model of the human intestinal epithelium to investigate the transport, across the intestinal barrier in both the absorption and excretion directions, of Si supplied as orthosilicic acid stabilized by vanillin complex (OSA-VC). The transport of this species was found proportional to the initial concentration and to the duration of incubation, with absorption and excretion mean rates similar to those of Lucifer yellow, a marker of paracellular diffusion, and increasing in the presence of EGTA, a chelator of divalents cations including calcium. A cellular accumulation of Si, polarized from the apical side of cells, was furthermore detected. These results provide evidence that Si, ingested as a food supplement containing OSA-VC, crosses the intestinal mucosa by passive diffusion via the paracellular pathway through the intercellular tight junctions and accumulates intracellularly, probably by an uptake mechanism of facilitated diffusion. This study can help to further understand the kinetic of absorption of Si. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

PubMed Central

Dola, Vasantha Rao; Soni, Awakash; Agarwal, Pooja; Ahmad, Hafsa; Raju, Kanumuri Siva Rama; Rashid, Mamunur; Wahajuddin, Muhammad; Srivastava, Kumkum; Haq, W.; Dwivedi, A. K.; Puri, S. K.

2016-01-01

ABSTRACT A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile. PMID:27956423

Biotic and abiotic studies on the biological fate, transport and ecotoxicity of toxic and hazardous waste in the Mississippi River basin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abdelghani, A.; Pramar, Y.; Mandal, T.

1996-05-02

This project assesses the levels of xenobiotics in Devils Swamp and studies their biological fate, transport, ecotoxicity, and potential toxicity to man. This article reports on the following studies: assessment of the acute toxicity of individual xenobiotics and toxicity of organic compounds hexachlorobutadience (HCB) and hexachlorobenzene (HCBD) on juvenile crayfish; determination of the biotic influence of temperature, salinity, pH, oxidation-reduction potential, and sediment composition on the migration of xenobiotics; development of a pharmacokinetics model for xenobiotic absorption and storage, distribution and excretion by fish and crayfish.

Transcellular oxalate and Cl− absorption in mouse intestine is mediated by the DRA anion exchanger Slc26a3, and DRA deletion decreases urinary oxalate

PubMed Central

Freel, Robert W.; Whittamore, Jonathan M.

2013-01-01

Active transcellular oxalate transport in the mammalian intestine contributes to the homeostasis of this important lithogenic anion. Several members of the Slc26a gene family of anion exchangers have a measurable oxalate affinity and are expressed along the gut, apically and basolaterally. Mouse Slc26a6 (PAT1) targets to the apical membrane of enterocytes in the small intestine, and its deletion results in net oxalate absorption and hyperoxaluria. Apical exchangers of the Slc26a family that mediate oxalate absorption have not been established, yet the Slc26a3 [downregulated in adenoma (DRA)] protein is a candidate mediator of oxalate uptake. We evaluated the role of DRA in intestinal oxalate and Cl− transport by comparing unidirectional and net ion fluxes across short-circuited segments of small (ileum) and large (cecum and distal colon) intestine from wild-type (WT) and DRA knockout (KO) mice. In WT mice, all segments demonstrated net oxalate and Cl− absorption to varying degrees. In KO mice, however, all segments exhibited net anion secretion, which was consistently, and solely, due to a significant reduction in the absorptive unidirectional fluxes. In KO mice, daily urinary oxalate excretion was reduced 66% compared with that in WT mice, while urinary creatinine excretion was unchanged. We conclude that DRA mediates a predominance of the apical uptake of oxalate and Cl− absorbed in the small and large intestine of mice under short-circuit conditions. The large reductions in urinary oxalate excretion underscore the importance of transcellular intestinal oxalate absorption, in general, and, more specifically, the importance of the DRA exchanger in oxalate homeostasis. PMID:23886857

KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects.

PubMed

Huskey, Su-Er W; Zhu, Chun-qi; Fredenhagen, Andreas; Kühnöl, Jürgen; Luneau, Alexandre; Jian, Zhigang; Yang, Ziping; Miao, Zhuang; Yang, Fan; Jain, Jay P; Sunkara, Gangadhar; Mangold, James B; Stein, Daniel S

2016-05-01

KAE609 [(1'R,3'S)-5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent in clinical development for the treatment of malaria. This study investigated the absorption, distribution, metabolism, and excretion of KAE609 after oral administration of [(14)C]KAE609 in healthy subjects. After oral administration to human subjects, KAE609 was the major radioactive component (approximately 76% of the total radioactivity in plasma); M23 was the major circulating oxidative metabolite (approximately 12% of the total radioactivity in plasma). Several minor oxidative metabolites (M14, M16, M18, and M23.5B) were also identified, each accounting for approximately 3%-8% of the total radioactivity in plasma. KAE609 was well absorbed and extensively metabolized, such that KAE609 accounted for approximately 32% of the dose in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways. M23 was the major metabolite in feces. Subjects reported semen discoloration after dosing in prior studies; therefore, semen samples were collected once from each subject to further evaluate this clinical observation. Radioactivity excreted in semen was negligible, but the major component in semen was M23, supporting the rationale that this yellow-colored metabolite was the main source of semen discoloration. In this study, a new metabolite, M16, was identified in all biologic matrices albeit at low levels. All 19 recombinant human cytochrome P450 enzymes were capable of catalyzing the hydroxylation of M23 to form M16 even though the extent of turnover was very low. Thus, electrochemistry was used to generate a sufficient quantity of M16 for structural elucidation. Metabolic pathways of KAE609 in humans are summarized herein and M23 is the major metabolite in plasma and excreta. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Intestinal absorption, organ distribution, and urinary excretion of the rare sugar D-psicose

PubMed Central

Tsukamoto, Ikuko; Hossain, Akram; Yamaguchi, Fuminori; Hirata, Yuko; Dong, Youyi; Kamitori, Kazuyo; Sui, Li; Nonaka, Machiko; Ueno, Masaki; Nishimoto, Kazuyuki; Suda, Hirofumi; Morimoto, Kenji; Shimonishi, Tsuyoshi; Saito, Madoka; Song, Tao; Konishi, Ryoji; Tokuda, Masaaki

2014-01-01

Background The purpose of this study was to evaluate intestinal absorption, organ distribution, and urinary elimination of the rare sugar D-psicose, a 3-carbon stereoisomer of D-fructose that is currently being investigated and which has been found to be strongly effective against hyperglycemia and hyperlipidemia. Methods This study was performed using radioactive D-psicose, which was synthesized enzymatically from radioactive D-allose. Concentrations in whole blood, urine, and organs were measured at different time points until 2 hours after both oral and intravenous administrations and 7 days after a single oral administration (100 mg/kg body weight) to Wistar rats. Autoradiography was also performed by injecting 100 mg/kg body weight of 14C-labeled D-psicose or glucose intravenously to C3H mice. Results Following oral administration, D-psicose easily moved to blood. The maximum blood concentration (48.5±15.6 μg/g) was observed at 1 hour. Excretion to urine was 20% within 1 hour and 33% within 2 hours. Accumulation to organs was detected only in the liver. Following intravenous administration, blood concentration was decreased with the half-life=57 minutes, and the excretion to urine was up to almost 50% within 1 hour. Similarly to the results obtained with oral administration, accumulation to organs was detected only in the liver. Seven days after the single-dose oral administration, the remaining amounts in the whole body were less than 1%. Autoradiography of mice showed results similar to those in rats. High signals of 14C-labeled D-psicose were observed in liver, kidney, and bladder. Interestingly, no accumulation of D-psicose was observed in the brain. Conclusion D-psicose was absorbed well after oral administration and eliminated rapidly after both oral and intravenous administrations, with short duration of action. The study provides valuable pharmacokinetic data for further drug development of D-psicose. Because the findings were mainly based on animal study, it is necessary to implement human trials to study the metabolism pathway, which would give an important guide for human intake and food application of D-psicose. PMID:25378908

Absorption and retention of nickel from drinking water in relation to food intake and nickel sensitivity.

PubMed

Nielsen, G D; Søderberg, U; Jørgensen, P J; Templeton, D M; Rasmussen, S N; Andersen, K E; Grandjean, P

1999-01-01

Two studies were performed to examine the influence of fasting and food intake on the absorption and retention of nickel added to drinking water and to determine if nickel sensitization played any role in this regard. First, eight nonallergic male volunteers fasted overnight before being given nickel in drinking water (12 micrograms Ni/kg) and, at different time intervals, standardized 1400-kJ portions of scrambled eggs. When nickel was ingested in water 30 min or 1 h prior to the meal, peak nickel concentrations in serum occurred 1 h after the water intake, and the peak was 13-fold higher than the one seen 1 h after simultaneous intake of nickel-containing water and scrambled eggs. In the latter case, a smaller, delayed peak occurred 3 h after the meal. Median urinary nickel excretion half-times varied between 19.9 and 26.7 h. Within 3 days, the amount of nickel excreted corresponded to 2.5% of the nickel ingested when it was mixed into the scrambled eggs. Increasing amounts were excreted as the interval between the water and the meal increased, with 25.8% of the administered dose being excreted when the eggs were served 4 h prior to the nickel-containing drinking water. In the second experiment, a stable nickel isotope, 61Ni, was given in drinking water to 20 nickel-sensitized women and 20 age-matched controls, both groups having vesicular hand eczema of the pompholyx type. Nine of 20 nickel allergic eczema patients experienced aggravation of hand eczema after nickel administration, and three also developed a maculopapular exanthema. No exacerbation was seen in the control group. The course of nickel absorption and excretion in the allergic groups did not differ and was similar to the pattern seen in the first study, although the absorption in the women was less. A sex-related difference in gastric emptying rates may play a role. Thus, food intake and gastric emptying are of substantial significance for the bioavailability of nickel from aqueous solutions. Copyright 1999 Academic Press.

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats.

PubMed

Lu, Ying-Yuan; Wang, Xiao-Wei; Wang, Xin; Dai, Wen-Bing; Zhang, Qiang; Li, Pu; Lou, Ya-Qing; Lu, Chuang; Liu, Jun-Yi; Zhang, Guo-Liang

2016-07-01

The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C max) were 0.42, 1.50 and 2.55 μg/mL, the area under the curve (AUC0-t) were 0.89, 2.27 and 3.96 µg/h mL and the plasma half-life (t 1/2) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96-99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.

Model based on GRID-derived descriptors for estimating CYP3A4 enzyme stability of potential drug candidates

NASA Astrophysics Data System (ADS)

Crivori, Patrizia; Zamora, Ismael; Speed, Bill; Orrenius, Christian; Poggesi, Italo

2004-03-01

A number of computational approaches are being proposed for an early optimization of ADME (absorption, distribution, metabolism and excretion) properties to increase the success rate in drug discovery. The present study describes the development of an in silico model able to estimate, from the three-dimensional structure of a molecule, the stability of a compound with respect to the human cytochrome P450 (CYP) 3A4 enzyme activity. Stability data were obtained by measuring the amount of unchanged compound remaining after a standardized incubation with human cDNA-expressed CYP3A4. The computational method transforms the three-dimensional molecular interaction fields (MIFs) generated from the molecular structure into descriptors (VolSurf and Almond procedures). The descriptors were correlated to the experimental metabolic stability classes by a partial least squares discriminant procedure. The model was trained using a set of 1800 compounds from the Pharmacia collection and was validated using two test sets: the first one including 825 compounds from the Pharmacia collection and the second one consisting of 20 known drugs. This model correctly predicted 75% of the first and 85% of the second test set and showed a precision above 86% to correctly select metabolically stable compounds. The model appears a valuable tool in the design of virtual libraries to bias the selection toward more stable compounds. Abbreviations: ADME - absorption, distribution, metabolism and excretion; CYP - cytochrome P450; MIFs - molecular interaction fields; HTS - high throughput screening; DDI - drug-drug interactions; 3D - three-dimensional; PCA - principal components analysis; CPCA - consensus principal components analysis; PLS - partial least squares; PLSD - partial least squares discriminant; GRIND - grid independent descriptors; GRID - software originally created and developed by Professor Peter Goodford.

Computational Breakthrough of Natural Lead Hits from the Genus of Arisaema against Human Respiratory Syncytial Virus.

PubMed

Kant, Kamal; Lal, Uma Ranjan; Ghosh, Manik

2018-01-01

To date, efforts for the prevention and treatment of human respiratory syncytial virus (RSV) infection have been still vain, and there is no safe and effective clinical accepted vaccine. Arisaema genus has claimed for various traditional bioactivities, but scientific assessments are quite limited. This encouraged us to carry out our present study on around 60 phytoconstituents of different Arisaema species as a natural inhibitor against the human RSV. Selected 60 phytochemical entities were evaluated on the docking behavior of human RSV receptor (PDB: 4UCC) using Maestro 9.3 (Schrödinger, LLC, Cambridge, USA). Furthermore, kinetic properties and toxicity nature of top graded ligands were analyzed through QikProp and ProTox tools. Notably, rutin (glide score: -8.49), schaftoside (glide score: -8.18) and apigenin-6,8-di-C-β-D-galactoside (glide score - 7.29) have resulted in hopeful natural lead hits with an ideal range of kinetic descriptors values. ProTox tool (oral rodent toxicity) has resulted in likely toxicity targets of apex-graded tested ligands. Finally, the whole efforts can be explored further as a model to confirm its anti-human RSV potential with wet laboratory experiments. Rutin, schaftoside, and apigenin-6,8-di-C-β-D-galactoside showed promising top hits docking profile against human respiratory syncytial virusMoreover, absorption, distribution, metabolism, excretion properties (QikProp) of top hits resulted within an ideal range of kinetic descriptorsProTox tool highlighted toxicity class ranges, LD 50 values, and possible toxicity targets of apex-graded tested ligands. Abbreviations used: RSV: Respiratory syncytial virus, PRRSV: Porcine respiratory and reproductive syndrome virus, ADME-T: Absorption, distribution, metabolism, excretion, and toxicity.

A Workflow to Investigate Exposure and Pharmacokinetic ...

EPA Pesticide Factsheets

Background: Adverse outcome pathways (AOPs) link adverse effects in individuals or populations to a molecular initiating event (MIE) that can be quantified using in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires incorporation of knowledge on exposure, along with absorption, distribution, metabolism, and excretion (ADME) properties of chemicals.Objectives: We developed a conceptual workflow to examine exposure and ADME properties in relation to an MIE. The utility of this workflow was evaluated using a previously established AOP, acetylcholinesterase (AChE) inhibition.Methods: Thirty chemicals found to inhibit human AChE in the ToxCast™ assay were examined with respect to their exposure, absorption potential, and ability to cross the blood–brain barrier (BBB). Structures of active chemicals were compared against structures of 1,029 inactive chemicals to detect possible parent compounds that might have active metabolites.Results: Application of the workflow screened 10 “low-priority” chemicals of 30 active chemicals. Fifty-two of the 1,029 inactive chemicals exhibited a similarity threshold of ≥ 75% with their nearest active neighbors. Of these 52 compounds, 30 were excluded due to poor absorption or distribution. The remaining 22 compounds may inhibit AChE in vivo either directly or as a result of metabolic activation.Conclusions: The incorporation of exposure and ADME properties into the conceptual workflow e

Cytotoxicity evaluation of symmetrically branched glycerol trimer in human hepatocellular carcinoma HepG2 cells.

PubMed

Miyamoto, Licht; Watanabe, Masashi; Kono, Mai; Matsushita, Tsuyoshi; Hattori, Hatsuhiko; Ishizawa, Keisuke; Nemoto, Hisao; Tsuchiya, Koichiro

2012-01-01

An appropriate balance between lipophilicity and hydrophilicity is necessary for pharmaceuticals to achieve fine Absorption, Distribution, Metabolism and Excretion (ADME) properties including absorption and distribution, in particular. We have designed and proposed symmetrically branched oligoglycerols (BGL) as an alternative approach to improve the lipophilic-hydrophilic balance. We have previously shown that stability in circulation and water-solubility of such molecules as proteins, liposomes and hydrophobic compounds are much improved by conjugation to BGL. Albeit these successful applications of BGL, little was known whether BGL could be used in safety. Thus we conducted evaluation of the cytotoxicity of a representative BGL, symmetrically branched glycerol trimer (BGL003) in the cultured cells to clarify its biological safeness. Here we demonstrate that water-solubility of an extremely hydrophobic agent, fenofibrate was more than 2,000-fold improved just by conjugated with BGL003. BGL003 did not exhibit any significant cytotoxicity in human hepatocarcinoma HepG2 cells. Thus BGL003 should be safe and suitable strategy to endow hydrophobic molecules with much hydrophilicity.

The babel of the ABCs: novel transporters involved in the regulation of sterol absorption and excretion.

PubMed

Ordovas, Jose M; Tai, E Shyong

2002-01-01

Hypercholesterolaemia is a major risk factor for coronary heart disease (CHD). Therefore, the reduction of low-density lipoprotein (LDL) cholesterol is one of the primary targets of the current recommendations to decrease CHD risk in the population. Whereas, the mechanisms involved in de novo cholesterol synthesis and its uptake by cells via the LDL receptor are well known, we still need better understanding about the mechanisms involved in intestinal cholesterol absorption and excretion. The recent discovery of ABCG5 and ABCG8 transporters will significantly improve our understanding of cholesterol trafficking and it will lead to better and new therapeutic strategies to maintain cholesterol homeostasis.

Absorption and metabolism of milk thistle flavanolignans in humans.

PubMed

Calani, Luca; Brighenti, Furio; Bruni, Renato; Del Rio, Daniele

2012-12-15

This study evaluated the absorption and metabolism of milk thistle flavonolignans silychristin, silydianin, silybin and isosilybin isomers (all together known as silymarin) in humans. Fourteen volunteers consumed an extract of milk thistle and urine was collected up to 48 h after consumption. Thirty-one metabolites were identified in urine by means of HPLC-MS/MS, monoglucuronides being the most common excreted form, followed by sulphate-glucuronides and diglucuronides, respectively. The excretion of monoglucuronides peaked 2 h after consumption, whereas sulphate-glucuronide and diglucuronide excretion peaked at 8 h. The bioavailability of milk thistle flavanolignans was 0.45±0.28% (mean±SD). In conclusion, milk thistle flavonolignans are extensively modified after ingestion and recovered in urine as sulpho- and glucuronyl-conjugates, indicating a strong affinity for hepatic phase II enzymes. All future studies (in vitro and in vivo) dealing with the effects of milk thistle should start by considering the modification of its flavonolignans after ingestion by humans. Copyright © 2012 Elsevier GmbH. All rights reserved.

Estimation of the percutaneous absorption of styrene in an industrial situation.

PubMed

Limasset, J C; Simon, P; Poirot, P; Subra, I; Grzebyk, M

1999-01-01

This field study was designed to compare the level of styrene absorbed percutaneously with that absorbed by inhalation in a real situation in the fiberglass-reinforced polyester industry. The study protocol consisted of comparisons of the patterns of urinary excretion of styrene metabolites by four groups of workers, all of whom performed the same task at the same time in the same workshop but wore the following different protective equipment: total protection with an insulating suit and mask, respiratory equipment only, percutaneous protection only, and no protection. The urinary excretion level of the group with total protection did not significantly differ from that of the group with respiratory protection only. Precutaneous absorption is not a particularly important pathway for styrene absorption during stratification work in the polyester industry. Completely insulating personal protective equipment provides no greater level of protection than does a respirator at positive pressure alone.

Vitamin B12 absorption from eggs.

PubMed

Doscherholmen, A; McMahon, J; Ripley, D

1975-09-01

The assimilation of 57Co B12 from in vivo labeled eggs was much inferior to that of a comparable amount of crystalline 57Co B12. Furthermore, the absorption varied with the form in which the eggs were served. Judged by the urinary excretion test and the plasma absorption of radioactivity the average absorption from boiled and fried eggs was more than twice that from scrambled whole eggs, but less than half that absorbed from crystalline 57Co B12.

Diuretics and disorders of calcium homeostasis.

PubMed

Grieff, Marvin; Bushinsky, David A

2011-11-01

Diuretics commonly are administered in disorders of sodium balance. Loop diuretics inhibit the Na-K-2Cl transporter and also increase calcium excretion. They are often used in the treatment of hypercalcemia. Thiazide diuretics block the thiazide-sensitive NaCl transporter in the distal convoluted tubule, and can decrease calcium excretion. They are often used in the treatment of nephrolithiasis. Carbonic anhydrase inhibitors decrease bicarbonate absorption and the resultant metabolic acidosis can increase calcium excretion. Their use can promote nephrocalcinosis and nephrolithiasis. This review will address the use of diuretics on disorders of calcium homeostasis. Copyright © 2011 Elsevier Inc. All rights reserved.

The excretion and metabolism of oral 14C-pyridostigmine in the rat

PubMed Central

Husain, M. A.; Roberts, J. B.; Thomas, B. H.; Wilson, A.

1968-01-01

1. Pyridostigmine labelled with carbon-14 in the methyl group of the quaternary nitrogen has been used to investigate the excretion and metabolism of the drug after administration of single doses (500 μg) to the rat by stomach tube. 2. Pyridostigmine is slowly excreted in the urine; the maximum excretion occurs between 1-3 hr after administration. In 24 hr 42% of the dose is excreted in urine and 38.4% is present in faeces and intestinal contents. 3. The peak concentration of radioactivity in liver and blood occurs about 2 hr after administration. 4. About 75% of the radioactivity in urine is present as unchanged pyridostigmine, the remainder as metabolite. 5. The results are compared with those previously obtained after oral administration of neostigmine. 6. It is concluded that after oral administration the absorption of pyridostigmine is greater and the metabolism substantially less than that of neostigmine. PMID:5687596

Gastrointestinal uptake and distribution of copper in rainbow trout.

PubMed

Clearwater, S J; Baskin, S J; Wood, C M; McDonald, D G

2000-08-01

A single dose of radioactive copper ((64)Cu or new Cu) was infused into the stomach of rainbow trout (Oncorhynchus mykiss) to model dietary copper (Cu) uptake under conditions of a normal nutritional dose and optimum environmental temperature (16 degrees C, 0.117 microg Cu g(-)(1 )body mass). The distribution of new Cu to the gut and internal organs occurred in two phases: rapid uptake by the gut tissues (almost complete by 24 h post-infusion) followed by slower uptake by the internal organs. By 72 h, 60 % of the dose had been excreted, 19 % was still retained in the gut tissue, 10 % remained in the lumen and 12 % had been absorbed across the gut and partitioned amongst the internal organs. A reduction in water temperature of 10 degrees C (to 6 degrees C) significantly retarded components of new Cu distribution (movement of the bolus along the gut and excretion); nonetheless, by 72 h, the fraction absorbed by all the internal organs was similar to that at 16 degrees C. An increase in water temperature of 3 degrees C (to 19 degrees C) caused a pronounced increase in internal organ uptake by 24 h to approximately double the uptake occurring at 16 degrees C. The uptake of new Cu by the gut tissue had a low temperature coefficient (Q(10)<1) consistent with simple diffusion, while the temperature coefficient for transfer of new Cu from gut tissue to the internal organs was high (Q(10)>2), consistent with facilitated transport. Internally, the liver and gall bladder (including bile) were the target organs for dietary Cu partitioning since they were the only organs that concentrated new Cu from the plasma. Individual tissues differed in terms of the exchange of their background Cu pools with new Cu. The background Cu in the walls of the gastrointestinal tract (excluding stomach) exchanged 45-94 % with new Cu from the gut lumen, while tissues such as the stomach, gills, kidney, carcass and fat had 5-7 % exchangeable background Cu. The liver, heart, spleen, ovary, bile and plasma had only 0.2-0.8 % exchangeable background Cu. The gastrointestinal tissues appear to act as a homeostatic organ, regulating the absorption of nutritional (non-toxic) doses of Cu (0. 117 microg g(-)(1 )body mass day(-)(1)) by the internal organs. Within the dose range we used and at optimal temperature (16 degrees C), the new Cu content of the gut tissues fluctuated, but absorption of new Cu by the internal organs remained relatively constant. For example, predosing the fish with non-radioactive Cu caused new Cu absorption by the gut tissues to double and decreased new Cu excretion from 38 to 1.5 %, but had no effect on new Cu uptake by the internal organs. Feeding fish after application of the normal liquid dose of new Cu also had no effect on new Cu uptake by the internal organs, even though the presence of food in the digestive tract reduced the binding of new Cu to the gut tissues and assisted with the excretion of new Cu. The gut was therefore able to regulate new Cu internalization at this dosage. Higher new Cu doses (10, 100 and 1000 times the normal dose), however, evoked regurgitation and increased new Cu excretion within 4 h of application but did not elevate new Cu levels in gut tissue beyond a threshold of approximately 40 microg of new Cu. Only at the highest dose (1000 times the normal dose, 192 microg g(-)(1 )body mass), equivalent to toxic concentrations in the daily diet (7000 microg Cu g(-)(1 )dry mass food), was the buffering capacity of the gut overwhelmed, resulting in an increase in internal new Cu uptake.

The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients.

PubMed

Malingré, M M; Schellens, J H; Van Tellingen, O; Ouwehand, M; Bardelmeijer, H A; Rosing, H; Koopman, F J; Schot, M E; Ten Bokkel Huinink, W W; Beijnen, J H

2001-11-16

The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m(-2) dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m(-2), for the other three 15 ml m(-2). Prior to paclitaxel administration patients received 15 mg kg(-1) oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C(max)) and area under the concentration-time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m(-2), paclitaxel C(max) and AUC values were 0.10 +/- 0.06 microM and 1.29 +/- 0.99 microM h(-1), respectively, whereas these values were 0.31 +/- 0.06 microM and 2.61 +/- 1.54 microM h(-1), respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m(-2), paclitaxel excretion in faeces was 38.8 +/- 13.0% of the administered dose, whereas this value was 18.3 +/-15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel

Protective Effects of Tinospora cordifolia on Hepatic and Gastrointestinal Toxicity Induced by Chronic and Moderate Alcoholism.

PubMed

Sharma, Bhawana; Dabur, Rajesh

2016-01-01

Heavy alcohol intake depletes the plasma vitamins due to hepatotoxicity and decreased intestinal absorption. However, moderate alcohol intake is often thought to be healthy. Therefore, effects of chronic moderate alcohol intake on liver and intestine were studied using urinary vitamin levels. Furthermore, effects of Tinospora cordifolia water extract (TCE) (hepatoprotective) on vitamin excretion and intestinal absorption were also studied. In the study, asymptomatic moderate alcoholics (n = 12) without chronic liver disease and healthy volunteers (n = 14) of mean age 39 ± 2.2 (mean ± SD) were selected and divided into three groups. TCE treatment was performed for 14 days. The blood and urine samples were collected on Day 0 and 14 after treatment with TCE and analyzed. In alcoholics samples, a significant increase in the levels of gamma-glutamyl transferase, aspartate transaminase, alanine transaminase, Triglyceride, Cholesterol, HDL and LDL (P < 0.05) was observed but their level get downregulated after TCE intervention. Multivariate analysis of metabolites without missing values showed an increased excretion of 7-dehydrocholesterol, orotic acid, pyridoxine, lipoamide and niacin and TCE intervention depleted their levels (P < 0.05). In contrast, excretion of biotin, xanthine, vitamin D2 and 2-O-p-coumaroyltartronic acid (CA, an internal marker of intestinal absorption) were observed to be decreased in alcoholic samples; however, TCE intervention restored the CA and biotin levels. Vitamin metabolism biomarkers, i.e. homocysteine and xanthurenic acid, were also normalized after TCE intervention. Overall data depict that moderate alcohol intake is also hepatotoxic and decreases intestinal absorption. However, TCE treatment effectively increased the intestinal absorption and retaining power of liver that regulated alcohol-induced multivitamin deficiency. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Predicting transporter-mediated drug interactions: Commentary on: "Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin and rosuvastatin" and "Validation of a microdose probe drug cocktail for clinical drug interaction assessments for drug transporters and CYP3A".

PubMed

Zhang, L; Sparreboom, A

2017-04-01

Transporters, expressed in various tissues, govern the absorption, distribution, metabolism, and excretion of drugs, and consequently their inherent safety and efficacy profiles. Drugs may interact with a transporter as a substrate and/or an inhibitor. Understanding transporter-mediated drug-drug interactions (DDIs), in addition to enzyme-mediated DDIs, is an integral part of risk assessment in drug development and regulatory review because the concomitant use of more than one medication in patients is common. © 2016 ASCPT.

Translating Pharmacokinetic and Pharmacodynamic Data into Practice.

PubMed

Visser, Marike

2018-05-01

Pharmacokinetic (PK) and pharmacodynamic (PD) publications provide scientific evidence for incorporation in evidence-based veterinary medicine, aiding the clinician in selecting doses and dosing intervals. PK and PD studies have reported wide variations within exotic species, due to physiologic differences in absorption, distribution, metabolism, and excretion. PK studies offer species-specific data to help tailor doses and dosing routes to individual patients, minimize toxicity, and provide a cornerstone for PD studies to determine drug efficacy. This article reviews the application of PK parameters and the challenges in determining the PD activity of drugs, with a particular emphasis on exotic species. Copyright © 2018 Elsevier Inc. All rights reserved.

[Drugs in pregnancy].

PubMed

Danchev, N; Astrug, A; Tsankova, V; Nikolova, I

2006-01-01

The use of drugs in pregnancy is being discussed. The influence of different factors, both physiological and drug related (physicochemical characteristics, dose, duration of pharmacotherapy) on the processes of absorption, distribution, protein binding, metabolism and excretion are reviewed. The up-to-date classification of the drugs in relation to their effects on the fetus is presented. Special emphasize is given to drugs (antibiotics, cardio-vascular, psychotropic etc.) used for the treatment of acute and chronic conditions in the course of pregnancy. Drugs used for symptoms like pain, high temperature and constipation are also reviewed. Recommendations for the use of safer drugs in pregnancy are given. Drugs with proven teratogenic effects are presented.

Absorption, distribution and excretion of inhaled hydrogen fluoride in the rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morris, J.B.

1979-01-01

Rats were subjected to whole body HF exposure for 6 hrs or to nose-only HF exposure for 1 hr. Total and/or ionic fluoride concentrations in selected tissues were determined at various times following exposure. In rats sacrificed 6 hrs after whole body exposure, dose-dependent increases in lung, plasma, and kidney total and ionic fluoride concentration occurred. Rats excreted more fluoride in the urine after whole body exposure than could be explained by the amount of HF inhaled. Considerable evidence suggests that airborne HF deposits on fur and is then ingested due to preening activity. Urinary fluoride excretion was increased bymore » nose-only exposure. The urinary fluoride excretion accounted for approximately twice the fluoride estimated to be inhaled during exposure. Tissue fluoride concentrations were elevated immediately after nose-only exposure. Fluoride concentrations in lung and kidney returned to control levels within 12 hrs. Plasma fluoride concentration was slightly elevated 24 hrs after the start of the 1 hr exposure but was at control levels at 96 hrs. Immediately following nose-only exposure, lung ionic fluoride concentrations were less than plasma ionic fluoride concentrations suggesting that the fluoride in the lung had reached that site via plasma transport rather than by inhalation. A dose-dependent increase in plasma ionic fluoride concentration occurred after upper respiratory tract HF exposure providing strong evidence that fluoride is absorbed systemically from that site. The plasma ionic fluoride concentration after upper respiratory tract exposure was of sufficient magnitude to account for the plasma fluoride concentrations observed in intact nose-only exposed rats. (ERB)« less

Magnesium metabolism in 4-year-old to 8-year-old children

USDA-ARS?s Scientific Manuscript database

Magnesium (Mg) is a key factor in bone health, but few studies have evaluated Mg intake or absorption and their relationship with bone mineral content (BMC) or bone mineral density (BMD) in children. We measured Mg intake, absorption, and urinary excretion in a group of children 4 to 8 years of age....

Ultrastructure and immunolocalization of digestive enzymes in the midgut of Podisus nigrispinus (Heteroptera: Pentatomidae).

PubMed

Fialho, Maria do Carmo Q; Terra, Walter R; Moreira, Nathália R; Zanuncio, José C; Serrão, Jose Eduardo

2013-07-01

The predatory stinkbug Podisus nigrispinus has been utilized in biological control programs. Its midgut is anatomically divided into anterior, middle and posterior regions, which play different roles in the digestive process. We describe the midgut ultrastructure and the secretion of digestive enzymes in the midgut of P. nigrispinus. Midguts were analyzed with transmission electron microscopy and the digestive enzymes amylase, cathepsin L, aminopeptidase and α-glucosidase were immunolocalized. The ultrastructural features of the digestive cells in the anterior, middle and posterior midgut regions suggest that they play a role in digestive enzyme synthesis, ion and nutrient absorption, storage and excretion. The digestive enzymes have different distribution along the midgut regions of the predator P. nigrispinus. Amylase, aminopeptidase and α-glucosidase occur in three midgut regions, whereas cathepsin L occurs in the middle and posterior midgut regions. The anterior midgut region of P. nigrispinus seems to play a role in water absorption, the middle midgut may be involved in nutrient absorption and the posterior midgut region is responsible for water transport to the midgut lumen. Copyright © 2013 Elsevier Ltd. All rights reserved.

Genomic study of the absorption mechanism of p-coumaric acid and caffeic acid of extract of Ananas comosus L. leaves.

PubMed

Dang, Yun-jie; Zhu, Chun-yan

2015-03-01

Cardiac disease has emerged as the leading cause of death worldwide, and food rich in phenolic acids has drawn much attention as sources of active substances of hypolipidemic drug. Ananas comosus L. (pineapple) is one of the most popular tropical and subtropical fruits. Isolated from pineapple leaves, EAL(Extract of Ananas Comosus L. Leaves) is rich in phenolic acids, such as p-coumaric acid, caffeic acid, and other phenolics, highly relevant to the putative cardiovascular-protective effects, which suggests its potential to be a new plant medicine for treatment of cardiac disease, but little is known about absorption, distribution, metabolism, and excretion of EAL in animals or human beings. In this study, we employed cDNA microarray, Caco-2 cell lines, and rat intestinal model to explore the absorption behavior of p-coumaric acid and caffeic acid in EAL. The permeation of 2 substances was concentration and time dependent. Results also indicated that monocarboxylic acid transporter was involved in the transepithelial transport of p-coumaric acid and caffeic acid. © 2015 Institute of Food Technologists®

Renal Control of Calcium, Phosphate, and Magnesium Homeostasis

PubMed Central

Chonchol, Michel; Levi, Moshe

2015-01-01

Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys. PMID:25287933

Effect of urinary pH and nicotine excretion rate on plasma nicotine during cigarette smoking and chewing nicotine gum

PubMed Central

Feyerabend, C.; Russell, M. A. H.

1978-01-01

1 Plasma nicotine levels produced by chewing nicotine gum were compared with those obtained by cigarette smoking under conditions of controlled urinary pH. 2 Although absorption was slower, plasma levels comparable to cigarette smoking were built up on 4 mg (but not 2 mg) nicotine gum. 3 Urinary excretion of nicotine was influenced markedly by pH and the rate of urine flow. 4 Plasma nicotine was higher under alkaline compared to acidic conditions (P < 0.001) but the rate of urinary nicotine excretion appeared to have little effect on the plasma level.

Effects of habitual chitosan intake on bone mass, bone-related metabolic markers and duodenum CaBP D9K mRNA in ovariectomized SHRSP rats.

PubMed

Yang, Chu-Ya; Oh, Tae-Woong; Nakajima, Daito; Maeda, Atsuko; Naka, Tatsuki; Kim, Chang-Sun; Igawa, Shoji; Ohta, Fukio

2002-10-01

We have demonstrated that the habitual intake of chitosan can decrease bone mass in ovariectomized (OVX) SHRSP rats fed a low-Ca diet (0.1%). In the present study, we examined both the etiology of bone loss induced by dietary chitosan and the preventive effect of vitamin C supplementation. Rats were OVX and maintained on one of the following diets for 6 wk: 10% cellulose (CE). 10% chitosan (CH) or 10% chitosan with sodium ascorbate (CHVC). CH caused a significant reduction in bone mineral density (BMD) and stiffness in femurs and the fourth lumbar vertebrae (L4). There was no significant difference in intestinal Ca absorption between CH and CE, whereas CH intake significantly reduced intestinal P absorption. The bone loss in CH rats was accompanied with an increase in urinary Ca excretion and a decrease in serum Ca as well as a significant increment In serum PTH and 1,25(OH)2D3. The vitamin D receptor and calcium binding protein D9K mRNAs were also significantly increased in the duodenum of CH rats. Vitamin C supplementation to CH caused an increase in the Ca and P contents of femurs as well as BMD of the L4, with a decrease in urinary Ca excretion. These results indicate that dietary chitosan with low Ca intake possibly induces the loss of bone mass by enhancing urinary Ca excretion rather than by inhibiting Ca absorption, and that vitamin C supplementation could prevent bone loss caused by chitosan through the increment of retained Ca followed by suppression of urinary Ca excretion.

Effect of chronic lead intoxication on the distribution and elimination of amoxicillin in goats

PubMed Central

Soliman, Ahmed M.; Abu-Basha, Ehab A.; Youssef, Salah A. H.; Amer, Aziza M.; Murphy, Patricia A.; Hauck, Catherine C.; Gehring, Ronette

2013-01-01

A study of amoxicillin pharmacokinetics was conducted in healthy goats and goats with chronic lead intoxication. The intoxicated goats had increased serum concentrations of liver enzymes (alanine aminotransferase and γ-glutamyl transferase), blood urea nitrogen, and reactivated δ-aminolevulinic acid dehydratase compared to the controls. Following intravenous amoxicillin (10 mg/kg bw) in control and lead-intoxicated goats, elimination half-lives were 4.14 and 1.26 h, respectively. The volumes of distribution based on the terminal phase were 1.19 and 0.38 L/kg, respectively, and those at steady-state were 0.54 and 0.18 L/kg, respectively. After intramuscular (IM) amoxicillin (10 mg/kg bw) in lead-intoxicated goats and control animals, the absorption, distribution, and elimination of the drug were more rapid in lead-intoxicated goats than the controls. Peak serum concentrations of 21.89 and 12.19 µg/mL were achieved at 1 h and 2 h, respectively, in lead-intoxicated and control goats. Amoxicillin bioavailability in the lead-intoxicated goats decreased 20% compared to the controls. After amoxicillin, more of the drug was excreted in the urine from lead-intoxicated goats than the controls. Our results suggested that lead intoxication in goats increases the rate of amoxicillin absorption after IM administration and distribution and elimination. Thus, lead intoxication may impair the therapeutic effectiveness of amoxicillin. PMID:23820209

Effect of chronic lead intoxication on the distribution and elimination of amoxicillin in goats.

PubMed

Soliman, Ahmed M; Abu-Basha, Ehab A; Youssef, Salah A H; Amer, Aziza M; Murphy, Patricia A; Hauck, Catherine C; Gehring, Ronette; Hsu, Walter H

2013-01-01

A study of amoxicillin pharmacokinetics was conducted in healthy goats and goats with chronic lead intoxication. The intoxicated goats had increased serum concentrations of liver enzymes (alanine aminotransferase and γ-glutamyl transferase), blood urea nitrogen, and reactivated δ-aminolevulinic acid dehydratase compared to the controls. Following intravenous amoxicillin (10 mg/kg bw) in control and lead-intoxicated goats, elimination half-lives were 4.14 and 1.26 h, respectively. The volumes of distribution based on the terminal phase were 1.19 and 0.38 L/kg, respectively, and those at steady-state were 0.54 and 0.18 L/kg, respectively. After intramuscular (IM) amoxicillin (10 mg/kg bw) in lead-intoxicated goats and control animals, the absorption, distribution, and elimination of the drug were more rapid in lead-intoxicated goats than the controls. Peak serum concentrations of 21.89 and 12.19 μg/mL were achieved at 1 h and 2 h, respectively, in lead-intoxicated and control goats. Amoxicillin bioavailability in the lead-intoxicated goats decreased 20% compared to the controls. After amoxicillin, more of the drug was excreted in the urine from lead-intoxicated goats than the controls. Our results suggested that lead intoxication in goats increases the rate of amoxicillin absorption after IM administration and distribution and elimination. Thus, lead intoxication may impair the therapeutic effectiveness of amoxicillin.

Drug-like properties and the causes of poor solubility and poor permeability.

PubMed

Lipinski, C A

2000-01-01

There are currently about 10000 drug-like compounds. These are sparsely, rather than uniformly, distributed through chemistry space. True diversity does not exist in experimental combinatorial chemistry screening libraries. Absorption, distribution, metabolism, and excretion (ADME) and chemical reactivity-related toxicity is low, while biological receptor activity is higher dimensional in chemistry space, and this is partly explainable by evolutionary pressures on ADME to deal with endobiotics and exobiotics. ADME is hard to predict for large data sets because current ADME experimental screens are multi-mechanisms, and predictions get worse as more data accumulates. Currently, screening for biological receptor activity precedes or is concurrent with screening for properties related to "drugability." In the future, "drugability" screening may precede biological receptor activity screening. The level of permeability or solubility needed for oral absorption is related to potency. The relative importance of poor solubility and poor permeability towards the problem of poor oral absorption depends on the research approach used for lead generation. A "rational drug design" approach as exemplified by Merck advanced clinical candidates leads to time-dependent higher molecular weight, higher H-bonding properties, unchanged lipophilicity, and, hence, poorer permeability. A high throughput screening (HTS)-based approach as exemplified by unpublished data on Pfizer (Groton, CT) early candidates leads to higher molecular weight, unchanged H-bonding properties, higher lipophilicity, and, hence, poorer aqueous solubility.

Colonic catabolism of dietary phenolic and polyphenolic compounds from Concord grape juice.

PubMed

Stalmach, Angelique; Edwards, Christine A; Wightman, Jolynne D; Crozier, Alan

2013-01-01

After acute ingestion of 350 ml of Concord grape juice, containing 528 μmol of (poly)phenolic compounds, by healthy volunteers, a wide array of phase I and II metabolites were detected in the circulation and excreted in urine. Ingestion of the juice by ileostomists resulted in 40% of compounds being recovered intact in ileal effluent. The current study investigated the fate of these undigested (poly)phenolic compounds on reaching the colon. This was achieved through incubation of the juice using an in vitro model of colonic fermentation and through quantification of catabolites produced after colonic degradation and their subsequent absorption prior to urinary excretion by healthy subjects and ileostomy volunteers. A total of 16 aromatic and phenolic compounds derived from colonic metabolism of Concord grape juice (poly)phenolic compounds were identified by GC-MS in the faecal incubation samples. Thirteen urinary phenolic acids and aromatic compounds were excreted in significantly increased amounts after intake of the juice by healthy volunteers, whereas only two of these compounds were excreted in elevated amounts by ileostomists. The production of phenolic acids and aromatic compounds by colonic catabolism contributed to the bioavailability of Concord grape (poly)phenolic compounds to a much greater extent than phase I and II metabolites originating from absorption in the upper gastrointestinal tract. Catabolic pathways are proposed, highlighting the impact of colonic microbiota and subsequent phase II metabolism prior to excretion of phenolic compounds derived from (poly)phenolic compounds in Concord grape juice, which pass from the small to the large intestine.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Boyd, G.S.; Merrick, M.V.; Monks, R.

Four selenium-labeled free bile acids and four selenium-labeled conjugated bile acids, labeled with Se-75 at the C-19, C-22, C-23, or C-24 position, have been synthesized and their absorption and excretion compared with that of (24-/sup 14/C)cholic acid, following both oral and intravenous administration. All but one of the compounds is absorbed and excreted in bile to a significant extent. One compound, SeHCAT, has been selected for particular study. It is quantitatively absorbed from the gut at the same rate as cholic acid, and both are excreted into the bile at the same rate. It remains almost entirely confined to themore » enterohepatic circulation (the gut, liver, and biliary tree) and excretion is exclusively fecal. Such a compound offers the possibility of a simple, novel, and aesthetically acceptalbe method investigating small-bowel disease.« less

A Study of the Skin Absorption of Ethylbenzene in Man

PubMed Central

Dutkiewicz, Tadeusz; Tyras, Halina

1967-01-01

The absorption of ethylbenzene through the skin of the hand and the forearm in men was investigated experimentally. Both the absorption of liquid ethylbenzene and the absorption from aqueous solutions were studied. The rate of absorption of liquid ethylbenzene was 22 to 33 mg./cm.2/hr, and the rates from aqueous solutions were 118 and 215 μg./cm.2/hr from mean concentrations of 112 and 156 mg./litre. The mandelic acid excreted in urine was equivalent to about 4·6% of the absorbed dose—much less than after lung absorption. Urinary mandelic acid does not provide a reliable index of absorption when there is simultaneous skin and lung exposure. PMID:6073092

Renal control of calcium, phosphate, and magnesium homeostasis.

PubMed

Blaine, Judith; Chonchol, Michel; Levi, Moshe

2015-07-07

Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys. Copyright © 2015 by the American Society of Nephrology.

Urinary thioether of employees of a chemical plant.

PubMed

Vainio, H; Savolainen, H; Kilpikari, I

1978-08-01

The thiols in the morning urine of 224 employees of a chemical plant were determined after alkaline hydrolysis of all urinary thioethers. The highest thioether excretion was found in rubber workers and radial tyre builders in comparison with clerks, plastic monomer mixers and footwear preparers. Smoking and medication tended to increase thioether excretion. Urinary thioether determination may prove to be a valuable tool in assessing exposure to mixtures of chemicals regardless of the route of absorption.

Urinary thioether of employees of a chemical plant.

PubMed Central

Vainio, H; Savolainen, H; Kilpikari, I

1978-01-01

The thiols in the morning urine of 224 employees of a chemical plant were determined after alkaline hydrolysis of all urinary thioethers. The highest thioether excretion was found in rubber workers and radial tyre builders in comparison with clerks, plastic monomer mixers and footwear preparers. Smoking and medication tended to increase thioether excretion. Urinary thioether determination may prove to be a valuable tool in assessing exposure to mixtures of chemicals regardless of the route of absorption. PMID:698138

Physiological and molecular ontogeny of branchial and extra-branchial urea excretion in posthatch rainbow trout (Oncorhynchus mykiss)

PubMed Central

Wood, Chris M.

2015-01-01

All teleost fish produce ammonia as a metabolic waste product. In embryos, ammonia excretion is limited by the chorion, and fish must detoxify ammonia by synthesizing urea via the ornithine urea cycle (OUC). Although urea is produced by embryos and larvae, urea excretion (Jurea) is typically low until yolk sac absorption, increasing thereafter. The aim of this study was to determine the physiological and molecular characteristics of Jurea by posthatch rainbow trout (Oncorhynchus mykiss). Following hatch, whole body urea concentration decreased over time, while Jurea increased following yolk sac absorption. From 12 to 40 days posthatch (dph), extra-branchial routes of excretion accounted for the majority of Jurea, while the gills became the dominant site for Jurea only after 55 dph. This represents the most delayed branchial ontogeny of any process studied to date. Urea transporter (UT) gene expression in the gills and skin increased over development, consistent with increases in branchial and extra-branchial Jurea. Following exposure to 25 mmol/l urea, the accumulation and subsequent elimination of exogenous urea was much greater at 55 dph than 12 dph, consistent with increased UT expression. Notably, UT gene expression in the gills of 55 dph larvae increased in response to high urea. In summary, there is a clear increase in urea transport capacity over posthatch development, despite a decrease in OUC activity. PMID:26608657

Vasopressin regulates renal calcium excretion in humans

PubMed Central

Hanouna, Guillaume; Haymann, Jean-Philippe; Baud, Laurent; Letavernier, Emmanuel

2015-01-01

Antidiuretic hormone or arginine vasopressin (AVP) increases water reabsorption in the collecting ducts of the kidney. Three decades ago, experimental models have shown that AVP may increase calcium reabsorption in rat kidney. The objective of this study was to assess whether AVP modulates renal calcium excretion in humans. We analyzed calcium, potassium, and sodium fractional excretion in eight patients affected by insipidus diabetes (nephrogenic or central) under acute vasopressin receptor agonist action and in 10 patients undergoing oral water load test affected or not by inappropriate antidiuretic hormone secretion (SIADH). Synthetic V2 receptor agonist (dDAVP) reduced significantly calcium fractional excretion from 1.71% to 0.58% (P < 0.05) in patients with central diabetes insipidus. In patients with nephrogenic diabetes insipidus (resistant to AVP), calcium fractional excretion did not change significantly after injection (0.48–0.68%, P = NS). In normal subjects undergoing oral water load test, calcium fractional excretion increased significantly from 1.02% to 2.54% (P < 0.05). Patients affected by SIADH had a high calcium fractional excretion at baseline that remained stable during test from 3.30% to 3.33% (P = NS), possibly resulting from a reduced calcium absorption in renal proximal tubule. In both groups, there was a significant correlation between urine output and calcium renal excretion. In humans, dDAVP decreases calcium fractional excretion in the short term. Conversely, water intake, which lowers AVP concentration, increases calcium fractional excretion. The correlation between urine output and calcium excretion suggests that AVP-related antidiuresis increases calcium reabsorption in collecting ducts. PMID:26620256

Risk of Therapeutic Failure due to Ineffectiveness of Medication

NASA Technical Reports Server (NTRS)

Woring, Virginia E.

2011-01-01

Given that terrestrial medical practices must be used as the basis for drug choice and use on missions, there is a possibility that medications used will be ineffective or inappropriate for the actual circumstances encountered on missions. Because the human body undergoes a variety of physiological changes during spaceflight, there is a risk that terrestrial medications may not perform as expected when used during spaceflight. Alterations in physiology due to spaceflight could result in unexpected drug action on the body (pharmacodynamics) or in unusual drug absorption, distribution, metabolism or excretion (pharmacokinetics). The spaceflight environment may also have direct effects on stored drugs themselves, leading to premature inactivation or degradation of stored drugs.

Urinary isoflavone excretion as a compliance measure in a soy intervention among young girls: a pilot study

PubMed Central

Maskarinec, G; Oshiro, C; Morimoto, Y; Hebshi, S; Novotny, R; Franke, AA

2006-01-01

Objective To investigate the compliance of young girls with a soy intervention. Design An 8-week dietary intervention and urine sample collection. Setting Free-living girls. Subjects A convenience sample of 8-to 14-y-old girls (20 started and 17 finished the study) recruited through flyers distributed to staff members and previous study participants. Intervention The girls consumed one daily serving of soymilk, soy nuts, or tofu, completed 3-day food records, kept daily soy intake logs, and collected weekly urine samples. Main outcome measures Compliance with the intervention was evaluated by daily soy intake logs, 3-day food records analyzed by the center’s Food Composition and Food Groups Servings Databases, and weekly urinary isoflavone excretion using high-pressure liquid chromatography. The statistical analysis included paired t-tests, analysis of variance, and Spearman’s rank-order correlation coefficients. Results Daily soy intake logs indicated a mean intake of 6.28 servings out of a maximum of 7.0 servings per week. The food records revealed a six-fold increase in isoflavone intake during the study period (P < 0.01) which was confirmed by an increase in urinary isoflavone excretion of similar magnitude (23.3–142.1 nmol/mg creatinine, P = 0.02). Conclusions This study demonstrated the ability of young girls to consume one daily soy serving and the usefulness of urinary isoflavones as a primary compliance measure. The high urinary isoflavone excretion levels detected in girls as compared to adult women suggest less intestinal degradation and/or greater absorption of isoflavones in nonadult populations. This finding requires further investigations into the pharmacokinetics of isoflavones. PMID:15523482

A novel double-tracer technique to characterize absorption, distribution, metabolism and excretion (ADME) of [14C]tofogliflozin after oral administration and concomitant intravenous microdose administration of [13C]tofogliflozin in humans.

PubMed

Schwab, Dietmar; Portron, Agnes; Backholer, Zoe; Lausecker, Berthold; Kawashima, Kosuke

2013-06-01

Human mass balance studies and the assessment of absolute oral bioavailability (F) are usually assessed in separate studies. Intravenous microdose administration of an isotope tracer concomitant to an unlabeled oral dose is an emerging technique to assess F. We report a novel double-tracer approach implemented for tofogliflozin combining oral administration of a radiolabel tracer with concomitant intravenous administration of a stable isotope tracer. Tofogliflozin is a potent and selective sodium/glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus currently in clinical development. The objectives of the present study were to assess the systemic exposure of major circulating metabolites, excretion balance, F and contribution of renal clearance (CLR) to total clearance (CL) of tofogliflozin in healthy subjects within one study applying a novel double-tracer technique. Six healthy male subjects received 20 mg [(12)C/(14)C]tofogliflozin (3.73 MBq) orally and a concomitant microdose of 0.1 mg [(13)C]tofogliflozin intravenously. Pharmacokinetics of tofogliflozin were determined for the oral and intravenous route; the pharmacokinetics of the metabolites M1 and M5 were determined for the oral route. Quantification of [(12)C]tofogliflozin in plasma and urine and [(13)C]tofogliflozin in plasma was performed by selective LC-MS/MS methods. For the pre-selected metabolites of tofogliflozin, M1 and M5, a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) was applied to plasma and urine samples. Total radioactivity was assessed in plasma, urine and feces. Pharmacokinetic analysis was conducted by non-compartmental methods. The pharmacokinetics of tofogliflozin in healthy subjects were characterized by an F of 97.5 ± 12.3 %, CL of 10.0 ± 1.3 l/h and volume of distribution at steady-state (V(ss)) of 50.6 ± 6.7 l. The main route of elimination of total drug-related material was by excretion into urine (77.0 ± 4.1 % of the dose). The observed CL(R) of 25.7 ± 5.0 ml/min was higher than the product of the estimated glomerular filtration rate (eGFR) and fraction unbound in plasma (f(u)) (eGFR × f(u) 15 ml/min), indicating the presence of net active tubular secretion in the renal elimination of tofogliflozin. However, CLR contributed only 15.5 % to the CL of tofogliflozin, suggesting that reductions in CLR by renal impairment won't significantly affect systemic exposure to tofogliflozin. Tofogliflozin and its metabolite M1 were the only major circulating entities accounting for 46 ± 8.6 and 50 ± 8.2 %, respectively, of total circulating drug-related material, while the metabolite M5 was a minor circulating metabolite accounting for 3.0 ± 0.3 % of total circulating drug-related material. Both the M1 and M5 metabolites were excreted into urine and the major metabolite M1 did not exhibit active tubular secretion. These results demonstrate the utility of the double-tracer approach to provide essential pharmacokinetic data and excretion data for drug-related material in one study at the same dosing occasion. The data obtained allowed the characterization of absorption, distribution, metabolism and excretion of tofogliflozin. Tofogliflozin exhibited highly favorable pharmacokinetic properties as demonstrated by its high F, low CL and a low V(ss. The presence of only one major circulating metabolite of tofogliflozin was unambiguously demonstrated. As a drug targeting the kidney, luminal exposure of the kidney is achieved by renal filtration and active tubular secretion.

The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients

PubMed Central

Malingré, M M; Schellens, J H M; Tellingen, O Van; Ouwehand, M; Bardelmeijer, H A; Rosing, H; Koopman, F J; Schot, M E; Huinink, W W Ten Bokkel; Beijnen, J H

2001-01-01

The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m−2 dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m−2, for the other three 15 ml m−2. Prior to paclitaxel administration patients received 15 mg kg−1 oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C max) and area under the concentration–time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m−2, paclitaxel C max and AUC values were 0.10 ± 0.06 μM and 1.29 ± 0.99 μM h−1, respectively, whereas these values were 0.31 ± 0.06 μM and 2.61 ± 1.54 μM h−1, respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m−2, paclitaxel excretion in faeces was 38.8 ± 13.0% of the administered dose, whereas this value was 18.3 ±15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel © 2001 Cancer Research Campaign   http://www.bjcancer.com PMID:11720431

A novel formulation of veggies with potent liver detoxifying activity.

PubMed

Jain, Mohit M; Kumari, Nirmala; Rai, Geeta

2015-01-01

LXR (encoded by NR1H2 and 3) and FXR (known as bile acid receptor) encoded by NR1H4 (nuclear receptor subfamily 1, group H and member 4) are nuclear receptors in humans and are important regulators of bile acid production, cholesterol, fatty acid and glucose homeostasis hence responsible for liver detoxification. Several strategies for drug design with numerous ligands for this target have failed owing to the inability of the ligand to access the target/receptor or their early metabolisation. In this work, we have evaluated FXR and LXR structure bound with agonist and compared the binding energy affinity of active ligands present in live green-real veggies with reference drugs (ligands) present in the market. A high throughput screening combined with molecular docking, absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions, log P values and percentage of human oral absorption value led to the identification of two compounds present in live green-real veggies with strong potential for liver detoxification.

Membrane transporters in drug development

PubMed Central

2011-01-01

Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In addition, what criteria should trigger follow-up clinical studies, and which clinical studies should be conducted if needed. In this article, we provide the recommendations of the International Transporter Consortium on these issues, and present decision trees that are intended to help guide clinical studies on the currently recognized most important drug transporter interactions. The recommendations are generally intended to support clinical development and filing of a new drug application. Overall, it is advised that the timing of transporter investigations should be driven by efficacy, safety and clinical trial enrolment questions (for example, exclusion and inclusion criteria), as well as a need for further understanding of the absorption, distribution, metabolism and excretion properties of the drug molecule, and information required for drug labeling. PMID:20190787

Estimating the population distribution of usual 24-hour sodium excretion from timed urine void specimens using a statistical approach accounting for correlated measurement errors.

PubMed

Wang, Chia-Yih; Carriquiry, Alicia L; Chen, Te-Ching; Loria, Catherine M; Pfeiffer, Christine M; Liu, Kiang; Sempos, Christopher T; Perrine, Cria G; Cogswell, Mary E

2015-05-01

High US sodium intake and national reduction efforts necessitate developing a feasible and valid monitoring method across the distribution of low-to-high sodium intake. We examined a statistical approach using timed urine voids to estimate the population distribution of usual 24-h sodium excretion. A sample of 407 adults, aged 18-39 y (54% female, 48% black), collected each void in a separate container for 24 h; 133 repeated the procedure 4-11 d later. Four timed voids (morning, afternoon, evening, overnight) were selected from each 24-h collection. We developed gender-specific equations to calibrate total sodium excreted in each of the one-void (e.g., morning) and combined two-void (e.g., morning + afternoon) urines to 24-h sodium excretion. The calibrated sodium excretions were used to estimate the population distribution of usual 24-h sodium excretion. Participants were then randomly assigned to modeling (n = 160) or validation (n = 247) groups to examine the bias in estimated population percentiles. Median bias in predicting selected percentiles (5th, 25th, 50th, 75th, 95th) of usual 24-h sodium excretion with one-void urines ranged from -367 to 284 mg (-7.7 to 12.2% of the observed usual excretions) for men and -604 to 486 mg (-14.6 to 23.7%) for women, and with two-void urines from -338 to 263 mg (-6.9 to 10.4%) and -166 to 153 mg (-4.1 to 8.1%), respectively. Four of the 6 two-void urine combinations produced no significant bias in predicting selected percentiles. Our approach to estimate the population usual 24-h sodium excretion, which uses calibrated timed-void sodium to account for day-to-day variation and covariance between measurement errors, produced percentile estimates with relatively low biases across low-to-high sodium excretions. This may provide a low-burden, low-cost alternative to 24-h collections in monitoring population sodium intake among healthy young adults and merits further investigation in other population subgroups. © 2015 American Society for Nutrition.

MTBE inhaled alone and in combination with gasoline vapor: uptake, distribution, metabolism, and excretion in rats.

PubMed

Benson, J M; Barr, E B; Krone, J R

2001-05-01

The purpose of these studies was to extend previous evaluation of methyl tert-butyl ether (MTBE)* tissue distribution, metabolism, and excretion in rats to include concentrations more relevant to human exposure (4 and 40 ppm) and to determine the effects of coinhalation of the volatile fraction of unleaded gasoline on the tissue distribution, metabolism, and excretion of MTBE. Groups of male F344 rats were exposed nose-only for 4 hours to 4, 40, or 400 ppm 14C-MTBE or to 20 or 200 ppm of the light fraction of unleaded gasoline (LFG) containing 4 or 40 ppm 14C-MTBE, respectively. To evaluate the effects of repeated inhalation of LFG on MTBE tissue distribution, metabolism, and excretion, rats were exposed for 4 hours on each of 7 consecutive days to 20 or 200 ppm LFG with MTBE (4 or 40 ppm) followed on the eighth day by a similar exposure to LFG containing 14C-MTBE. Subgroups of rats were evaluated for respiratory parameters, initial body burdens, rates and routes of excretion, and tissue distribution and elimination. The concentrations of MTBE and its chief metabolite, tert-butyl alcohol (TBA), were measured in blood and kidney immediately after exposure, and the major urinary metabolites-2-hydroxyisobutyric acid (IBA) and 2-methyl-1,2-propanediol (2MePD)-were measured in urine. Inhalation of MTBE alone or as a component of LFG had no concentration-dependent effect on respiratory minute volume. The initial body burdens of MTBE equivalents achieved after 4 hours of exposure to MTBE did not increase linearly with exposure concentration. MTBE equivalents rapidly distributed to all tissues examined, with the largest percentages distributed to liver. The observed initial body burden did not increase linearly between 4 and 400 ppm. At 400 ppm, elimination half-times of MTBE equivalents from liver increased and from lung, kidney, and testes decreased compared with the two smaller doses. Furthermore, at 400 ppm the elimination half-time for volatile organic compounds (VOCs) in breath was significantly shorter and the percentage of the initial body burden of MTBE equivalents eliminated as VOCs in breath increased significantly. These changes probably reflect a saturation of blood with MTBE at 400 ppm and strongly suggest that the uptake and fate of MTBE are notably different at exposure concentrations above and below 400 ppm. Single and repeated coexposure to 20 and 200 ppm LFG with MTBE had opposite effects on the total body burden of MTBE equivalents present at the end of exposures compared with those achieved after 4 and 40 ppm MTBE exposures: 20 ppm LFG increased and 200 ppm LFG significantly decreased the burdens of MTBE equivalents present. The effects of coexposure to LFG on blood levels of MTBE equivalents paralleled the effects on body burden. These differences in overall uptake of MTBE equivalents cannot be attributed to alterations of minute volume. The reason for the increase in overall uptake after 20-ppm LFG exposure is not clear. Decreased MTBE absorption (uptake) after single and repeated coexposure to 200 ppm LFG may be due to a decrease in solubility of MTBE in blood caused by inhalation of other hydrocarbons. Investigations on the blood/air partition coefficient of MTBE in the absence and presence of LFG would be needed to confirm this hypothesis. Single and repeated coexposure to either 20 or 200 ppm LFG significantly decreased the percentage of the initial body burden from MTBE equivalents in tissues, including liver, kidney, and testes, immediately and 72 hours after

Impact of beta-cyclodextrin and resistant starch on bile acid metabolism and fecal steroid excretion in regard to their hypolipidemic action in hamsters.

PubMed

Trautwein, E A; Forgbert, K; Rieckhoff, D; Erbersdobler, H F

1999-01-29

To examine the impact on bile acid metabolism and fecal steroid excretion as a mechanism involved in the lipid-lowering action of beta-cyclodextrin and resistant starch in comparison to cholestyramine, male golden Syrian hamsters were fed 0% (control), 8% or 12% of beta-cyclodextrin or resistant starch or 1% cholestyramine. Resistant starch, beta-cyclodextrin and cholestyramine significantly lowered plasma total cholesterol and triacylglycerol concentrations compared to control. Distinct changes in the bile acid profile of gallbladder bile were caused by resistant starch, beta-cyclodextrin and cholestyramine. While cholestyramine significantly reduced chenodeoxycholate independently of its taurine-glycine conjugation, beta-cyclodextrin and resistant starch decreased especially the percentage of taurochenodeoxycholate by -75% and -44%, respectively. As a result, the cholate:chenodeoxycholate ratio was significantly increased by 100% with beta-cyclodextrin and by 550% with cholestyramine while resistant starch revealed no effect on this ratio. beta-Cyclodextrin and resistant starch, not cholestyramine, significantly increased the glycine:taurine conjugation ratio demonstrating the predominance of glycine conjugated bile acids. Daily fecal excretion of bile acids was 4-times higher with 8% beta-cyclodextrin and 19-times with 1% cholestyramine compared to control. beta-Cyclodextrin and cholestyramine also induced a 2-fold increase in fecal neutral sterol excretion, demonstrating the sterol binding capacity of these two compounds. Resistant starch had only a modest effect on fecal bile acid excretion (80% increase) and no effect on excretion of neutral sterols, suggesting a weak interaction with intestinal steroid absorption. These data demonstrate the lipid-lowering potential of beta-cyclodextrin and resistant starch. An impaired reabsorption of circulating bile acids and intestinal cholesterol absorption leading to an increase in fecal bile acid and neutral sterol excretion is most likely the primary mechanism responsible for the lipid-lowering action of beta-cyclodextrin. In contrast, other mechanisms involving the alterations in the biliary bile acid profile or repressed hepatic lipogenesis, e.g., VLDL production, appear to be involved in the hypolipidemic effect of resistant starch.

Diet, but not oral probiotics, effectively reduces urinary oxalate excretion and calcium oxalate supersaturation.

PubMed

Lieske, John C; Tremaine, William J; De Simone, Claudio; O'Connor, Helen M; Li, Xujian; Bergstralh, Eric J; Goldfarb, David S

2010-12-01

We examined the effect of a controlled diet and two probiotic preparations on urinary oxalate excretion, a risk factor for calcium oxalate kidney stone formation, in patients with mild hyperoxaluria. Patients were randomized to a placebo, a probiotic, or a synbiotic preparation. This tested whether these probiotic preparations can increase oxalate metabolism in the intestine and/or decrease oxalate absorption from the gut. Patients were maintained on a controlled diet to remove the confounding variable of differing oxalate intake from food. Urinary oxalate excretion and calcium oxalate supersaturation on the controlled diet were significantly lower compared with baseline on a free-choice diet. Neither study preparation reduced urinary oxalate excretion nor calcium oxalate supersaturation. Fecal lactobacilli colony counts increased on both preparations, whereas enterococcal and yeast colony counts were increased on the synbiotic. Total urine volume and the excretion of oxalate and calcium were all strong independent determinants of urinary calcium oxalate supersaturation. Hence, dietary oxalate restriction reduced urinary oxalate excretion, but the tested probiotics did not influence urinary oxalate levels in patients on a restricted oxalate diet. However, this study suggests that dietary oxalate restriction is useful for kidney stone prevention.

Analysis methods and recent advances in nonlinear pharmacokinetics from in vitro through in loci to in vivo.

PubMed

Yamaoka, Kiyoshi; Takakura, Yoshinobu

2004-12-01

An attempt has been made to review the nonlinearities in the disposition in vitro, in situ, in loci and in vivo mainly from a theoretical point of view. Parallel Michaelis-Menten and linear (first-order) eliminations are often observed in the cellular uptake, metabolism and efflux of drugs. The well-stirred and parallel-tube models are mainly adopted under steady-state conditions in perfusion experiments, whereas distribution, tank-in-series and dispersion models are often used under nonsteady-state conditions with a pulse input. The analysis of the nonlinear local disposition in loci is reviewed from two points of view, namely an indirect method involving physiologically based pharmacokinetics (PBPK) and a direct (two or three samplings) method using live animals. The nonlinear global pharmacokinetics in vivo is reviewed with regard to absorption, elimination (metabolism and excretion) and distribution.

The tissue distribution and excretion study of paeoniflorin-6'-O-benzene sulfonate (CP-25) in rats.

PubMed

Zhao, Mingyi; Zhou, Peng; Yu, Jun; James, Asenso; Xiao, Feng; Wang, Chun; Wei, Wei

2018-03-09

Paeoniflorin-6'-O-benzene sulfonate (code: CP-25) is a novel ester derivative of paeoniflorin (Pae). Compared to Pae, CP-25 has higher lipid solubility, bioavailability and better bioactivity. However, the tissue distribution and excretion of CP-25 still remain unknown. The LC-MS method was applied to investigate the tissue distribution and excretion of CP-25 in rats. As such, 50 mg/kg of CP-25 and Pae were administered to rats in multiple doses via an oral route. CP-25 and Pae were distributed widely and rapidly in all the tested tissues. Compared with Pae, the concentrations of CP-25 were almost increased evidently in most tissues. The highest CP-25 level was found in the liver (1476.33 ± 535.20 ng/g, male; 1970.38 ± 177.21 ng/g, female) at 3 h, and a high concentration of CP-25 was detected in male and female intestine, synovium, muscle, lung, and brain. Following a single oral dose of 50 mg/kg of CP-25 in rats, the total excretion of CP-25 was merely 21.8% (18.40, 3.19 and 0.22% for feces, bile and urine, respectively) in males; and was approximately 21.3% (14.04, 7.16 and 0.14% for feces, bile and urine, respectively) in females. The results indicated that the CP-25 concentration was higher in major tissues than Pae; CP-25 was primarily excreted through the feces; and there were gender-related differences in the tissue distribution and excretion.

Stimulation of Intestinal Cl- Secretion Through CFTR by Caffeine Intake in Salt-Sensitive Hypertensive Rats.

PubMed

Wei, Xiao; Lu, Zongshi; Yang, Tao; Gao, Peng; Chen, Sijiao; Liu, Daoyan; Zhu, Zhiming

2018-03-16

High salt consumption is a major risk factor for hypertension, and sodium homeostasis is regulated by both intestinal sodium absorption and urinary sodium excretion. Chronic caffeine intake has been reported to attenuate salt-sensitive hypertension by promoting urinary sodium excretion; however, its exact role in intestinal sodium absorption remains unknown. Here, we investigated whether and how chronic caffeine consumption antagonizes salt-sensitive hypertension by inhibiting intestinal sodium absorption. Dahl salt-sensitive rats were fed 8% NaCl chow and 0.1% caffeine in their drinking water for 15 days. The blood pressure and fecal sodium content were measured. The effect of caffeine on the movement of Cl- in enterocyte cells was determined with the Ussing chamber assay. Rats that were treated with caffeine displayed significantly lower mean blood pressure and higher fecal sodium content than the controls. Consistent with these findings, caffeine intake decreased fluid absorption by the intestine in the fluid perfusion experiment. Further, the results from the Ussing chamber assay indicated that caffeine promoted Cl- secretion through enterocyte apical cystic fibrosis transmembrane conductance regulator (CFTR), and thus inhibited sodium absorption. Moreover, depletion of cAMP or inhibition of CFTR completely abolished the effect of caffeine on Cl- secretion. The results indicate that chronic caffeine consumption reduces sodium absorption by promoting CFTR-mediated Cl- secretion in the intestine, which contributes to the anti-hypertensive effect of caffeine in salt-sensitive rats. © 2018 The Author(s). Published by S. Karger AG, Basel.

Physiological and molecular ontogeny of branchial and extra-branchial urea excretion in posthatch rainbow trout (Oncorhynchus mykiss).

PubMed

Zimmer, Alex M; Wood, Chris M

2016-02-01

All teleost fish produce ammonia as a metabolic waste product. In embryos, ammonia excretion is limited by the chorion, and fish must detoxify ammonia by synthesizing urea via the ornithine urea cycle (OUC). Although urea is produced by embryos and larvae, urea excretion (J(urea)) is typically low until yolk sac absorption, increasing thereafter. The aim of this study was to determine the physiological and molecular characteristics of J(urea) by posthatch rainbow trout (Oncorhynchus mykiss). Following hatch, whole body urea concentration decreased over time, while J(urea) increased following yolk sac absorption. From 12 to 40 days posthatch (dph), extra-branchial routes of excretion accounted for the majority of J(urea), while the gills became the dominant site for J(urea) only after 55 dph. This represents the most delayed branchial ontogeny of any process studied to date. Urea transporter (UT) gene expression in the gills and skin increased over development, consistent with increases in branchial and extra-branchial J(urea). Following exposure to 25 mmol/l urea, the accumulation and subsequent elimination of exogenous urea was much greater at 55 dph than 12 dph, consistent with increased UT expression. Notably, UT gene expression in the gills of 55 dph larvae increased in response to high urea. In summary, there is a clear increase in urea transport capacity over posthatch development, despite a decrease in OUC activity. Copyright © 2016 the American Physiological Society.

Percutaneous absorption of selenium sulfide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farley, J.; Skelly, E.M.; Weber, C.B.

1986-01-01

The purpose of this study was to determine selenium levels in the urine of Tinea patients before and after overnight application of a 2.5% selenium sulfide lotion. Selenium was measured by atomic absorption spectroscopy (AAS). Hydride generation and carbon rod atomization were studied. It was concluded from this study that selenium is absorbed through intact skin. Selenium is then excreted, at least partially, in urine, for at least a week following treatment. The data show that absorption and excretion of selenium vary on an individual basis. Selenium levels in urine following a single application of selenium sulfide lotion do notmore » indicate that toxic amounts of selenium are being absorbed. Repeated treatments with SeS/sub 2/ result in selenium concentrations in urine which are significantly higher than normal. Significant matrix effects are observed in the carbon rod atomization of urine samples for selenium determinations, even in the presence of a matrix modifier such as nickel. The method of standard additions is required to obtain accurate results in the direct determination of selenium in urine by carbon rod AAS.« less

Tissue distribution and excretion kinetics of orally administered silica nanoparticles in rats

PubMed Central

Lee, Jeong-A; Kim, Mi-Kyung; Paek, Hee-Jeong; Kim, Yu-Ri; Kim, Meyoung-Kon; Lee, Jong-Kwon; Jeong, Jayoung; Choi, Soo-Jin

2014-01-01

Purpose The effects of particle size on the tissue distribution and excretion kinetics of silica nanoparticles and their biological fates were investigated following a single oral administration to male and female rats. Methods Silica nanoparticles of two different sizes (20 nm and 100 nm) were orally administered to male and female rats, respectively. Tissue distribution kinetics, excretion profiles, and fates in tissues were analyzed using elemental analysis and transmission electron microscopy. Results The differently sized silica nanoparticles mainly distributed to kidneys and liver for 3 days post-administration and, to some extent, to lungs and spleen for 2 days post-administration, regardless of particle size or sex. Transmission electron microscopy and energy dispersive spectroscopy studies in tissues demonstrated almost intact particles in liver, but partially decomposed particles with an irregular morphology were found in kidneys, especially in rats that had been administered 20 nm nanoparticles. Size-dependent excretion kinetics were apparent and the smaller 20 nm particles were found to be more rapidly eliminated than the larger 100 nm particles. Elimination profiles showed 7%–8% of silica nanoparticles were excreted via urine, but most nanoparticles were excreted via feces, regardless of particle size or sex. Conclusion The kidneys, liver, lungs, and spleen were found to be the target organs of orally-administered silica nanoparticles in rats, and this organ distribution was not affected by particle size or animal sex. In vivo, silica nanoparticles were found to retain their particulate form, although more decomposition was observed in kidneys, especially for 20 nm particles. Urinary and fecal excretion pathways were determined to play roles in the elimination of silica nanoparticles, but 20 nm particles were secreted more rapidly, presumably because they are more easily decomposed. These findings will be of interest to those seeking to predict potential toxicological effects of silica nanoparticles on target organs. PMID:25565843

[Renal excretion of total porphyrins and hippuric acid in rats].

PubMed

Gartzke, J; Burck, D

1986-09-01

The amounts of total porphyrins, hippuric acid and creatinine, excreted in urine by adult male Wistar rats, exhibited normal distributions for hippuric acid and creatinine, but a bimodal distribution for total porphyrins. This typical distribution of total porphyrins was still observed when creatinine was used as reference parameter. In biochemical and toxicological experiments in rats, the tested parameters should be therefore be investigated for homogeneity.

Development of an Excel-based laboratory information management system for improving workflow efficiencies in early ADME screening.

PubMed

Lu, Xinyan

2016-01-01

There is a clear requirement for enhancing laboratory information management during early absorption, distribution, metabolism and excretion (ADME) screening. The application of a commercial laboratory information management system (LIMS) is limited by complexity, insufficient flexibility, high costs and extended timelines. An improved custom in-house LIMS for ADME screening was developed using Excel. All Excel templates were generated through macros and formulae, and information flow was streamlined as much as possible. This system has been successfully applied in task generation, process control and data management, with a reduction in both labor time and human error rates. An Excel-based LIMS can provide a simple, flexible and cost/time-saving solution for improving workflow efficiencies in early ADME screening.

Synthesis of isotopically labeled daclatasvir for use in human clinical studies.

PubMed

Easter, John A; Burrell, Richard C; Bonacorsi, Samuel J

2016-04-01

Daclatasvir is a novel hepatitis C virus NS5A inhibitor developed by Bristol-Myers Squibb and marketed as Daklinza®. The need to support the development of daclatasvir required the synthesis of carbon-14 labeled material for use in human absorption, distribution, metabolism, and excretion studies. A total of 7.53 mCi of [(14) C]-daclatasvir was synthesized in eight steps from commercially available [(14) C]-copper cyanide. The radiochemical purity was 99.6%, and specific activity was 3.86 μCi/mg. To support a human absolute bioavailability study, 5.56 g of [(13) C2 , (15) N4 ]-daclatasvir was synthesized in four steps. Copyright © 2016 John Wiley & Sons, Ltd.

FISSION PRODUCT METABOLISM AND RESPONSE IN LABORATORY AND DOMESTIC ANIMALS AND PLANNING STUDY FOR EVALUATION OF RADIOACTIVE CONTAMINATION OF THE FOOD CHAIN. Progress Report April 1, 1961-January 31, 1962

DOE Office of Scientific and Technical Information (OSTI.GOV)

Comar, C.L.; Wasserman, R.H.; Lengemann, F.W.

Studies are reported of the absorption, transport, and movement of Ca and Sr across membranes and intestinal tissue, and of the skeletal uptake and urinary excretion of these two elements. The behavior of lactose-1-C/sup 14/ within the mucosal epithelium of the ileum is described. Radioiodine metabolism is studied. The distribution of Cs and Sr in milk products is investigated. Factors sffecting the retention and metabolism of Cs/sup 137/ are analyzed. The construction and description of a whole-body counting facility is given. Examinations of radioactive contamination of the food chain are outlined. (T.F.H.)

ADMET in silico modelling: towards prediction paradise?

PubMed

van de Waterbeemd, Han; Gifford, Eric

2003-03-01

Following studies in the late 1990s that indicated that poor pharmacokinetics and toxicity were important causes of costly late-stage failures in drug development, it has become widely appreciated that these areas should be considered as early as possible in the drug discovery process. However, in recent years, combinatorial chemistry and high-throughput screening have significantly increased the number of compounds for which early data on absorption, distribution, metabolism, excretion (ADME) and toxicity (T) are needed, which has in turn driven the development of a variety of medium and high-throughput in vitro ADMET screens. Here, we describe how in silico approaches will further increase our ability to predict and model the most relevant pharmacokinetic, metabolic and toxicity endpoints, thereby accelerating the drug discovery process.

Metabolism-Activated Multitargeting (MAMUT): An Innovative Multitargeting Approach to Drug Design and Development.

PubMed

Mátyus, Péter; Chai, Christina L L

2016-06-20

Multitargeting is a valuable concept in drug design for the development of effective drugs for the treatment of multifactorial diseases. This concept has most frequently been realized by incorporating two or more pharmacophores into a single hybrid molecule. Many such hybrids, due to the increased molecular size, exhibit unfavorable physicochemical properties leading to adverse effects and/or an inappropriate ADME (absorption, distribution, metabolism, and excretion) profile. To avoid this limitation and achieve additional therapeutic benefits, here we describe a novel multitargeting strategy based on the synergistic effects of a parent drug and its active metabolite(s). The concept of metabolism-activated multitargeting (MAMUT) is illustrated using a number of examples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Chrono-nutrition and chrono-exercise].

PubMed

Shibata, Shigenobu; Sasaki, Hiroyuki; Ikeda, Yuko

2013-12-01

The circadian rhythm controls many physiological functions, such as feeding, motor activity, endocrine secretion and autonomic nerve. Regular feeding pattern can entrain the peripheral circadian clock, whereas peripheral clock systems can control the absorption distribution, metabolism and excretion of nutrients, suggesting mutual interactions between circadian clocks and nutrition/food. The interactions were so-called by "chrono-nutrition", and bigger meals for breakfast were good for entrainment of peripheral clock and protection of obesity. Similar to chrono-nutrition the timing of exercise ("chrono-exercise") is important for both entrainment signals and energy expenditure. Evening exercise and/or feeding then exercise was good timing exercise for protection of obesity. Taken all, it is suggested that timing of feeding and exercise is now one of key factors for metabolic syndrome.

Pyopneumothorax following suicidal kerosene ingestion.

PubMed

Verma, S K; Kapoor, Neha; Bhaskar, Ravi; Upadhyay, Rashmi

2012-12-18

Liquid hydrocarbons derived from petroleum are widely used in household and industry. Many hydrocarbons in kerosene, such as hexane, naphthalene, octane and phenanthrene, are toxic to humans. Pulmonary toxicity is the major cause of morbidity and mortality followed by central nervous-system and cardiovascular complications. As kerosene is a mixture of chemicals, there is no definitive absorption, distribution, metabolism and excretion. The major route of exposure is by inhalation of liquid (aspiration). Kerosene vapours may be mildly irritating to the respiratory system and spray applications of kerosene may provoke signs of pulmonary irritation such as coughing and dyspnoea. Kerosene aspiration leads to inflammation and loss of surfactant. Secondary effects in the lungs include pneumothorax, pneumatocele or bronchopleural fistula. Here, we are presenting a case of pyopneumothorax after kerosene consumption.

Drug efficiency: a new concept to guide lead optimization programs towards the selection of better clinical candidates.

PubMed

Braggio, Simone; Montanari, Dino; Rossi, Tino; Ratti, Emiliangelo

2010-07-01

As a result of their wide acceptance and conceptual simplicity, drug-like concepts are having a major influence on the drug discovery process, particularly in the selection of the 'optimal' absorption, distribution, metabolism, excretion and toxicity and physicochemical parameters space. While they have an undisputable value when assessing the potential of lead series or in evaluating inherent risk of a portfolio of drug candidates, they result much less useful in weighing up compounds for the selection of the best potential clinical candidate. We introduce the concept of drug efficiency as a new tool both to guide the drug discovery program teams during the lead optimization phase and to better assess the developability potential of a drug candidate.

Disposition of Naringenin via Glucuronidation Pathway Is Affected by Compensating Efflux Transporters of Hydrophilic Glucuronides

PubMed Central

Xu, Haiyan; Kulkarni, Kaustubh H.; Singh, Rashim; Yang, Zhen; Wang, Stephen W.J.; Tam, Vincent H.; Hu, Ming

2010-01-01

The purposes of this study were to investigate how efflux transporters and UDP-glucuronosyltransferases (UGT) affect the disposition of naringenin. A rat intestinal perfusion model with bile duct cannulation was used along with rat intestinal and liver microsomes. In the intestinal perfusion model, both absorption and subsequent excretion of naringenin metabolites were rapid and site-dependent (p < 0.05). Naringenin was absorbed the most in colon and its glucuronides were excreted the most in duodenum. In metabolism studies, the intrinsic clearance value of naringenin glucuronidation was the highest in jejunum microsomes, followed by liver, ileal and colonic microsomes. The rapid metabolism in microsomes did not always translate into more efficient excretion in the rat perfusion model, however, because of presence of rate-limiting efflux transporters. When used separately, MK-571 (an inhibitor of multidrug resistance-related protein 2 or Mrp2) or dipyridamole (an inhibitor of breast cancer resistance protein or Bcrp1) did not affect excretion of naringenin glucuronides, but when used together, they significantly (p < 0.05) decreased intestinal and biliary excretion of naringenin glucuronides. In conclusion, efflux transporters Mrp2 and Bcrp1 are shown to compensate for each other and enable the intestinal excretion of flavonoid (i.e., naringenin) glucuronides. PMID:19736994

BILIARY EXCRETION AND TISSUE DISTRIBUTION OF CADMIUM-109 ADMINISTERED TO RATS

EPA Science Inventory

The difference in the excretion of cadmium in urine and feces was measured in rats with either ligated or intact bile ducts. Three days following a single oral-administration of cadmium-109 plus stabe cadmium chloride, 0.004 percent of the dose was excreted in the urine of rats w...

[Trans-intestinal cholesterol excretion (TICE): a new route for cholesterol excretion].

PubMed

Blanchard, Claire; Moreau, François; Cariou, Bertrand; Le May, Cédric

2014-10-01

The small intestine plays a crucial role in dietary and biliary cholesterol absorption, as well as its lymphatic secretion as chylomicrons (lipoprotein exogenous way). Recently, a new metabolic pathway called TICE (trans-intestinal excretion of cholesterol) that plays a central role in cholesterol metabolism has emerged. TICE is an inducible way, complementary to the hepatobiliary pathway, allowing the elimination of the plasma cholesterol directly into the intestine lumen through the enterocytes. This pathway is poorly characterized but several molecular actors of TICE have been recently identified. Although it is a matter of debate, two independent studies suggest that TICE is involved in the anti-atherogenic reverse cholesterol transport pathway. Thus, TICE is an innovative drug target to reduce -cardiovascular diseases. © 2014 médecine/sciences – Inserm.

Major human milk oligosaccharides are absorbed into the systemic circulation after oral administration in rats.

PubMed

Vazquez, E; Santos-Fandila, A; Buck, R; Rueda, R; Ramirez, M

2017-01-01

Human milk oligosaccharides (HMO) are involved in many biological functions influencing infant health. Although HMO act locally at the intestine, recent evidence has demonstrated that HMO are partially incorporated into the systemic circulation of breast-fed infants. In the last few years, a large amount of research has been conducted using preclinical models to uncover new biological functions of HMO. The aim of this study was to evaluate the absorption and urine excretion of HMO in rats. We administered a single oral dose of the following HMO: 2'-fucosyllactose (2'-FL), 6'-sialyllactose and lacto-N-neotetraose at different concentrations to adult rats. The time course of absorption of HMO into the bloodstream and their appearance in urine was studied. Our results showed that rats, similar to human infants, are able to effectively absorb a portion of HMO from the intestine into plasma and to excrete them in urine. On the basis of this, we also conducted a specific kinetic absorption study with 2'-FL, the most predominant HMO in human milk, in 9-11-d-old rat pups. Our results confirmed that a significant amount of 2'-FL was absorbed into the systemic circulation and subsequently excreted in urine during lactation in rats in a dose-depended manner. We also found basal levels of these HMO in plasma and urine of adult rats as well as rat pups as a natural result of nursing. Our data suggest that the rat may be a useful preclinical model that provides new insights into the metabolism and functions of HMO.

The effects of co-administration of butter on the absorption, metabolism and excretion of catechins in rats after oral administration of tea polyphenols.

PubMed

Zhang, Liang; Han, Yuhui; Xu, Liwei; Liang, Yuhong; Chen, Xin; Li, Junsong; Wan, Xiaochun

2015-07-01

In Southwest China, tea polyphenols are usually utilized by way of butter tea. Tea polyphenols inhibit the absorption and biosynthesis of fatty acids in vivo, but the effects of butter on the pharmacokinetics of tea polyphenols have drawn less concern. A rapid UHPLC-MS/MS method was used to quantitatively determine the catechins in the plasma, feces and bile of rats after the oral administration of tea polyphenol or its combination with butter. In comparison with the single tea polyphenol treatment, the maximum plasma concentrations (Cmax) of the free EGCG, EGC, EC, GCG, GC and ECG significantly decreased after the co-administration of butter. The mean residence times (MRT) of the free EGCG, EGC, EC, GC and ECG were also significantly prolonged. When the plasma samples were treated with β-glucuronidase and arylsulfatase, the pharmacokinetic parameters of the total catechins (free and conjugated forms) were not affected by the co-administration of butter. These results indicated that the total absorption of catechins was not affected by butter, but the metabolism of catechins had been changed. Furthermore, the fecal catechins were significantly increased by butter. The total fecal amount and excretion ratio of all catechins were increased highly. The biliary excretion of EGCG, EGC, EC, GCG and GC was significantly increased by the co-administration of butter. To sum up, the butter changed the metabolism of catechins in vivo by decreasing the plasma concentration of the free catechins but increasing the conjugated catechins.

A novel description of FDG excretion in the renal system: application to metformin-treated models

NASA Astrophysics Data System (ADS)

Garbarino, S.; Caviglia, G.; Sambuceti, G.; Benvenuto, F.; Piana, M.

2014-05-01

This paper introduces a novel compartmental model describing the excretion of 18F-fluoro-deoxyglucose (FDG) in the renal system and a numerical method based on the maximum likelihood for its reduction. This approach accounts for variations in FDG concentration due to water re-absorption in renal tubules and the increase of the bladder’s volume during the FDG excretion process. From the computational viewpoint, the reconstruction of the tracer kinetic parameters is obtained by solving the maximum likelihood problem iteratively, using a non-stationary, steepest descent approach that explicitly accounts for the Poisson nature of nuclear medicine data. The reliability of the method is validated against two sets of synthetic data realized according to realistic conditions. Finally we applied this model to describe FDG excretion in the case of animal models treated with metformin. In particular we show that our approach allows the quantitative estimation of the reduction of FDG de-phosphorylation induced by metformin.

Pharmacokinetic evaluation of ipamorelin and other peptidyl growth hormone secretagogues with emphasis on nasal absorption.

PubMed

Johansen, P B; Hansen, K T; Andersen, J V; Johansen, N L

1998-11-01

1. The pharmacokinetics of three new peptidyl growth hormone secretagogues, ipamorelin (NNC 26-0161), NNC 26-0194 and NNC 26-0235, were compared with two well-known hexapeptides, GHRP-2 and GHRP-6, in the male rat following different routes of administration. 2. Following i.v. bolus injection, plasma concentrations of the peptides declined biexponentially. Ipamorelin differed markedly from the other peptides investigated, demonstrating a systemic plasma clearance 5-fold lower than that of GHRP-6. Ipamorelin was mainly excreted in the urine, whereas GHRP-6 was predominantly excreted in the bile. NNC 26-0194 and NNC 26-0235 also showed high biliary excretions. Ipamorelin and the two NNC peptides were moderately resistant towards metabolism as 60-80% of the administered dose could be recovered from bile and urine as intact peptide. 3. After intranasal application, the bioavailability of ipamorelin was estimated at approximately 20%. Higher bioavailabilities of approximately 50% were determined for NNC 26-0235, NNC 26-0194 and GHRP-2, whereas the nasal absorption of GHRP-6 was somewhat lower. Thus, the peptides could be easily transported across the nasal epithelium suggesting that the nasal route seems promising for systemic delivery of this family of peptidyl growth hormone secretagogues.

Whole body acid-base modeling revisited.

PubMed

Ring, Troels; Nielsen, Søren

2017-04-01

The textbook account of whole body acid-base balance in terms of endogenous acid production, renal net acid excretion, and gastrointestinal alkali absorption, which is the only comprehensive model around, has never been applied in clinical practice or been formally validated. To improve understanding of acid-base modeling, we managed to write up this conventional model as an expression solely on urine chemistry. Renal net acid excretion and endogenous acid production were already formulated in terms of urine chemistry, and we could from the literature also see gastrointestinal alkali absorption in terms of urine excretions. With a few assumptions it was possible to see that this expression of net acid balance was arithmetically identical to minus urine charge, whereby under the development of acidosis, urine was predicted to acquire a net negative charge. The literature already mentions unexplained negative urine charges so we scrutinized a series of seminal papers and confirmed empirically the theoretical prediction that observed urine charge did acquire negative charge as acidosis developed. Hence, we can conclude that the conventional model is problematic since it predicts what is physiologically impossible. Therefore, we need a new model for whole body acid-base balance, which does not have impossible implications. Furthermore, new experimental studies are needed to account for charge imbalance in urine under development of acidosis. Copyright © 2017 the American Physiological Society.

Physiological disposition and metabolism of enalapril maleate in laboratory animals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tocco, D.J.; deLuna, F.A.; Duncan, A.E.

N-(1-(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline (MK-422), is a potent angiotensin I-converting enzyme (ACE) inhibitor, but as a diacid is poorly absorbed in laboratory animals. Enalapril maleate, the monoethyl ester of MK-422, proved to be significantly better absorbed in both rats and dogs. Peak levels of radioactivity in plasma occurred in 30 min in rats and 2 hr in dogs after a single dose of /sup 14/C-enalapril maleate (1 mg/kg, po). Rats excreted 26% of the dose in the urine and 72% in the feces in 72 hr; dogs excreted 40% of the dose in the urine and 36% in the feces. After the intravenousmore » dose, the presence of radioactivity in the feces of both species suggested that some biliary excretion had occurred. Absorption was estimated to be 34% in the rat and 61% in the dog. The major metabolite of enalapril maleate in dogs, accounting for 86% of the urine radioactivity, was identified as MK-422 by GC/MS. A procedure was developed for the quantitation of MK-422 and enalapril in plasma and urine by their inhibition of purified ACE. The assays showed that enalapril was absorbed intact in dogs and converted to MK-422 after absorption.« less

Barley β-glucan increases fecal bile acid excretion and short chain fatty acid levels in mildly hypercholesterolemic individuals.

PubMed

Thandapilly, Sijo J; Ndou, Saymore P; Wang, Yanan; Nyachoti, Charles M; Ames, Nancy P

2018-06-20

The cholesterol-lowering effect of barley β-glucan has been proposed to be the result of a pleiotropic effect, which involves several biological mechanisms such as gut fermentation, inhibition of intestinal cholesterol absorption and increased bile acid excretion and its synthesis. However, one of the recent studies from our laboratory indicated that increased bile acid excretion and subsequent increase in its synthesis, but not the inhibition of cholesterol absorption or synthesis might be responsible for the cholesterol-lowering effect of barley β-glucan. Accordingly, the primary objective of the present study was to investigate the concentration of bile acids (BA), neutral sterols (NS) and short chain fatty acids (SCFA) excreted through the feces by mildly hypercholesterolemic subjects who consumed diets containing barley β-glucan with varying molecular weights (MW) and concentrations. In a controlled, four phase, crossover trial, 30 mildly hypercholesterolemic but otherwise healthy subjects were randomly assigned to receive breakfast containing 3 g high MW (HMW), 5 g low MW (LMW), 3 g LMW barley β-glucan or a control diet for 5 weeks. The concentrations of BA, NS and SCFA in the feces were measured at the end of each treatment phase. Compared to the other treatment groups, 3 g day-1 HMW barley β-glucan consumption resulted in increased lithocholic acid (LCA) excretion (P < 0.001) but not LMW β-glucan, even at the high dose of 5 g day-1. Increased fermentability of fibre was also evident from a significant increase in fecal total SCFA concentrations in response to the 3 g HMW β-glucan diet compared to the 3 g LMW barley β-glucan and control diet (P = 0.0015). In summary, the current results validate our previous report on the role of fecal bile acid excretion in cholesterol lowering through the consumption of barley β-glucan. In addition, increased SCFA concentrations indicate that an increase in β-glucan molecular weight promotes hindgut fermentation, which might also be playing a role in attenuating cholesterol levels.

Iron and vegetarian diets.

PubMed

Saunders, Angela V; Craig, Winston J; Baines, Surinder K; Posen, Jennifer S

2013-08-19

Vegetarians who eat a varied and well balanced diet are not at any greater risk of iron deficiency anaemia than non-vegetarians. A diet rich in wholegrains, legumes, nuts, seeds, dried fruits, iron-fortified cereals and green leafy vegetables provides an adequate iron intake. Vitamin C and other organic acids enhance non-haem iron absorption, a process that is carefully regulated by the gut. People with low iron stores or higher physiological need for iron will tend to absorb more iron and excrete less. Research to date on iron absorption has not been designed to accurately measure absorption rates in typical Western vegetarians with low ferritin levels.

Mineral balance and bone turnover in adolescents with anorexia nervosa.

PubMed

Abrams, S A; Silber, T J; Esteban, N V; Vieira, N E; Stuff, J E; Meyers, R; Majd, M; Yergey, A L

1993-08-01

We evaluated seven female adolescents with anorexia nervosa to determine whether calcium metabolism was affected by their disorder. We measured calcium absorption, urinary calcium excretion, and calcium kinetics, using a dual-tracer, stable-isotope technique during the first weeks of an inpatient nutritional rehabilitation program. Results were compared with those from a control group of seven healthy adolescent girls of similar ages. The percentage of absorption of calcium was lower in subjects with anorexia nervosa than in control subjects (16.2% +/- 6.3% vs 24.6% +/- 7.2%; p < 0.05). Urinary calcium excretion was greater in subjects with anorexia nervosa than in control subjects (6.4 +/- 2.5 vs 1.6 +/- 0.7 mg.kg-1 x day-1; p < 0.01) and was associated with bone resorption rather than calcium hyper-absorption. Calcium kinetic studies demonstrated a decreased rate of bone formation and an increased rate of bone resorption. These results suggest marked abnormalities in mineral metabolism in patients with anorexia nervosa. From these results, we hypothesize that improvement in bone mineralization during recovery from anorexia nervosa will require resolution of hormonal abnormalities, including hypercortisolism, in addition to increased calcium intake.

Biocompatible near-infrared fluorescent nanoparticles for macro and microscopic in vivo functional bioimaging

PubMed Central

Chu, Liliang; Wang, Shaowei; Li, Kanghui; Xi, Wang; Zhao, Xinyuan; Qian, Jun

2014-01-01

Near-infrared (NIR) imaging technology has been widely used for biomedical research and applications, since it can achieve deep penetration in biological tissues due to less absorption and scattering of NIR light. In our research, polymer nanoparticles with NIR fluorophores doped were synthesized. The morphology, absorption/emission features and chemical stability of the fluorescent nanoparticles were characterized, separately. NIR fluorescent nanoparticles were then utilized as bright optical probes for macro in vivo imaging of mice, including sentinel lymph node (SLN) mapping, as well as distribution and excretion monitoring of nanoparticles in animal body. Furthermore, we applied the NIR fluorescent nanoparticles in in vivo microscopic bioimaging via a confocal microscope. Under the 635 nm-CW excitation, the blood vessel architecture in the ear and the brain of mice, which were administered with nanoparticles, was visualized very clearly. The imaging depth of our one-photon microscopy, which was assisted with NIR fluorescent nanoprobes, can reach as deep as 500 μm. Our experiments show that NIR fluorescent nanoparticles have great potentials in various deep-tissue imaging applications. PMID:25426331

Semisynthesis, Characterization and Evaluation of New Adenosine Derivatives as Antiproliferative Agents.

PubMed

Valdés Zurita, Francisco; Brown Vega, Nelson; Gutiérrez Cabrera, Margarita

2018-05-08

We describe the semisynthesis and biological effects of adenosine derivatives, which were anticipated to function as agonists for the A₃ receptor. Molecular docking was used to select candidate compounds. Fifteen nucleoside derivatives were obtained through nucleophilic substitutions of the N ⁶-position of the nucleoside precursor 6-chloropurine riboside by amines of different origin. All compounds were purified by column chromatography and further characterized by spectroscopic and spectrometric techniques, showing moderate yield. These molecules were then evaluated for their antiproliferative activity in human gastric cancer cells expressing the A₃ receptor. We found that the compounds obtained have antiproliferative activity and that new structural modifications can enhance their biological activity. The ADME (Absorption, Distribution, Metabolism and Excretion) properties of the most active compounds were also evaluated theoretically.

Pyopneumothorax following suicidal kerosene ingestion

PubMed Central

Verma, S K; Kapoor, Neha; Bhaskar, Ravi; Upadhyay, Rashmi

2012-01-01

Liquid hydrocarbons derived from petroleum are widely used in household and industry. Many hydrocarbons in kerosene, such as hexane, naphthalene, octane and phenanthrene, are toxic to humans. Pulmonary toxicity is the major cause of morbidity and mortality followed by central nervous-system and cardiovascular complications.1 As kerosene is a mixture of chemicals, there is no definitive absorption, distribution, metabolism and excretion. The major route of exposure is by inhalation of liquid (aspiration). Kerosene vapours may be mildly irritating to the respiratory system and spray applications of kerosene may provoke signs of pulmonary irritation such as coughing and dyspnoea. Kerosene aspiration leads to inflammation and loss of surfactant. Secondary effects in the lungs include pneumothorax, pneumatocele or bronchopleural fistula. Here, we are presenting a case of pyopneumothorax after kerosene consumption. PMID:23257648

Pharmacokinetics of Drugs in Cachectic Patients: A Systematic Review

PubMed Central

Trobec, Katja; Kerec Kos, Mojca; von Haehling, Stephan; Springer, Jochen; Anker, Stefan D.; Lainscak, Mitja

2013-01-01

Cachexia is a weight-loss process caused by an underlying chronic disease such as cancer, chronic heart failure, chronic obstructive pulmonary disease, or rheumatoid arthritis. It leads to changes in body structure and function that may influence the pharmacokinetics of drugs. Changes in gut function and decreased subcutaneous tissue may influence the absorption of orally and transdermally applied drugs. Altered body composition and plasma protein concentration may affect drug distribution. Changes in the expression and function of metabolic enzymes could influence the metabolism of drugs, and their renal excretion could be affected by possible reduction in kidney function. Because no general guidelines exist for drug dose adjustments in cachectic patients, we conducted a systematic search to identify articles that investigated the pharmacokinetics of drugs in cachectic patients. PMID:24282510

Therapeutic perspectives of epigenetically active nutrients

PubMed Central

Remely, M; Lovrecic, L; de la Garza, A L; Migliore, L; Peterlin, B; Milagro, F I; Martinez, A J; Haslberger, A G

2015-01-01

Many nutrients are known for a wide range of activities in prevention and alleviation of various diseases. Recently, their potential role in regulating human health through effects on epigenetics has become evident, although specific mechanisms are still unclear. Thus, nutriepigenetics/nutriepigenomics has emerged as a new and promising field in current epigenetics research in the past few years. In particular, polyphenols, as part of the central dynamic interaction between the genome and the environment with specificity at physiological concentrations, are well known to affect mechanisms underlying human health. This review summarizes the effects of dietary compounds on epigenetic mechanisms in the regulation of gene expression including expression of enzymes and other molecules responsible for drug absorption, distribution, metabolism and excretion in cancer, metabolic syndrome, neurodegenerative disorders and hormonal dysfunction. PMID:25046997

ADME-Tox profiles of some food additives and pesticides

NASA Astrophysics Data System (ADS)

Craciun, Dana; Modra, Dorina; Isvoran, Adriana

2015-12-01

Within this study we compute the Absorption, Distribution, Metabolism, Excretion and Toxicity (ADME-Tox) profiles of several commonly used food additives and some pesticides. As expected, all the food additives considered in this study provided to be safe, their ADME-Tox profiles indicating that they have a good oral bioavailability and they do not produce phosphoslipidosis. The ADME-Tox profiles of the pesticides indicate that, with a few exceptions, they are highly toxic (some of them being not approved in the EU, but still used in other countries) and may cause many diseases. Our results are in good agreement with published data concerning the considered food additives and pesticides revealing that the ADME-Tox profiling method may be successfully used to test other chemicals than drug candidates.

21 CFR 331.80 - Professional labeling.

Code of Federal Regulations, 2010 CFR

2010-04-01

... low phosphate diet to prevent formation of phosphate urinary stones, through the reduction of... gastrointestinal tract and renal excretion of aluminum is impaired in renal failure. Aluminum is not well removed... complexes with phosphate in the gastrointestinal tract, thus decreasing phosphate absorption. Prolonged use...

Physiological responses and scope for growth upon medium-term exposure to the combined effects of ocean acidification and temperature in a subtidal scavenger Nassarius conoidalis.

PubMed

Zhang, Haoyu; Shin, Paul K S; Cheung, S G

2015-05-01

Physiological responses (ingestion rate, absorption rate and efficiency, respiration, rate, excretion rate) and scope for growth of a subtidal scavenging gastropod Nassarius conoidalis under the combined effects of ocean acidification (pCO2 levels: 380, 950, 1250 μatm) and temperature (15, 30 °C) were investigated for 31 days. There was a significant reduction in all the physiological rates and scope for growth following short-term exposure (1-3 days) to elevated pCO2 except absorption efficiency at 15 °C and 30 °C, and respiration rate and excretion rate at 15 °C. The percentage change in the physiological rates ranged from 0% to 90% at 15 °C and from 0% to 73% at 30 °C when pCO2 was increased from 380 μatm to 1250 μatm. The effect of pCO2 on the physiological rates was enhanced at high temperature for ingestion, absorption, respiration and excretion. When the exposure period was extended to 31 days, the effect of pCO2 was significant on the ingestion rate only. All the physiological rates remained unchanged when temperature increased from 24 °C to 30 °C but the rates at 15 °C were significantly lower, irrespective of the duration of exposure. Our data suggested that a medium-term exposure to ocean acidification has no effect on the energetics of N. conoidalis. Nevertheless, the situation may be complicated by a longer term of exposure and/or a reduction in salinity in a warming world. Copyright © 2015 Elsevier Ltd. All rights reserved.

The New Nordic Diet: phosphorus content and absorption.

PubMed

Salomo, Louise; Poulsen, Sanne K; Rix, Marianne; Kamper, Anne-Lise; Larsen, Thomas M; Astrup, Arne

2016-04-01

High phosphorus content in the diet may have adverse effect on cardiovascular health. We investigated whether the New Nordic Diet (NND), based mainly on local, organic and less processed food and large amounts of fruit, vegetables, wholegrain and fish, versus an Average Danish Diet (ADD) would reduce the phosphorus load due to less phosphorus-containing food additives, animal protein and more plant-based proteins. Phosphorus and creatinine were measured in plasma and urine at baseline, week 12 and week 26 in 132 centrally obese subjects with normal renal function as part of a post hoc analysis of data acquired from a 26-week controlled trial. We used the fractional phosphorus excretion as a measurement of phosphorus absorption. Mean baseline fractional phosphorus excretion was 20.9 ± 6.6 % in the NND group (n = 82) and 20.8 ± 5.5 % in the ADD group (n = 50) and was decreased by 2.8 ± 5.1 and 3.1 ± 5.4 %, respectively, (p = 0.6) at week 26. At week 26, the mean change in plasma phosphorus was 0.04 ± 0.12 mmol/L in the NND group and -0.03 ± 0.13 mmol/L in the ADD group (p = 0.001). Mean baseline phosphorus intake was 1950 ± 16 mg/10 MJ in the NND group and 1968 ± 22 mg/10 MJ in the ADD group and decreased less in the NND compared to the ADD (67 ± 36 mg/10 MJ and -266 ± 45 mg/day, respectively, p < 0.298). Contrary to expectations, the NND had a high phosphorus intake and did not decrease the fractional phosphorus excretion compared with ADD. Further modifications of the diet are needed in order to make this food concept beneficial regarding phosphorus absorption.

Modeling Calcium Loss from Bones During Space Flight

NASA Technical Reports Server (NTRS)

Wastney, Meryl E.; Morukov, Boris V.; Larina, Irina M.; Abrams, Steven A.; Nillen, Jeannie L.; Davis-Street, Janis E.; Lane, Helen W.; Smith, Scott M.; Paloski, W. H. (Technical Monitor)

1999-01-01

Calcium loss from bones during space flight creates a risk for astronauts who travel into space, and may prohibit space flights to other planets. The problem of calcium loss during space flight has been studied using animal models, bed rest (as a ground-based model), and humans in-flight. In-flight studies have typically documented bone loss by comparing bone mass before and after flight. To identify changes in metabolism leading to bone loss, we have performed kinetic studies using stable isotopes of calcium. Oral (Ca-43) and intravenous (Ca-46) tracers were administered to subjects (n=3), three-times before flight, once in-flight (after 110 days), and three times post-flight (on landing day, and 9 days and 3 months after flight). Samples of blood, saliva, urine, and feces were collected for up to 5 days after isotope administration, and were analyzed for tracer enrichment. Tracer data in tissues were analyzed using a compartmental model for calcium metabolism and the WinSAAM software. The model was used to: account for carryover of tracer between studies, fit data for all studies using the minimal number of changes between studies, and calculate calcium absorption, excretion, bone calcium deposition and bone calcium resorption. Results showed that fractional absorption decreased by 50% during flight and that bone resorption and urinary excretion increased by 50%. Results were supported by changes in biochemical markers of bone metabolism. Inflight bone loss of approximately 250 mg Ca/d resulted from decreased calcium absorption combined with increased bone resorption and excretion. Further studies will assess the time course of these changes during flight, and the effectiveness of countermeasures to mitigate flight-induced bone loss. The overall goal is to enable human travel beyond low-Earth orbit, and to allow for better understanding and treatment of bone diseases on Earth.

Amino acid derivatives of 5-ASA as novel prodrugs for intestinal drug delivery.

PubMed

Clerici, C; Gentili, G; Boschetti, E; Santucci, C; Aburbeh, A G; Natalini, B; Pellicciari, R; Morelli, A

1994-12-01

In an attempt to obtain site-specific delivery of 5-ASA in the intestinal tract, we have determined the extent of absorption and metabolism of a number of novel 5-ASA derivatives, namely, (N-L-glutamyl)-amino-2-salicylic acid (1), (N-L-aspartyl)-amino-2-salicylic-acid (2), 5-aminosalicyl-L-proline-L-leucine (3), and 5-(N-L-glutamyl)-aminosalicyl-L-proline-L-leucine (4), which are selectively cleaved by intestinal brush border aminopeptidase A and carboxypeptidases. These novel prodrugs, 5-ASA, and sulfasalazine were administered to adult Fisher rats (N = 30) and to animals that had undergone prior colostomy (N = 30). Urine and feces were collected at timed intervals for 48 hr and the metabolites, 5-ASA, and N-acetyl-5-ASA were measured by high-performance liquid chromatography. The absorption and metabolism of all compounds were essentially identical in colostomized and normal animals. 5-ASA exhibited a rapid proximal intestinal absorption as evidenced by the high cumulative urinary excretion (> 65%) and low fecal excretion. Sulfasalazine, as expected, exhibited a lower urinary recovery (< 35%) and higher fecal excretion of 5-ASA and its metabolite. The novel glutamate and aspartate derivatives (1 and 2) behaved similarly to sulfasalazine, while administration of the proline-leucine derivative (3) resulted in urinary and fecal recovery values intermediate with respect to those observed with 5-ASA and sulfasalazine. 5-(N-L-Glutamyl)-aminosalicyl-L-proline-L-leucine yielded the highest fecal recovery of 5-ASA and its N-acetyl derivative, indicating a more efficient delivery to the distal bowel. Amino acid derivatives of 5-ASA appear to be potentially useful prodrugs for the site-specific delivery of 5-ASA to different regions of the intestinal tract.

Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase

PubMed Central

Jang, Yura; Chung, Hye Jin; Hong, Jung Wan; Yun, Cheol-Won; Chung, Hesson

2017-01-01

Paclitaxel is a most widely used anticancer drug with low oral bioavailability, thus it is currently administered via intravenous infusion. DHP107 is a lipid-based paclitaxel formulation that can be administered as an oral solution. In this study, we investigated the mechanism of paclitaxel absorption after oral administration of DHP107 in mice and rats by changing the dosing interval, and evaluated the influence of bile excretion. DHP107 was orally administered to mice at various dosing intervals (2, 4, 8, 12, 24 h) to examine how residual DHP107 affected paclitaxel absorption during subsequent administration. Studies with small-angle X-ray diffraction (SAXS) and cryo-transmission electron microscopy (cryo-TEM) showed that DHP107 formed a lipidic sponge phase after hydration. The AUC values after the second dose were smaller than those after the first dose, which was correlated to the induction of expression of P-gp and CYP in the livers and small intestines from 2 h to 7 d after the first dose. The smaller AUC value observed after the second dose was also attributed to the intestinal adhesion of residual formulation. The adhered DHP107 may have been removed by ingested food, thus resulting in a higher AUC. In ex vivo and in vivo mucoadhesion studies, the formulation adhered to the villi for up to 24 h, and the amount of DHP107 that adhered was approximately half that of monoolein. The paclitaxel absorption after administration of DHP107 was not affected by bile in the cholecystectomy mice. The dosing interval and food intake affect the oral absorption of paclitaxel from DHP107, which forms a mucoadhesive sponge phase after hydration. Bile excretion does not affect the absorption of paclitaxel from DHP107 in vivo. PMID:27867185

Absorption mechanism of DHP107, an oral paclitaxel formulation that forms a hydrated lipidic sponge phase.

PubMed

Jang, Yura; Chung, Hye Jin; Hong, Jung Wan; Yun, Cheol-Won; Chung, Hesson

2017-01-01

Paclitaxel is a most widely used anticancer drug with low oral bioavailability, thus it is currently administered via intravenous infusion. DHP107 is a lipid-based paclitaxel formulation that can be administered as an oral solution. In this study, we investigated the mechanism of paclitaxel absorption after oral administration of DHP107 in mice and rats by changing the dosing interval, and evaluated the influence of bile excretion. DHP107 was orally administered to mice at various dosing intervals (2, 4, 8, 12, 24 h) to examine how residual DHP107 affected paclitaxel absorption during subsequent administration. Studies with small-angle X-ray diffraction (SAXS) and cryo-transmission electron microscopy (cryo-TEM) showed that DHP107 formed a lipidic sponge phase after hydration. The AUC values after the second dose were smaller than those after the first dose, which was correlated to the induction of expression of P-gp and CYP in the livers and small intestines from 2 h to 7 d after the first dose. The smaller AUC value observed after the second dose was also attributed to the intestinal adhesion of residual formulation. The adhered DHP107 may have been removed by ingested food, thus resulting in a higher AUC. In ex vivo and in vivo mucoadhesion studies, the formulation adhered to the villi for up to 24 h, and the amount of DHP107 that adhered was approximately half that of monoolein. The paclitaxel absorption after administration of DHP107 was not affected by bile in the cholecystectomy mice. The dosing interval and food intake affect the oral absorption of paclitaxel from DHP107, which forms a mucoadhesive sponge phase after hydration. Bile excretion does not affect the absorption of paclitaxel from DHP107 in vivo.

Omeprazole suppressed plasma magnesium level and duodenal magnesium absorption in male Sprague-Dawley rats.

PubMed

Thongon, Narongrit; Penguy, Jirawat; Kulwong, Sasikan; Khongmueang, Kanyanat; Thongma, Matthana

2016-11-01

Hypomagnesemia is the most concerned side effect of proton pump inhibitors (PPIs) in chronic users. However, the mechanism of PPIs-induced systemic Mg 2+ deficit is currently unclear. The present study aimed to elucidate the direct effect of short-term and long-term PPIs administrations on whole body Mg 2+ homeostasis and duodenal Mg 2+ absorption in rats. Mg 2+ homeostasis was studied by determining the serum Mg 2+ level, urine and fecal Mg 2+ excretions, and bone and muscle Mg 2+ contents. Duodenal Mg 2+ absorption as well as paracellular charge selectivity were studied. Our result showed that gastric and duodenal pH markedly increased in omeprazole-treated rats. Omeprazole significantly suppressed plasma Mg 2+ level, urinary Mg 2+ excretion, and bone and muscle Mg 2+ content. Thus, omeprazole induced systemic Mg 2+ deficiency. By using Ussing chamber techniques, it was shown that omeprazole markedly suppressed duodenal Mg 2+ channel-driven and Mg 2+ channel-independent Mg 2+ absorptions and cation selectivity. Inhibitors of mucosal HCO 3 - secretion significantly increased duodenal Mg 2+ absorption in omeprazole-treated rats. We therefore hypothesized that secreted HCO 3 - in duodenum decreased luminal proton, this impeded duodenal Mg 2+ absorption. Higher plasma total 25-OH vitamin D, diuresis, and urine PO 4 3- were also demonstrated in hypomagnesemic rats. As a compensatory mechanism for systemic Mg 2+ deficiency, the expressions of duodenal transient receptor potential melastatin 6 (TRPM6), cyclin M4 (CNNM4), claudin (Cldn)-2, Cldn-7, Cldn-12, and Cldn-15 proteins were enhanced in omeprazole-treated rats. Our findings support the potential role of duodenum on the regulation of Mg 2+ homeostasis.

Contribution of dietary oxalate to urinary oxalate excretion

NASA Technical Reports Server (NTRS)

Holmes, R. P.; Goodman, H. O.; Assimos, D. G.

2001-01-01

BACKGROUND: The amount of oxalate excreted in urine has a significant impact on calcium oxalate supersaturation and stone formation. Dietary oxalate is believed to make only a minor (10 to 20%) contribution to the amount of oxalate excreted in urine, but the validity of the experimental observations that support this conclusion can be questioned. An understanding of the actual contribution of dietary oxalate to urinary oxalate excretion is important, as it is potentially modifiable. METHODS: We varied the amount of dietary oxalate consumed by a group of adult individuals using formula diets and controlled, solid-food diets with a known oxalate content, determined by a recently developed analytical procedure. Controlled solid-food diets were consumed containing 10, 50, and 250 mg of oxalate/2500 kcal, as well as formula diets containing 0 and 180 mg oxalate/2500 kcal. Changes in the content of oxalate and other ions were assessed in 24-hour urine collections. RESULTS: Urinary oxalate excretion increased as dietary oxalate intake increased. With oxalate-containing diets, the mean contribution of dietary oxalate to urinary oxalate excretion ranged from 24.4 +/- 15.5% on the 10 mg/2500 kcal/day diet to 41.5 +/- 9.1% on the 250 mg/2500 kcal/day diet, much higher than previously estimated. When the calcium content of a diet containing 250 mg of oxalate was reduced from 1002 mg to 391 mg, urinary oxalate excretion increased by a mean of 28.2 +/- 4.8%, and the mean dietary contribution increased to 52.6 +/- 8.6%. CONCLUSIONS: These results suggest that dietary oxalate makes a much greater contribution to urinary oxalate excretion than previously recognized, that dietary calcium influences the bioavailability of ingested oxalate, and that the absorption of dietary oxalate may be an important factor in calcium oxalate stone formation.

Radionuclides in haematology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lewis, S.M.; Bayly, R.J.

1986-01-01

This book contains the following chapters: Some prerequisites to the use of radionuclides in haematology; Instrumentation and counting techniques; In vitro techniques; Cell labelling; Protein labelling; Autoradiography; Imaging and quantitative scanning; Whole body counting; Absorption and excretion studies; Blood volume studies; Plasma clearance studies; and Radionuclide blood cell survival studies.

Tropical enteropathy in Rhodesia.

PubMed

Thomas, G; Clain, D J; Wicks, A C

1976-11-01

Tropical enteropathy, which may be related to tropical sprue, has been described in many developing countries including parts of Africa. The jejunal changes of enteropathy are seen in Rhodesians of all social and racial categories. Xylose excretion, however, is related to socioeconomic status, but not race. Upper socioeconomic Africans and Europeans excrete significantly more xylose than lower socioeconomic Africans. Vitamin B12 and fat absorption are normal, suggesting predominant involvement of the proximal small intestine. Tropical enteropathy in Rhodesia is similar to that seen in Nigeria but is associated with less malabsorption than is found in the Caribbean, the Indian subcontinent, and South East Asia. The possible aetiological factors are discussed. It is postulated that the lighter exposure of upper class Africans and Europeans to repeated gastrointestinal infections may accound for their superior xylose absorption compared with Africans of low socioeconomic circumstances. It is further suggested that the milder enteropathy seen in Africa may be explained by a lower prevalence of acute gastroenteritis than in experienced elsewhere in the tropics.

Effect of Hibiscus sabdariffa L. Dried Calyx Ethanol Extract on Fat Absorption-Excretion, and Body Weight Implication in Rats

PubMed Central

Carvajal-Zarrabal, O.; Hayward-Jones, P. M.; Orta-Flores, Z.; Nolasco-Hipólito, C.; Barradas-Dermitz, D. M.; Aguilar-Uscanga, M. G.; Pedroza-Hernández, M. F.

2009-01-01

The effect of Hibiscus sabdariffa L. (Hs) calyx extract on fat absorption-excretion and body weight in rats, was investigated. Rats were fed with either a basal diet (SDC = Control diet) or the same diet supplemented with Hs extracts at 5%, 10% and 15% (SD5, SD10 and SD15). Only SD5 did not show significant increases in weight, food consumption and efficiency compared to SDC. The opposite occurred in SD15 group which showed a significant decrease for these three parameters. The SD10 responses were similar to SD15, with the exception of food consumption. In both SDC and SD5 groups, no body weight loss was observed; however, only in the latter group was there a significantly greater amount of fatty acids found in feces. A collateral effect emerging from the study is that components of Hs extract at the intermediate and greater concentrations used in this experiment could be considered possible antiobesity agents. PMID:19756159

COMPARATIVE TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC (IAS) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (ASV) AND ARSENITE (ASIII)

EPA Science Inventory

COMPARATIVE TISSUE DISTRIBUTION AND URINARY EXCRETION OF INORGANIC ARSENIC (iAs) AND ITS METHYLATED METABOLITES IN MICE FOLLOWING ORAL ADMINISTRATION OF ARSENATE (AsV) AND ARSENITE (AsIII). E M Kenyon, L M Del Razo and M F Hughes. U.S. EPA, ORD, NHEERL, ETD, PKB, RTP, NC, USA; ...

Multiple resistance to carcinogens and xenobiotics: P-glycoproteins as universal detoxifiers.

PubMed

Efferth, Thomas; Volm, Manfred

2017-07-01

The detoxification of toxic substances is of general relevance in all biological systems. The plethora of exogenous xenobiotic compounds and endogenous toxic metabolic products explains the evolutionary pressure of all organisms to develop molecular mechanisms to detoxify and excrete harmful substances from the body. P-glycoprotein and other members of the ATP-binding cassette (ABC) transporter family extrude innumerous chemical compounds out of cells. Their specific expression in diverse biological contexts cause different phenotypes: (1) multidrug resistance (MDR) and thus failure of cancer chemotherapy, (2) avoidance of accumulation of carcinogens and prevention of carcinogenesis in healthy tissues, (3) absorption, distribution, metabolization and excretion (ADME) of pharmacological drugs in human patients, (4) protection from environmental toxins in aquatic organisms (multi-xenobiotic resistance, MXR). Hence ABC-transporters may have opposing effects for organismic health reaching from harmful in MDR of tumors to beneficial for maintenance of health in MXR. While their inhibition by specific inhibitors may improve treatment success in oncology and avoid carcinogenesis, blocking of ABC-transporter-driven efflux by environmental pollutants leads to ecotoxicological consequences in marine biotopes. Poisoned seafood may enter the food-chain and cause intoxications in human beings. As exemplified with ABC-transporters, joining forces in interdisciplinary research may, therefore, be a wise strategy to fight problems in human medicine and environmental sciences.

Dietary Hyaluronic Acid Migrates into the Skin of Rats

PubMed Central

Mitsugi, Koichi; Odanaka, Wataru; Seino, Satoshi; Masuda, Yasunobu

2014-01-01

Hyaluronic acid is a constituent of the skin and helps to maintain hydration. The oral intake of hyaluronic acid increases water in the horny layer as demonstrated by human trials, but in vivo kinetics has not been shown. This study confirmed the absorption, migration, and excretion of 14C-labeled hyaluronic acid (14C-hyaluronic acid). 14C-hyaluronic acid was orally or intravenously administered to male SD rats aged 7 to 8 weeks. Plasma radioactivity after oral administration showed the highest level 8 hours after administration, and orally administered 14C-hyaluronic acid was found in the blood. Approximately 90% of 14C-hyaluronic acid was absorbed from the digestive tract and used as an energy source or a structural constituent of tissues based on tests of the urine, feces, expired air, and cadaver up to 168 hours (one week) after administration. The autoradiographic results suggested that radioactivity was distributed systematically and then reduced over time. The radioactivity was higher in the skin than in the blood at 24 and 96 hours after administration. The results show the possibility that orally administered hyaluronic acid migrated into the skin. No excessive accumulation was observed and more than 90% of the hyaluronic acid was excreted in expired air or urine. PMID:25383371

Dietary hyaluronic acid migrates into the skin of rats.

PubMed

Oe, Mariko; Mitsugi, Koichi; Odanaka, Wataru; Yoshida, Hideto; Matsuoka, Ryosuke; Seino, Satoshi; Kanemitsu, Tomoyuki; Masuda, Yasunobu

2014-01-01

Hyaluronic acid is a constituent of the skin and helps to maintain hydration. The oral intake of hyaluronic acid increases water in the horny layer as demonstrated by human trials, but in vivo kinetics has not been shown. This study confirmed the absorption, migration, and excretion of (14)C-labeled hyaluronic acid ((14)C-hyaluronic acid). (14)C-hyaluronic acid was orally or intravenously administered to male SD rats aged 7 to 8 weeks. Plasma radioactivity after oral administration showed the highest level 8 hours after administration, and orally administered (14)C-hyaluronic acid was found in the blood. Approximately 90% of (14)C-hyaluronic acid was absorbed from the digestive tract and used as an energy source or a structural constituent of tissues based on tests of the urine, feces, expired air, and cadaver up to 168 hours (one week) after administration. The autoradiographic results suggested that radioactivity was distributed systematically and then reduced over time. The radioactivity was higher in the skin than in the blood at 24 and 96 hours after administration. The results show the possibility that orally administered hyaluronic acid migrated into the skin. No excessive accumulation was observed and more than 90% of the hyaluronic acid was excreted in expired air or urine.

Dietary hyperoxaluria is not reduced by treatment with lactic acid bacteria

PubMed Central

2013-01-01

Background Secondary hyperoxaluria either based on increased intestinal absorption of oxalate (enteric), or high oxalate intake (dietary), is a major risk factor of calcium oxalate urolithiasis. Oxalate-degrading bacteria might have beneficial effects on urinary oxalate excretion resulting from decreased intestinal oxalate concentration and absorption. Methods Twenty healthy subjects were studied initially while consuming a diet normal in oxalate. Study participants were then placed on a controlled oxalate-rich diet for a period of 6 weeks. Starting with week 2 of the oxalate-rich diet, participants received 2.6 g/day of a lactic acid bacteria preparation for 5 weeks. Finally, subjects were examined 4 weeks after treatment while consuming again a normal-oxalate diet. Participants provided weekly 24-hour urine specimens. Analyses of blood samples were performed before and at the end of treatment. Results Urinary oxalate excretion increased significantly from 0.354 ± 0.097 at baseline to 0.542 ± 0.163 mmol/24 h under the oxalate-rich diet and remained elevated until the end of treatment, as did relative supersaturation of calcium oxalate. Plasma oxalate concentration was significantly higher after 5 weeks of treatment compared to baseline. Four weeks after treatment, urinary oxalate excretion and relative supersaturation of calcium oxalate fell to reach initial values. Conclusions Persistent dietary hyperoxaluria and increased plasma oxalate concentration can already be induced in healthy subjects without disorders of oxalate metabolism. The study preparation neither reduced urinary oxalate excretion nor plasma oxalate concentration. The preparation may be altered to select for lactic acid bacteria strains with the highest oxalate-degrading activity. PMID:24330782

Pharmacokinetics of S-Allyl-l-cysteine in Rats Is Characterized by High Oral Absorption and Extensive Renal Reabsorption.

PubMed

Amano, Hirotaka; Kazamori, Daichi; Itoh, Kenji

2016-02-01

S-Allylcysteine (SAC) is a key component of aged garlic extract, one of many garlic products. However, information on its pharmacokinetics has been scant except for data from a few animal studies. We designed this study to determine the overall pharmacokinetics of SAC in rats. After oral or intravenous administration of SAC to rats at a dose of 5 mg/kg, the plasma concentration-time profile of SAC and its metabolites, as well as the amounts excreted in bile and urine, were analyzed by using liquid chromatography tandem mass spectrometry. After oral administration, SAC was well absorbed with a bioavailability of 98%. Two major metabolites of SAC, N-acetyl-S-allylcysteine (NAc-SAC) and N-acetyl-S-allylcysteine sulfoxide (NAc-SACS), were detected in plasma, but their concentrations were markedly lower than those of SAC. SAC was metabolized to a limited extent, but most of the orally absorbed SAC was excreted into urine in the form of its N-acetylated metabolites. The amounts of SAC, NAc-SAC, and NAc-SACS excreted in urine over 24 h were 2.9%, 80%, and 11% of the orally administered SAC, respectively. The very low renal clearance (0.016 L ⋅ h(-1) ⋅ kg(-1)) of SAC indicated that it undergoes extensive renal reabsorption. These results collectively suggested that SAC was ultimately metabolized to NAc-SAC and NAc-SACS through the cycles of urinary excretion, renal reabsorption, and systemic recirculation. The pharmacokinetics of SAC in rats were characterized by high oral absorption, limited metabolism, and extensive renal reabsorption, all of which potentially contribute to its high and relatively long-lasting plasma concentrations. © 2016 American Society for Nutrition.

A Phase I Study to Investigate the Absorption, Pharmacokinetics, and Excretion of [(14)C]Prucalopride After a Single Oral Dose in Healthy Volunteers.

PubMed

Flach, Stephen; Scarfe, Graeme; Dragone, Jeffrey; Ding, Jie; Seymour, Mark; Pennick, Mike; Pankratz, Todd; Troy, Steven; Getsy, Jay

2016-09-01

Chronic constipation is a prevalent gastrointestinal disorder globally. It is often treated with medications such as laxatives. Newer therapies to improve gastric motility include the selective 5-hydroxytryptamine receptor-4 agonist prucalopride, which is licensed for the treatment of chronic constipation in adults. The aim of this study was to investigate the pharmacokinetic properties and excretion of prucalopride in healthy individuals, using a microtracer approach with (14)C radioactivity detection using liquid scintillation counting and accelerator mass spectrometry. This was a single-period, open-label, nonrandomized absorption, metabolism, and excretion study of [(14)C]prucalopride. Participants were 6 healthy men aged 18 to 50 years. After screening, participants were administered a single dose of [(14)C]prucalopride succinate 2 mg (~200 nCi). Postadministration, urine, feces, and blood samples were collected over a 10-day period. Safety and adverse event data were also collected. Almost 100% of the administered dose of radioactivity was recovered, with a mean (SD) of 84.2% (8.88%) recovered in urine and 13.3% (1.73%) recovered in feces. The mean blood-to-plasma concentration ratio of 1.9 indicated uptake of prucalopride into blood cells. The renal clearance of prucalopride was 17.0 (2.5) L/h, which is higher than the glomerular filtration rate in healthy individuals, suggesting active renal transport of prucalopride. Prucalopride was well tolerated, with no serious adverse events reported. Prucalopride was well absorbed and excreted mainly by the kidneys, including both passive and active transporter mechanisms. Quantitative recovery of the radioactive dose was achieved. Consistent with previous studies, prucalopride was generally well tolerated. ClinicalTrials.gov identifier: NCT01807000. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The ctenidium of the giant clam, Tridacna squamosa, expresses an ammonium transporter 1 that displays light-suppressed gene and protein expression and may be involved in ammonia excretion.

PubMed

Boo, Mel V; Hiong, Kum C; Goh, Enan J K; Choo, Celine Y L; Wong, Wai P; Chew, Shit F; Ip, Yuen K

2018-04-24

Ammonium transporters (AMTs) can participate in ammonia uptake or excretion across the plasma membrane of prokaryotic, plant and invertebrate cells. The giant clam, Tridacna squamosa, harbors nitrogen-deficient symbiotic zooxanthellae, and normally conducts light-enhanced ammonia absorption to benefit the symbionts. Nonetheless, it can excrete ammonia when there is a supply of exogenous nitrogen or exposed to continuous darkness. This study aimed to elucidate the role of AMT1 in the ctenidium of T. squamosa by cloning and characterizing the AMT1/AMT1, determining its subcellular localization, and examining changes in its transcript and protein expression levels in response to light exposure. The cDNA coding sequence of AMT1 from T. squamosa consisted of 1527 bp and encoded 508 amino acids of 54.6 kDa. AMT1-immunofluorescence was detected mainly at the apical epithelium of ctenidial filaments, and it decreased significantly after 12 h of exposure to light. By contrast, the epithelial cells surrounding the tertiary water channels in the ctentidium, which are known to exhibit light-enhanced glutamine synthetase expression and take part in the assimilation of exogenous ammonia in light, did not display any AMT1-immunolabelling. Furthermore, the transcript level and protein abundance of ctenidial AMT1/AMT1 decreased significantly at the 6th and 12th h of light exposure. Taken together, these results indicate that AMT1 might participate in ammonia excretion instead of ammonia absorption and assimilation in T. squamosa. It is probable that the expression levels of AMT1/AMT1 need to be down-regulated during light exposure to achieve light-enhanced ammonia uptake.

Calcium Kinetics During Space Flight

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Wastney, Meryl E.; OBrien, Kimberly O.; Lane, Helen W.

1999-01-01

Bone loss is one of the most detrimental effects of space flight, threatening to limit the duration of human space missions. The ability to understand and counteract this loss will be critical for crew health and safety during and after extended-duration missions. The hypotheses to be tested in this project are that space flight alters calcium homeostasis and bone mineral metabolism, and that calcium homeostasis and bone mineral metabolism will return to baseline within days to weeks of return to Earth. These hypotheses will be evidenced by elevated rates of bone mineral resorption and decreased bone mineral deposition, decreased absorption of dietary calcium, altered calcitropic endocrine profiles, elevated excretion of calcium in urine and feces, and elevated excretion of markers of bone resorption. The second hypothesis will be evidenced by return of indices of calcium homeostasis and bone metabolism to preflight levels within days to weeks of return to Earth. Studies will be conducted on International Space Station astronauts before, during, and after extended-duration flights. Measurements of calcium kinetics, bone mass, and endocrine/biochemical markers of bone and calcium homeostasis will be conducted. Kinetic studies utilizing dual isotope tracer kinetic studies and mathematical modeling techniques will allow for determination of bone calcium deposition, bone calcium resorption, dietary calcium absorption and calcium excretion (both urinary and endogenous fecal excretion). These studies will build upon preliminary work conducted on the Russian Mir space station. The results from this project will be critical for clarifying how microgravity affects bone and calcium homeostasis, and will provide an important control point for assessment of countermeasure efficacy. These results are expected to aid in developing countermeasures for bone loss, both for space crews and for individuals on Earth who have metabolic bone diseases.

Association of urinary citrate excretion, pH, and net gastrointestinal alkali absorption with diet, diuretic use, and blood glucose concentration.

PubMed

Perinpam, Majuran; Ware, Erin B; Smith, Jennifer A; Turner, Stephen T; Kardia, Sharon L R; Lieske, John C

2017-10-01

Urinary citrate (Ucit) protects against urinary stone formation. Acid base status and diet influence Ucit. However, the effect of demographics, diet, and glucose metabolism on Ucit excretion, urinary pH (U-pH) and net gastrointestinal alkali absorption (NAA) are not known. Twenty-four hour urine samples, blood glucose, creatinine, and cystatin C were obtained from non-Hispanic white sibships in Rochester, MN ( n  = 446; 64.5 ± 9 years; 58% female). Diet was assessed by a food frequency questionnaire. The impact of blood glucose, demographics and dietary elements on Ucit excretion, U-pH, and NAA were evaluated in bivariate and multivariable models and interaction models that included age, sex, and weight. NAA significantly associated with Ucit and U-pH In multivariate models Ucit increased with age, weight, eGFR C ys , and blood glucose, but decreased with loop diuretic and thiazide use. U-pH decreased with serum creatinine, blood glucose, and dietary protein but increased with dietary potassium. NAA was higher in males and increased with age, weight, eGFR C ys and dietary potassium. Significant interactions were observed for Ucit excretion with age and blood glucose, weight and eGFR C ys, and sex and thiazide use. Blood glucose had a significant and independent effect on U-pH and also Ucit. This study provides the first evidence that blood glucose could influence urinary stone risk independent of urinary pH, potentially providing new insight into the association of obesity and urinary stone disease. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Importance of colonic support for energy absorption as small-bowel failure proceeds.

PubMed

Nordgaard, I; Hansen, B S; Mortensen, P B

1996-08-01

Digestive processes in the human colon are affected by the bacterial fermentation of malabsorbed carbohydrates and protein to short-chain fatty acids, which are absorbed and supply energy. Energy absorption was measured by assessing fecal bomb calorimetry in 148 patients with extremely different small-bowel lengths. Colectomy increased fecal loss of energy by 0.8 MJ/d and carbohydrate excretion fivefold in patients with a small-bowel length between normal and 150-200 cm. Patients with 100-150 cm small bowel, with and without a colon, excreted 1.3 +/- 0.3 and 4.7 +/- 0.5 MJ/d, respectively (P = 0.002), a difference of 3.4 MJ/d. Patients with < 100 cm small bowel excreted 3.1 +/- 0.4 and 8.0 +/- 1.3 MJ/d, respectively (P = 0.03), a difference of 4.9 MJ/d. Similar and highly significant differences were calculated by linear-regression analysis. Considerably less energy was excreted as carbohydrate than as fat in patients with preserved colonic function, probably because fermentation removed carbohydrate as absorbed short-chain fatty acids, whereas a comparable amount of energy was lost as carbohydrate and fat in patients without colonic function. The correlation between malabsorbed energy and small-bowel length was poor (r = -0.41) but increased when data for patients with and without a colon were separated (r = -0.56 and r = -0.58, respectively). Small-bowel length, however, was still an inaccurate measure of intestinal failure to absorb nutrient energy. In conclusion, colonic digestion may support energy supply with up to approximately 4.2 MJ/d as small-bowel failure proceeds, but it is of minor importance in patients with a small-bowel length > 200 cm or malabsorption < 2.1 MJ/d.

Variable Isoflavone Contents of Red Clover Products Affect Intestinal Disposition of Biochanin A, Formononetin, Genistein and Daidzein

PubMed Central

Wang, Stephen W.J.; Chen, Yan; Joseph, Tiby; Hu, Ming

2009-01-01

Marketed red clover products use a wide variety of labels and the isoflavone contents from the lable is ambiguous. In the present study, we analyzed the content of various isoflavone products, and determined a) the content and b) how sample matrix of red clover products affects intestinal disposition of main isoflavones within it using the human intestinal Caco-2 cell model. Analysis using high and ultra-performance liquid chromatography indicates that the isoflavone content varied significantly (p<0.05) between the chosen products. Consequently, rates of isoflavone absorption across the Caco-2 cell monolayers varied (p<0.05) greatly. Unexpectedly, permeabilities of biochanin A and formononetin (two key biomarkers) were found to be significantly affected (p<0.05) by the product matrix. As expected, biochanin A was the only isoflavone with noticeable metabolite peaks in both apical and basolateral sides. Interestingly, rates of metabolism and the polarity of the glucuronidated biochanin A excretion were also significantly altered (p<0.05) by product matrix. Studies using breast cancer resistance protein inhibitor dipyridamole showed that both the apical and basolateral excretion of biochanin A glucuronides were significantly (P<0.05) reduced (7.5 and 9.4-fold, respectively) when dipyridamole is present. This provides evidence that BCRP is the main transporter responsible for the apical efflux of isoflavone glucuronides. In conclusion, the isoflavone contents of the marketed red clover products are highly variable, and product matrix significantly affected intestinal disposition of red clover isoflavones by altering their absorption rates, permeabilities, biochanin A glucuronide excretion rates, and the polarity of biochanin A glucuronide excretion. This research provides scientific evidence to support the standardization effort so that consumers can make intelligent product choices. PMID:18370585

Titanium Dioxide Nanoparticle-Biomolecule Interactions Influence Oral Absorption

PubMed Central

Jo, Mi-Rae; Yu, Jin; Kim, Hyoung-Jun; Song, Jae Ho; Kim, Kyoung-Min; Oh, Jae-Min; Choi, Soo-Jin

2016-01-01

Titanium dioxide (TiO2) nanoparticles (NPs) have been widely applied in various industrial fields, such as electronics, packaging, food, and cosmetics. Accordingly, concerns about the potential toxicity of TiO2 NPs have increased. In order to comprehend their in vivo behavior and potential toxicity, we must evaluate the interactions between TiO2 NPs and biomolecules, which can alter the physicochemical properties and the fate of NPs under physiological conditions. In the present study, in vivo solubility, oral absorption, tissue distribution, and excretion kinetics of food grade TiO2 (f-TiO2) NPs were evaluated following a single-dose oral administration to rats and were compared to those of general grade TiO2 (g-TiO2) NPs. The effect of the interactions between the TiO2 NPs and biomolecules, such as glucose and albumin, on oral absorption was also investigated, with the aim of determining the surface interactions between them. The intestinal transport pathway was also assessed using 3-dimensional culture systems. The results demonstrate that slightly higher oral absorption of f-TiO2 NPs compared to g-TiO2 NPs could be related to their intestinal transport mechanism by microfold (M) cells, however, most of the NPs were eliminated through the feces. Moreover, the biokinetics of f-TiO2 NPs was highly dependent on their interaction with biomolecules, and the dispersibility was affected by modified surface chemistry. PMID:28335354

Determination of neostigmine and pyridostigmine in the urine of patients with myasthenia gravis

PubMed Central

Nowell, P. T.; Scott, Carol A.; Wilson, A.

1962-01-01

A method has been described for the estimation of neostigmine and pyridostigmine in urine by ion exchange treatment and colorimetric estimation of the blue complex produced when either of the drugs is made to react with bromophenol blue. Urine containing 2 μg/ml. or more of neostigmine or 3 μg/ml. or more of pyridostigmine can be quantitatively estimated. After intramuscular injection of neostigmine to patients with myasthenia gravis, up to 67% of the drug is excreted, whilst after oral administration less than 5% is excreted. When pyridostigmine is given by mouth, the amount of drug excreted in the urine varies between approximately 2 and 16%. It has been established by chromatographic analysis that the blue complexes formed under these conditions are due only to neostigmine and pyridostigmine respectively and that the quantitative estimation described is a true measure of the amount of these drugs excreted in the urine. The significance of these results is discussed in relation to the absorption and metabolism of the two drugs. PMID:14480648

Pharmacokinetics of experimental pentavalent antimony after intramuscular administration in adult volunteers.

PubMed

Vásquez, Laura; Scorza Dagert, José V; Scorza, José V; Vicuña-Fernández, Nelson; de Peña, Yaneira Petit; López, Sabrina; Bendezú, Herminia; Rojas, Elina; Vásquez, Libia; Pérez, Belén

2006-05-01

Pentavalent antimony (SbV) has demonstrated therapeuticeffectiveness against clinical manifestations of leishmaniasis, an infection caused by Leishmania, a genus of flagellate protozoa comprising parasites of worldwide distribution. Approximately 1.8 million new cases are reported annually. The aim of this study was to assess the pharmacokinetics of the investigational generic SbV, Ulamina (pentachloride of antimony + N-methylglucamine), in healthy adult volunteers. In this study, SbV was administered IM as a single 5-mg/kg dose.Blood samples were collected at 0.25, 0.75, 1, 2, 4, 8, 12, and 24 hours after administration; urine samples were collected at 6-hour intervals during the 24-hour postadministration period. Determination of trivalent antimony, SbV, and total antimony concentrations in blood and urine samples was carried out using atomic absorption spectrometry. Clinical history was reviewed and the subjects were monitored before and after administration of SbV using physical examination, weight, and hepatic- and renal-function studies. The pharmacokinetic parameters calculated were Cmax, Tmax, absorption constant (Ka), elimination constant (Kel), AUC2-24h, AUC0-∞, elimination phase (t½β), volume of distribution (Vd), and urinary excretion rate. Five subjects (3 men, 2 women; mean age, 28 years [range, 18-34 years]) were included in the study. One hour after drug administration the following values were obtained: Cmax, 1.1 μg/mL; Tmax, 1.3 hours; Ka, 1.87 hours; Kel, 0.043 hours; AUC0-24h, 12.26 μg/mL · h; AUC0-∞, 19.84 μg/mL · h; t½β, 17.45 hours; Vd, 6.6 L/kg; and urinary excretion rate, 2.8 μg/h; these were mean values for the entire study group. The single dose was well tolerated by all subjects. The investigational generic SbV, Ulamina, was associated with linearelimination after IM administration of a single 5-mg/kg dose. A 2-compartment pharmacokinetic model was observed in these volunteers; the mean t½β, was 17.45 hours and the mean Vd was 6.6 L/kg.

Chiral Polychlorinated Biphenyls: Absorption, Metabolism and Excretion – A Review

PubMed Central

Kania-Korwel, Izabela; Lehmler, Hans-Joachim

2015-01-01

Seventy eight out of the 209 possible polychlorinated biphenyl (PCB) congeners are chiral, nineteen of which exist under ambient conditions as stable rotational isomers that are non-superimposable mirror images of each other. These congeners (C-PCBs) represent up to 6% by weight of technical PCB mixtures and undergo considerable atropisomeric enrichment in wildlife, laboratory animals and humans. The objective of this review is to summarize our current knowledge of the processes involved in the absorption, metabolism and excretion of C-PCBs and their metabolites in laboratory animals and humans. C-PCBs are absorbed and excreted by passive diffusion, a process that, like other physicochemical processes, is inherently not atropselective. In mammals, metabolism by cytochrome P450 (P450) enzymes represents a major route of elimination for many C-PCBs. In vitro studies demonstrate that C-PCBs with a 2,3,6-trichlorosubstituion pattern in one phenyl ring are readily oxidized to hydroxylated PCB metabolites (HO-PCBs) by P450 enzymes, such as rat CYP2B1, human CYP2B6 and dog CYP2B11. The oxidation of C-PCBs is atropselective, thus resulting in a species and congener-dependent atropisomeric enrichment of C-PCBs and their metabolites. This atropisomeric enrichment of C-PCBs and their metabolites likely plays a poorly understood role in the atropselective toxicity of C-PCBs and, therefore, warrants further investigation. PMID:25651810

Dietary hydroxypropyl methylcellulose increases excretion of saturated and trans fats by hamsters fed fast food diets.

PubMed

Yokoyama, Wallace; Anderson, William H K; Albers, David R; Hong, Yun-Jeong; Langhorst, Marsha L; Hung, Shao-Ching; Lin, Jiann-Tsyh; Young, Scott A

2011-10-26

In animal studies, hydroxypropyl methylcellulose (HPMC) intake results in increased fecal fat excretion; however, the effects on dietary saturated fatty acids (SATs) and trans-fatty acids (TRANS) remain unknown. This study investigated the effect of HPMC on digestion and absorption of lipids in male Golden Syrian hamsters fed either freeze-dried ground pizza (PZ), pound cake (PC), or hamburger and fries (BF) supplemented with dietary fiber from either HPMC or microcrystalline cellulose (MCC) for 3 weeks. We observed greater excretion of SATs and TRANS by both diets supplemented with HPMC or MCC as compared to the feed. SAT, TRANS, and unsaturated fatty acids (UNSAT) contents of feces of the PZ diet supplemented with HPMC were 5-8 times higher than diets supplemented with MCC and tended to be higher in the PC- and BF-HPMC supplemented diets as well. We also observed significant increases in fecal excretion of bile acids (2.6-3-fold; P < 0.05), sterols (1.1-1.5-fold; P < 0.05), and unsaturated fatty acids (UNSAT, 1.7-4.5-fold; P < 0.05). The animal body weight gain was inversely correlated with the excretion of fecal lipid concentrations of bile acids (r = -0.56; P < 0.005), sterols (r = -0.48; P < 0.005), SAT (r = -0.69; P < 0.005), UNSAT (r = -0.67; P < 0.005), and TRANS (r = -0.62; P < 0.005). Therefore, HPMC may be facilitating fat excretion in a biased manner with preferential fecal excretion of both TRANS and SAT in hamsters fed fast food diets.

Comparison of urinary excretion of radon from the human body before and after radon bath therapy.

PubMed

Kávási, Norbert; Kovács, Tibor; Somlai, János; Jobbágy, Viktor; Nagy, Katalin; Deák, Eszter; Berhés, István; Bender, Tamás; Ishikawa, Tetsuo; Tokonami, Shinji

2011-07-01

Theoretically, the human body absorbs radon through the lungs and the skin and excretes it through the lungs and the excretory organs during radon bath therapy. To check this theory, the radon concentrations in urine samples were compared before and after radon bath therapy. During the therapy, the geometric mean (GM) and the geometric standard deviation of the radon concentration in air and in the bath water were 979 Bq m(-3), 1.58 and 73.6 Bq dm(-3), 1.1, respectively. Since radon was detected in each urine sample (GM around 3.0 Bq dm(-3)), urinary excretion of radon was confirmed. The results of this study can neither reject nor confirm the hypothesis of radon absorption through the skin. A 15 times higher increment of inhaled radon level did not cause significant changes in radon of urine samples.

Absorption and excretion of 14C-perfluorooctanoic acid (PFOA)in angus cattle (Bos taurus)

USDA-ARS?s Scientific Manuscript database

Perfluorinated chemicals (PFCs), such as perfluorooctanoic acid (PFOA), are environmentally persistent industrial chemicals often found in biosolids. Application of these biosolids to pastures raises concern about accumulation of PFOA in the edible tissues of food animals. Because data on the absorp...

Physiologic effects of ergot alkaloids: What happens when excretion does not equal absorption?

USDA-ARS?s Scientific Manuscript database

Increased persistence of tall fescue (Lolium arundinaceum) infested with an endophytic fungus Epichloë coenophiala (formerly Neotyphodium coenophialum) in forage-based agriculture has led to increased effort in understanding the negative effects caused by consumption of ergot alkaloids by animals co...

Trace mineral absorption status in infants with ileostomies

USDA-ARS?s Scientific Manuscript database

Infants with ileostomies are often supplemented with zinc and limited in copper, because of potential increased bilious zinc loss and increased cholestasis due to reduced copper excretion. However, no data exist on zinc or copper balance in infants with ileostomies. To determine the effect of an ile...

Human Diet and Nutrition. LC Science Tracer Bullet.

ERIC Educational Resources Information Center

Rodgers, Kay, Comp.

This bibliography of publications on nutrition and diet includes materials on the following subjects: diet selection, nutritional content of foods, ingestion, digestion, absorption, transportation, metabolism, utilization of nutrients and food by the cells of the body, excretion, and the results of inadequate, deficient, or excessive nutrient…

Reducing mineral usage in feedlot diets for Nellore cattle: I. Impacts of calcium, phosphorus, copper, manganese, and zinc contents on microbial efficiency and ruminal, intestinal, and total digestibility of dietary constituents.

PubMed

Sathler, D F T; Prados, L F; Zanetti, D; Silva, B C; Filho, S C Valadares; Pacheco, M V C; Amaral, P M; Rennó, L N; Paulino, M F

2017-04-01

This study evaluated intake, microbial efficiency, and ruminal, small and large intestinal, and total digestibility of DM, OM, CP, and NDF, as well as availability of Ca, P, Mg, Na, K, Cu, Mn, and Zn in Zebu cattle fed with or without supplemental sources of Ca and P or a micromineral premix. Five rumen- and ileum-cannulated Nellore bulls (BW = 200 ± 10.5 kg; 9 mo) were used in the experiment, distributed in a 5 × 5 Latin square design. The experiment was developed in a 2 × 2 + 1 factorial design to measure the effects of mineral supplementation on intake, digestibility, and site of nutrient absorption. The factors consisted of 2 Ca and P levels (macromineral factor; CaP+ or CaP-) and 2 microminerals levels (micromineral factor; CuMnZn+ or CuMnZn-). In addition, a treatment with alimentary restriction (REST) was evaluated at 1.7% of BW. Nutrient fluxes were measured in the omasum and ileum, in addition to intake and fecal excretion. Microbial efficiency was estimated using purine derivative excretion. Dry matter, OM, NDF, CP intake, and total digestibility were not affected ( ≥ 0.058) by the absence of Ca, P, Cu, Mn, and Zn supplementation. Intake of Ca, P, and Mg were reduced ( < 0.01) by CaP-. The absence of CuMnZn reduced ( < 0.01) Cu, Mn, and Zn intake. Ruminal recycling of P, Na, and K is significant for increasing the influx of these minerals to the digestive tract; however, influences of treatments were not observed. The small and large intestines contributed to mineral absorption in different proportions ( < 0.05), according to minerals and treatments. Because of the similarity ( > 0.05) of OM, NDF, and CP digestion sites and coefficients, we assume that omitting supplemental sources of Ca, P, Cu, Mn, and Zn may be an option in raising cattle on feedlots. If supplementation is viable, knowledge about the specific absorption site of each mineral could positively impact choices about the supplemental source.

Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100.

PubMed

Yu, Rosie Z; Kim, Tae-Won; Hong, An; Watanabe, Tanya A; Gaus, Hans J; Geary, Richard S

2007-03-01

The pharmacokinetics of a 2'-O-(2-methoxyethyl)-modified oligonucleotide, ISIS 301012 [targeting human apolipoprotein B-100 (apoB-100)], was characterized in mouse, rat, monkey, and human. Plasma pharmacokinetics following parental administration was similar across species, exhibiting a rapid distribution phase with t(1/2alpha) of several hours and a prolonged elimination phase with t(1/2beta) of days. The prolonged elimination phase represents equilibrium between tissues and circulating drug due to slow elimination from tissues. Absorption was nearly complete following s.c. injection, with bioavailability ranging from 80 to 100% in monkeys. Plasma clearance scaled well across species as a function of body weight alone, and this correlation was improved when corrected for plasma protein binding. In all of the animal models studied, the highest tissue concentrations of ISIS 301012 were observed in kidney and liver. Urinary excretion was less than 3% in monkeys and human in the first 24 h. ISIS 301012 is highly bound to plasma proteins, probably preventing rapid removal by renal filtration. However, following 25 mg/kg s.c. administration in mouse and 5-mg/kg i.v. bolus administration in rat, plasma concentrations of ISIS 301012 exceeded their respective protein binding capacity. Thus, urinary excretion increased to 16% or greater within the first 24 h. Albeit slow, urinary excretion of ISIS 301012 and its shortened metabolites is the ultimate elimination pathway of this compound, as demonstrated by 32% of dose recovered in total excreta by 14 days in a rat mass balance study. The pharmacokinetics of ISIS 301012 in human is predictable from the pharmacokinetics measured in animals. The pharmacokinetic properties of ISIS 301012 provide guidance for clinical development and support infrequent dose administration.

Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

PubMed Central

Vrins, Carlos L. J.; van der Velde, Astrid E.; van den Oever, Karin; Levels, Johannes H. M.; Huet, Stephane; Oude Elferink, Ronald P. J.; Kuipers, Folkert; Groen, Albert K.

2009-01-01

Peroxisome proliferator-activated receptor delta (PPARδ) is involved in regulation of energy homeostasis. Activation of PPARδ markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased hepatobiliary cholesterol secretion, nor by reduced cholesterol absorption. To test the hypothesis that PPARδ activation leads to stimulation of transintestinal cholesterol efflux (TICE), we quantified it by intestine perfusions in FVB mice treated with PPARδ agonist GW610742. To exclude the effects on cholesterol absorption, mice were also treated with cholesterol absorption inhibitor ezetimibe or ezetimibe/GW610742. GW601742 treatment had little effect on plasma lipid levels but stimulated both fecal neutral sterol excretion (∼200%) and TICE (∼100%). GW610742 decreased intestinal Npc1l1 expression but had no effect on Abcg5/Abcg8. Interestingly, expression of Rab9 and LIMPII, encoding proteins involved in intracellular cholesterol trafficking, was increased upon PPARδ activation. Although treatment with ezetimibe alone had no effect on TICE, it reduced the effect of GW610742 on TICE. These data show that activation of PPARδ stimulates fecal cholesterol excretion in mice, primarily by the two-fold increase in TICE, indicating that this pathway provides an interesting target for the development of drugs aiming at the prevention of atherosclerosis. PMID:19439761

Absorption and excretion of 14C-perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) in beef cattle

USDA-ARS?s Scientific Manuscript database

Perfluoroalkyl compounds such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are industrial chemicals that are environmentally persistent. Both PFOS and PFOA are found in biosolids, and the application of these contaminated biosolids to pastures has raised concerns about possi...

Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds

PubMed Central

Loh, Yong Yao; Nagao, Kazunori; Hoover, Andrew J.; Hesk, David; Rivera, Nelo R.; Colletti, Steven L.; Davies, Ian W.; MacMillan, David W. C.

2018-01-01

Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp3 carbon-hydrogen bonds in a single step, using isotopically labeled water (D2O or T2O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T2O from T2, providing access to high-specific-activity T2O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies. PMID:29123019

Biokinetics of zinc oxide nanoparticles: toxicokinetics, biological fates, and protein interaction

PubMed Central

Choi, Soo-Jin; Choy, Jin-Ho

2014-01-01

Biokinetic studies of zinc oxide (ZnO) nanoparticles involve systematic and quantitative analyses of absorption, distribution, metabolism, and excretion in plasma and tissues of whole animals after exposure. A full understanding of the biokinetics provides basic information about nanoparticle entry into systemic circulation, target organs of accumulation and toxicity, and elimination time, which is important for predicting the long-term toxic potential of nanoparticles. Biokinetic behaviors can be dependent on physicochemical properties, dissolution property in biological fluids, and nanoparticle–protein interaction. Moreover, the determination of biological fates of ZnO nanoparticles in the systemic circulation and tissues is critical in interpreting biokinetic behaviors and predicting toxicity potential as well as mechanism. This review focuses on physicochemical factors affecting the biokinetics of ZnO nanoparticles, in concert with understanding bioavailable fates and their interaction with proteins. PMID:25565844

Propesticides and their use as agrochemicals.

PubMed

Jeschke, Peter

2016-02-01

The synthesis of propesticides is an important concept in design of modern agrochemicals with optimal efficacy, environmental safety, user friendliness and economic variability. Based on increasing knowledge of the biochemistry and genetics of major pest insects, weeds and agricultural pathogens, the search for selectivity has become an ever more important part of pesticide development and can be achieved by appropriate structural modifications of the active ingredient. Propesticides affect the absorption, distribution, metabolism and excretion parameters, which can lead to biological superiority of these modified active ingredients over their non-derivatised analogues. Various selected commercial propesticides testify to the successful utilisation of this concept in the design of agrochemicals. This review describes comprehensively the successful utilisation of propesticides and their role in syntheses of modern agrochemicals, exemplified by selected commercial products coming from different agrochemical areas. © 2015 Society of Chemical Industry.

Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations.

PubMed

Jin, Xiannu; Luong, Thu-Lan; Reese, Necole; Gaona, Heather; Collazo-Velez, Vanessa; Vuong, Chau; Potter, Brittney; Sousa, Jason C; Olmeda, Raul; Li, Qigui; Xie, Lisa; Zhang, Jing; Zhang, Ping; Reichard, Greg; Melendez, Victor; Marcsisin, Sean R; Pybus, Brandon S

2014-01-01

Malaria is a major health concern and affects over 300million people a year. Accordingly, there is an urgent need for new efficacious anti-malarial drugs. A major challenge in developing new anti-malarial drugs is to design active molecules that have preferable drug-like characteristics. These "drug-like" characteristics include physiochemical properties that affect drug absorption, distribution, metabolism, and excretion (ADME). Compounds with poor ADME profiles will likely fail in vivo due to poor pharmacokinetics and/or other drug delivery related issues. There have been numerous assays developed in order to pre-screen compounds that would likely fail in further development due to poor absorption properties including PAMPA, Caco-2, and MDCK permeability assays. The use of cell-based permeability assays such as Caco-2 and MDCK serve as surrogate indicators of drug absorption and transport, with the two approaches often used interchangeably. We sought to evaluate both approaches in support of anti-malarial drug development. Accordingly, a comparison of both assays was conducted utilizing apparent permeability coefficient (Papp) values determined from liquid chromatography/tandem mass spectrometry (LC-MS) analyses. Both Caco-2 and MDCK permeability assays produced similar Papp results for potential anti-malarial compounds with low and medium permeability. Differences were observed for compounds with high permeability and compounds that were P-gp substrates. Additionally, the utility of MDCK-MDR1 permeability measurements was demonstrated in probing the role of P-glycoprotein transport in Primaquine-Chloroquine drug-drug interactions in comparison with in vivo pharmacokinetic changes. This study provides an in-depth comparison of the Caco-2 and MDCK-MDR1 cell based permeability assays and illustrates the utility of cell-based permeability assays in anti-malarial drug screening/development in regard to understanding transporter mediated changes in drug absorption/distribution. Published by Elsevier Inc.

Effects of the antituberculous drug ethambutol on zinc balance, distribution, and turnover: short-term studies modeling chronic toxicity

DOE Office of Scientific and Technical Information (OSTI.GOV)

King, A.B.

1987-01-01

Alterations in Zn metabolism have been reported in both tuberculous patients and experimental animals receiving ethambutol (d-2-2'-ethylenediimino-di-1-butanol dihydrochloride) (EMB), and these changes have been associated with ocular side effects of EMB. EMB has chelating properties but is not likely to chelate Zn at physiologic pH. However, its acid metabolite is a stronger chelator. This research addressed whether EMB affects the absorption and disposition of dietary Zn, and whether effects of EMB on Zn are modified by (a) marginal Zn intake of (b) drugs that may induce metabolism of EMB. Weanling male Sprague-Dawley rats fed an AIN-76A diet received daily bymore » gavage either deionized water or EMB doses of 400-1600 mg/kg bw. in a preliminary, 15-day dose-response study and 400-600 mg/kg in three subsequent 15- to 30-day studies. Apparent absorption and biological turnover of Zn were measured by /sup 65/Zn balance and retention in rats fed adequate (49 ppm) or marginal (11 ppm) Zn. Effects of EMB were similar in both dietary groups. EMB treatment produced alopecia and reduced feed intake, feed efficiency, weight gain, and serum Zn, but showed no effect on hepatic, renal, or femoral Zn concentrations. Absorption, turnover, and urinary excretion of Zn were increased in rats fed EMB.« less

Ca2+-driven intestinal HCO3− secretion and CaCO3 precipitation in the European flounder in vivo: influences on acid-base regulation and blood gas transport

PubMed Central

Cooper, Christopher A.; Whittamore, Jonathan M.

2010-01-01

Marine teleost fish continuously ingest seawater to prevent dehydration and their intestines absorb fluid by mechanisms linked to three separate driving forces: 1) cotransport of NaCl from the gut fluid; 2) bicarbonate (HCO3−) secretion and Cl− absorption via Cl−/HCO3− exchange fueled by metabolic CO2; and 3) alkaline precipitation of Ca2+ as insoluble CaCO3, which aids H2O absorption). The latter two processes involve high rates of epithelial HCO3− secretion stimulated by intestinal Ca2+ and can drive a major portion of water absorption. At higher salinities and ambient Ca2+ concentrations the osmoregulatory role of intestinal HCO3− secretion is amplified, but this has repercussions for other physiological processes, in particular, respiratory gas transport (as it is fueled by metabolic CO2) and acid-base regulation (as intestinal cells must export H+ into the blood to balance apical HCO3− secretion). The flounder intestine was perfused in vivo with salines containing 10, 40, or 90 mM Ca2+. Increasing the luminal Ca2+ concentration caused a large elevation in intestinal HCO3− production and excretion. Additionally, blood pH decreased (−0.13 pH units) and plasma partial pressure of CO2 (Pco2) levels were elevated (+1.16 mmHg) at the highest Ca perfusate level after 3 days of perfusion. Increasing the perfusate [Ca2+] also produced proportional increases in net acid excretion via the gills. When the net intestinal flux of all ions across the intestine was calculated, there was a greater absorption of anions than cations. This missing cation flux was assumed to be protons, which vary with an almost 1:1 relationship with net acid excretion via the gill. This study illustrates the intimate link between intestinal HCO3− production and osmoregulation with acid-base balance and respiratory gas exchange and the specific controlling role of ingested Ca2+ independent of any other ion or overall osmolality in marine teleost fish. PMID:20130227

Ca2+-driven intestinal HCO(3)(-) secretion and CaCO3 precipitation in the European flounder in vivo: influences on acid-base regulation and blood gas transport.

PubMed

Cooper, Christopher A; Whittamore, Jonathan M; Wilson, Rod W

2010-04-01

Marine teleost fish continuously ingest seawater to prevent dehydration and their intestines absorb fluid by mechanisms linked to three separate driving forces: 1) cotransport of NaCl from the gut fluid; 2) bicarbonate (HCO(3)(-)) secretion and Cl(-) absorption via Cl(-)/HCO(3)(-) exchange fueled by metabolic CO(2); and 3) alkaline precipitation of Ca(2+) as insoluble CaCO(3), which aids H(2)O absorption). The latter two processes involve high rates of epithelial HCO(3)(-) secretion stimulated by intestinal Ca(2+) and can drive a major portion of water absorption. At higher salinities and ambient Ca(2+) concentrations the osmoregulatory role of intestinal HCO(3)(-) secretion is amplified, but this has repercussions for other physiological processes, in particular, respiratory gas transport (as it is fueled by metabolic CO(2)) and acid-base regulation (as intestinal cells must export H(+) into the blood to balance apical HCO(3)(-) secretion). The flounder intestine was perfused in vivo with salines containing 10, 40, or 90 mM Ca(2+). Increasing the luminal Ca(2+) concentration caused a large elevation in intestinal HCO(3)(-) production and excretion. Additionally, blood pH decreased (-0.13 pH units) and plasma partial pressure of CO(2) (Pco(2)) levels were elevated (+1.16 mmHg) at the highest Ca perfusate level after 3 days of perfusion. Increasing the perfusate [Ca(2+)] also produced proportional increases in net acid excretion via the gills. When the net intestinal flux of all ions across the intestine was calculated, there was a greater absorption of anions than cations. This missing cation flux was assumed to be protons, which vary with an almost 1:1 relationship with net acid excretion via the gill. This study illustrates the intimate link between intestinal HCO(3)(-) production and osmoregulation with acid-base balance and respiratory gas exchange and the specific controlling role of ingested Ca(2+) independent of any other ion or overall osmolality in marine teleost fish.

EXCRETION OF P$sup 32$ AFTER THERAPY FOR POLYCYTHEMIA RUBRA VERA

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weijer, D.L.; Duggan, H.E.; Scott, D.B.

1962-09-01

Fifteen subjects undergoing treatment for polycythemia rubra vera were given P/sup 32/. Carrier-free P/sup 32/ was administered intravenously in 11 and orally in 6. Total excretion studies were carried out in each case for periods of 5 to 22 days. Average urinary excretion of P/sup 32/, as a percentage of the initial dose to the end of 3 days for the entire series, was 14.3%, with limits of 6.4 and 18.7%. The corresponding 5-day average amounted to 17.8%, with limits of 7.5 and 22.5%. In the six patients treated orally, the average 3-day urinary excretion was 11.2% and for 5more » days was 14.2%. For the 11 patients treated intravenously, the average 3-day excretion was 16.1%, the average 5-day excretion 19.8%. The average fecal excretion as a percentage of the initial dose to the end of 3 days was 1.7%, with limits of 0.1 and 5.5%, and the average 5-day excretion was 2.5%, with limits 0.5 and 5.9%. In the orally treated fasting group the total stool excretion to the end of 3 days was 2.0 and 2.5% at the end of 5 days. Of the 10 polycythemia patients treated intravenously, the stool excretion to the end of 3 days was 1.5% and at 5 days 2.5%. Under fasting conditions (both before and after the administration of P/sup 32/) with little or no carrier added, the fecal excretion of P/sup 32/is small. Thus, the total excretion of P/sup 32/ does not differ significantly for oral and intravenous administration. Hence, despite contrary reports, it appears that under fasting conditions of administration it is not necessary to increase the oral dose of P/ sup 32/ to 4/3 of the intravenous dose in order to obtain equivalent absorption of the administered dose. It is concluded that the P/sup 32/ content of urine in the first 24 hr after therapy, by either route of administration, indicates whether or not a particular patient will retain the dose within normal limits. (BBB)« less

Evaluation of the Pharmacodynamic Effects of the Potassium Binder RDX7675 in Mice.

PubMed

Davidson, James P; King, Andrew J; Kumaraswamy, Padmapriya; Caldwell, Jeremy S; Korner, Paul; Blanks, Robert C; Jacobs, Jeffrey W

2018-05-01

Hyperkalemia is a common complication in patients with heart failure or chronic kidney disease, particularly those who are taking inhibitors of the renin-angiotensin-aldosterone system. RDX7675, the calcium salt of a reengineered polystyrene sulfonate-based resin, is a potassium binder that is being investigated as a novel treatment for hyperkalemia. This study evaluated the pharmacodynamic effects of RDX7675 in mice, compared to 2 current treatments, sodium polystyrene sulfonate (SPS) and patiromer. Seven groups of 8 male CD-1 mice were given either standard chow (controls) or standard chow containing 4.0% or 6.6% active moiety of RDX7675, patiromer, or SPS for 72 hours. Stool and urine were collected over the final 24 hours of treatment for ion excretion analyses. RDX7675 increased stool potassium (mean 24-hour excretion: 4.0%, 9.19 mg; 6.6%, 18.11 mg; both P < .0001) compared with controls (4.47 mg) and decreased urinary potassium (mean 24-hour excretion: 4.0%, 12.05 mg, P < .001; 6.6%, 6.68 mg, P < .0001; vs controls, 20.38 mg). The potassium-binding capacity of RDX7675 (stool potassium/gram of resin: 4.0%, 1.14 mEq/g; 6.6%, 1.32 mEq/g) was greater (all P < .0001) than for patiromer (4.0%, 0.63 mEq/g; 6.6%, 0.48 mEq/g) or SPS (4.0%, 0.73 mEq/g; 6.6% 0.55 mEq/g). RDX7675 and patiromer decreased urinary sodium (mean 24-hour excretion: 0.07-1.38 mg; all P < .001) compared to controls (5.01 mg). In contrast, SPS increased urinary sodium excretion (4.0%, 13.31 mg; 6.6%, 17.60 mg; both P < .0001) compared to controls. RDX7675 reduced intestinal potassium absorption and had a greater potassium-binding capacity than patiromer or SPS in mice. The calcium-based resins RDX7675 and patiromer reduced intestinal sodium absorption, unlike sodium-based SPS. These results support further studies in humans to confirm the potential of RDX7675 for the treatment of patients with hyperkalemia.

RECOMMENDATIONS FOR UO3 PLANT BIOASSAY

DOE Office of Scientific and Technical Information (OSTI.GOV)

Carbaugh, Eugene H.

2010-07-12

Alternative urine bioassay programs are described for application with decontamination and decommissioning activities at the Hanford UO3 Plant. The alternatives are based on quarterly or monthly urine bioassay for recycled uranium, assuming multiple acute inhalation intakes of recycled uranium occurring over a year. The inhalations are assumed to be 5µm AMAD particles of 80% absorption type F and 20% absorption type M. Screening levels, expressed as daily uranium mass excretion rates in urine, and the actions associated with these levels are provided for both quarterly and monthly sampling frequencies.

STUDY ON DIGESTION AND ABSORPTION FOLLOWING GASTROINTESTINAL SURGERIES WITH AN APPLICATION OF RADIOACTIVE ISOTOPES (WITH SPECIAL EMPHASIS ON CASES OF GASTRIC SURGERIES)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakayama, K.; Ohtsuka, A.; Kuraishi, T.

1959-10-31

The digestion and absorption of proteins and fats were studied in patients following radical surgery for carcinoma of the digestive tract. Proteins labeled with phosphorus-32 were synthesized in vivo using goat milk, hen eggs, and intestinal membrane and liver of a dog. Protein labeled with sulfur-35 was obtained from yeast. Amino acid was labeled with carbon-14. Sesame oil labeled with iodine-131 was used as an indicator of fat absorption. The indicators were given orally in test meals. Blood level and fecal and urinary excretion were measured. Procedures are outlined for preparing the labeled indicators. Data are tabulated. (C.H.)

Humanizing the zebrafish liver shifts drug metabolic profiles and improves pharmacokinetics of CYP3A4 substrates.

PubMed

Poon, Kar Lai; Wang, Xingang; Ng, Ashley S; Goh, Wei Huang; McGinnis, Claudia; Fowler, Stephen; Carney, Tom J; Wang, Haishan; Ingham, Phillip W

2017-03-01

Understanding and predicting whether new drug candidates will be safe in the clinic is a critical hurdle in pharmaceutical development, that relies in part on absorption, distribution, metabolism, excretion and toxicology studies in vivo. Zebrafish is a relatively new model system for drug metabolism and toxicity studies, offering whole organism screening coupled with small size and potential for high-throughput screening. Through toxicity and absorption analyses of a number of drugs, we find that zebrafish is generally predictive of drug toxicity, although assay outcomes are influenced by drug lipophilicity which alters drug uptake. In addition, liver microsome assays reveal specific differences in metabolism of compounds between human and zebrafish livers, likely resulting from the divergence of the cytochrome P450 superfamily between species. To reflect human metabolism more accurately, we generated a transgenic "humanized" zebrafish line that expresses the major human phase I detoxifying enzyme, CYP3A4, in the liver. Here, we show that this humanized line shows an elevated metabolism of CYP3A4-specific substrates compared to wild-type zebrafish. The generation of this first described humanized zebrafish liver suggests such approaches can enhance the accuracy of the zebrafish model for toxicity prediction.

A method for assessing carbohydrate energy absorption and its application to premature infants.

PubMed

Kien, C L; Sumners, J E; Stetina, J S; Heimler, R; Grausz, J P

1982-11-01

A method was developed for assessing indirectly the fecal excretion of carbohydrate-derived energy. Then, eight healthy premature infants (28 to 32 wk gestation, postnatal age 12 to 30 days) were randomly assigned to receive one of two formulas that differed only in the carbohydrate source: 100% lactose or 50% lactose: 50% glucose polymer (lactose + glucose polymer). Excreta collections were analyzed for total nitrogen, urea nitrogen, ammonia, fat, and total energy. Carbohydrate energy absorption was calculated. The formulas were well tolerated and stool frequency, energy intake, weight gain, and nitrogen balance were not different in the two formula groups. Also, there were no significant intergroup (lactose versus lactose + glucose polymer) differences in the coefficients (%) (x +/- SD) of fat absorption (90 +/- 6 versus 93 +/- 5) or carbohydrate energy absorption (96 +/- 1 versus 95 +/- 3). Thus, net carbohydrate-energy absorption appeared normal in these premature infants who showed no clinical formula intolerance.

Distribution, Metabolism and Toxic Effects of Beta-Cypermethrin in Lizards (Eremias argus) Following Oral Administration.

PubMed

Chen, Li; Xu, Peng; Diao, Jinling; Di, Shanshan; Li, Ruiting; Zhou, Zhiqiang

2016-04-05

Beta-cypermethrin (BCYP), a synthetic pyrethriod (PYR) pesticide which is a mixture of the alpha- and theta- cypermethrin, have been reported various toxicological profiles to non-target organisms. But little is known about assimilation, accumulation and toxic effects of BCYP in reptiles. The present study firstly elucidated absorption, tissue distribution, excretion of BCYP in Eremias argus . Treated group were administered orally with BCYP 20mg/kg body weight (bw) dissolved in corn oil. Neurotoxicity was observed at 24h after gavage, and the poisoning symptom ameliorated at 72h. The changes of BCYP concentration depended on degradation time and tissues. Lizards had a strong capacity to eliminate BCYP with different tissue distribution. The tissues concentration of BCYP from high to low were intestine, stomach, heart, kidney, blood, lung, liver and brain. Bimodal phenomena were observed in lung, liver and kidney. These results may be due to the activities of enzymes, circadian rhythm, and enterohepatic circulation in lizards. Based on the results of organ coefficient and histopathology analysis in liver, the liver was confirmed as the main target organ. Copyright © 2015 Elsevier B.V. All rights reserved.

The production of p-cresol sulfate and indoxyl sulfate in vegetarians versus omnivores.

PubMed

Patel, Kajal P; Luo, Frank J-G; Plummer, Natalie S; Hostetter, Thomas H; Meyer, Timothy W

2012-06-01

The uremic solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) are generated by colon bacteria acting on food components that escape absorption in the small bowel. The production of these potentially toxic compounds may thus be influenced by diet. This study examined whether production of PCS and IS is different in vegetarians and omnivores. The production of PCS and IS was assessed by measuring their urinary excretion rates in participants with normal kidney function. Studies were carried out in 15 vegetarians and 11 individuals consuming an unrestricted diet. Participants recorded food intake over 4 days and collected urine over the final 2 days of each of two study periods, which were 1 month apart. Average PCS excretion was 62% lower (95% confidence interval [95% CI], 15-83) and average IS excretion was 58% lower (95% CI, 39-71) in vegetarians than in participants consuming an unrestricted diet. Food records revealed that lower excretion of PCS and IS in vegetarians was associated with a 69% higher (95% CI, 20-139) fiber intake and a 25% lower (95% CI, 3-42) protein intake. PCS and IS excretion rates varied widely among individual participants and were not closely correlated with each other but tended to remain stable in individual participants over 1 month. PCS and IS production rates are markedly lower in vegetarians than in individuals consuming an unrestricted diet.

Consumption of a structured triacylglycerol containing behenic and oleic acids increases fecal fat excretion in humans.

PubMed

Kojima, Makiko; Arishima, Toshiharu; Shimizu, Ryoma; Kohno, Mitsutaka; Kida, Haruyasu; Hirotsuka, Motohiko; Ikeda, Ikuo

2013-01-01

We examined the fecal fat excretion of mildly hypertriacylglycerolemic subjects who ingested soft cookies containing 1(3)-behenoyl-2,3(1)-dioleoyl-rac-glycerol (BOO) for 7 days. The subjects included 14 healthy men (average age; 44.9 ± 1.7) whose fasting plasma triacylglycerol level ranged from 150 to 250 mg/dL. Every day for 7 days, the subjects ate 5 soft cookies containing margarine with the BOO-rich experimental oil (BOO intake, 2.46 g/day). The placebo group ate soft cookies containing margarine without BOO. This study was a randomized double-blind, placebo-controlled, crossover study. Feces were collected for 3 days prior to the end of the treatment period, and fecal fat and fatty acid composition were determined. The fecal wet weight was significantly increased in BOO group compared with that in the placebo group. Moreover, fecal fat and fatty acid level were significantly higher in the BOO group than in the placebo group. There were no significant differences in the fecal fatty acid composition of the BOO and placebo groups. These results suggest that dietary BOO increases fecal excretion of dietary fat in humans. However, BOO does not increase the excretion of specific fatty acids; it increases the excretion of all fatty acids of dietary origin, which may lead to lower and delay intestinal absorption of dietary fat.

Systemic Absorption of Rifamycin SV MMX Administered as Modified-Release Tablets in Healthy Volunteers▿

PubMed Central

Di Stefano, A. F. D.; Rusca, A.; Loprete, L.; Dröge, M. J.; Moro, L.; Assandri, A.

2011-01-01

The new oral 200-mg rifamycin SV MMX modified-release tablets, designed to deliver rifamycin SV directly into the colonic lumen, offer considerable advantages over the existing immediate-release antidiarrheic formulations. In two pharmacokinetics studies of healthy volunteers, the absorption, urinary excretion, and fecal elimination of rifamycin SV after single- and multiple-dose regimens of the new formulation were investigated. Concentrations in plasma of >2 ng/ml were infrequently and randomly quantifiable after single and multiple oral doses. The systemic exposure to rifamycin SV after single and multiple oral doses of MMX tablets under fasting and fed conditions or following a four-times-a-day (q.i.d.) or a twice-a-day (b.i.d.) regimen could be considered negligible. With both oral regimens, the drug was confirmed to be very poorly absorbable systemically. The amount of systemically absorbed antibiotic excreted by the renal route is far lower than 0.01% of the administered dose after both the single- and multiple-dose regimens. The absolute bioavailability, calculated as the mean percent ratio between total urinary excretion amounts (ΣXu) after a single intravenous injection and after a single oral dose under fasting conditions, was 0.0410 ± 0.0617. The total elimination of the unchanged rifamycin SV with feces was 87% of the administered oral dose. No significant effect of rifamycin SV on vital signs, electrocardiograms, or laboratory parameters was observed. PMID:21402860

High-fiber rye diet increases ileal excretion of energy and macronutrients compared with low-fiber wheat diet independent of meal frequency in ileostomy subjects.

PubMed

Isaksson, Hanna; Landberg, Rikard; Sundberg, Birgitta; Lundin, Eva; Hallmans, Göran; Zhang, Jie-Xian; Tidehag, Per; Erik Bach Knudsen, Knud; Moazzami, Ali A; Aman, Per

2013-01-01

Whole-grain foods and cereal dietary fiber intake is associated with lower body weight. This may partly result from lower energy utilization of high-fiber diets. In the present study, the impact on ileal excretion of energy and macronutrients in response to a rye bread high-fiber diet compared to a refined wheat low-fiber diet was investigated. Furthermore, the effect of meal frequency on apparent absorption of nutrients was studied for the first time. Ten participants that had undergone ileostomy consumed standardized iso-caloric diets, including low-fiber wheat bread (20 g dietary fiber per day) for 2 weeks followed by high-fiber rye bread (52 g dietary fiber per day) for 2 weeks. The diets were consumed in an ordinary (three meals per day) and a nibbling (seven meals per day) meal frequency in a cross-over design. Ileal effluents were collected during 24 h at the third day of each of the four dietary periods and analyzed for gross energy and nutrient contents. The results showed that intake of rye bread high-fiber diet compared to the refined wheat low-fiber diet caused an increase in ileal excretion of energy and macronutrients. The effect was independent of meal frequency. This suggests that a high intake of rye may result in lower availability of macronutrients for small intestinal digestion and absorption. A regular intake of rye may therefore have implications for weight management.

Dietary carbohydrate deprivation increases 24-hour nitrogen excretion without affecting postabsorptive hepatic or whole body protein metabolism in healthy men.

PubMed

Bisschop, P H; De Sain-Van Der Velden, M G M; Stellaard, F; Kuipers, F; Meijer, A J; Sauerwein, H P; Romijn, J A

2003-08-01

Because insulin is an important regulator of protein metabolism, we hypothesized that physiological modulation of insulin secretion, by means of extreme variations in dietary carbohydrate content, affects postabsorptive protein metabolism. Therefore, we studied the effects of three isocaloric diets with identical protein content and low-carbohydrate/high-fat (2% and 83% of total energy, respectively), intermediate-carbohydrate/intermediate-fat (44% and 41% of total energy, respectively), and high-carbohydrate/low-fat (85% and 0% of total energy, respectively) content in six healthy men. Whole body protein metabolism was assessed by 24-h urinary nitrogen excretion, postabsorptive leucine kinetics, and fibrinogen and albumin synthesis by infusion of [1-(13)C]leucine and [1-(13)C]valine. The low-carbohydrate/high-fat diet resulted in lower absorptive and postabsorptive plasma insulin concentrations, and higher rates of nitrogen excretion compared with the other two diets: 15.3 +/- 0.9 vs. 12.1 +/- 1.1 (P = 0.03) and 10.8 +/- 0.5 g/24 h (P = 0.005), respectively. Postabsorptive rates of appearance of leucine and of leucine oxidation were not different among the three diets. In addition, dietary carbohydrate content did not affect the synthesis rates of fibrinogen and albumin. In conclusion, eucaloric carbohydrate deprivation increases 24-h nitrogen loss but does not affect postabsorptive protein metabolism at the hepatic and whole body level. By deduction, dietary carbohydrate is required for an optimal regulation of absorptive, rather than postabsorptive, protein metabolism.

Normal distribution of urinary polyphenol excretion among Egyptian males 7-14 years old and changes following nutritional intervention with tomato juice (Lycopersicon esculentum).

PubMed

Hussein, Laila; Medina, Alexander; Barrionnevo, Ana; Lammuela-Raventos, Rosa M; Andres-Lacueva, Cristina

2009-06-01

The urinary flavonoids are considered a reliable biomarker for the intake of polyphenol-rich foods. To assess the normal distribution of urinary polyphenol [PP] excretion among healthy male children and adolescents on a typical Egyptian diet. To follow up the impact of nutritional intervention with tomato juice on the urinary excretion of [PP]. Forty-nine male subjects 7-14 years old collected a 24-h urine sample and filled a dietary record during a 7-day period. A daily serving of 230 g fresh tomato juice was followed for 18 days in a subgroup. Total urinary [PP] excretions were measured before and after termination of the intervention program. The total urinary [PP] was analyzed after a clean-up solid-phase extraction step by the Folin-Ciocalteu reagent in the 96 micro plates. The results were expressed as gallic acid equivalents (GAE). The urinary [PP] excretion averaged 48.6+/-5.5 mg GAE/24 h, equivalent to 89.5+/-8.4 mg GAE/g creatinine. The mean urinary [PP] excretion increased significantly (P<0.05) following the intervention with tomato juice (287.4+/-64.3 mg GAE/g creatinine) compared with the respective mean baseline level (94.5+/-8.92 mg GAE/g creatinine). Clinical laboratory reference limits for urinary polyphenols are presented for Egyptian male children and adolescents. Measuring the urinary polyphenol excretion proved a good biomarker for the dietary polyphenol intake and the results demonstrated that tomato [PP] was highly bioavailable in the human body.

Of TICE in Men.

PubMed

Cohen, David E

2016-12-13

Cholesterol homeostasis is achieved by balancing rates of endogenous synthesis, absorption, and elimination. Although biliary secretion into the intestinal lumen is classically considered as the only significant route for cholesterol elimination, Jakulj et al. (2016) reveal in this issue how transintestinal cholesterol excretion (TICE) accounts for substantial cholesterol losses. Copyright © 2016. Published by Elsevier Inc.

Potassium bicarbonate attenuates the urinary nitrogen excretion that accompanies an increase in dietary protein and may promote calcium absorption

USDA-ARS?s Scientific Manuscript database

Protein is an essential component of muscle and bone. However, the acidic byproducts of protein metabolism may have a negative impact on the musculoskeletal system particularly in older individuals with declining renal function. We sought to determine whether adding an alkaline salt, potassium bicar...

OBSERVATIONS CONCERNING THE PRODUCTION AND EXCRETION OF CHOLESTEROL IN MAMMALS

PubMed Central

Byers, Sanford O.; Friedman, Meyer; Biggs, Max W.; Gunning, Barbara

1953-01-01

Accumulation of cholate in plasma is the immediate cause of hypercholesteremia in the rat with bile duct ligation and in the normal rat given intravenous sodium cholate. The hypercholesteremia induced by cholate administration does not appear to be dependent upon any preceding change in the rates of absorption, excretion, synthesis, or redistribution of cholesterol in the tissues of the animal. Cholate administration seems to induce hypercholesteremia by impeding the normal rate of passage of cholesterol from the plasma into the liver; this impedance is probably due to an alteration of the cholesterol-binding power of plasma proteins induced by cholate. The chemical and physiological implications of this finding are discussed. PMID:13052817

The effect of carrier strontium on the absorption of oral doses of radioactive strontium in rats

PubMed Central

Harrison, G. E.; Jones, H. G.; Sutton, A.

1957-01-01

Carrier strontium had relatively little effect on the retention of an oral dose of radioactive strontium by the rat when it was administered immediately after the radioactive dose. The proportion of the radioactive dose which was excreted in the urine, on the other hand, increased progressively with the carrier dose. There was a decreased uptake of radioactive strontium in rats fed on a special low strontium diet. The effects of dietary strontium are discussed. Evidence was found of a discrimination by the rat against strontium in favour of calcium which was accounted for, at least in part, by a preferential urinary excretion of strontium. PMID:13460240

Calcium metabolism before, during, and after a 3-mo spaceflight: kinetic and biochemical changes

NASA Technical Reports Server (NTRS)

Smith, S. M.; Wastney, M. E.; Morukov, B. V.; Larina, I. M.; Nyquist, L. E.; Abrams, S. A.; Taran, E. N.; Shih, C. Y.; Nillen, J. L.; Davis-Street, J. E.;

Absorption, distribution, metabolism and excretion of loxoprofen after dermal application of loxoprofen gel to rats.

PubMed

Sawamura, Ryoko; Kazui, Miho; Kurihara, Atsushi; Izumi, Takashi

2014-11-01

1. Loxoprofen (LX), is a prodrug of the pharmacologically active form, trans-alcohol metabolite (trans-OH form), which shows very potent analgesic effect. In this study, the pharmacokinetics and metabolism of [(14)C]LX-derived radioactivity after dermal application of [(14)C]LX gel (LX-G) to rats were evaluated. 2. The area under concentration-time curve (AUC0-∞) of radioactivity in the plasma after the dermal application was 13.6% of that of the oral administration (p < 0.05). 3. After the dermal application, the radioactivity remained in the skin and skeletal muscle at the treated site for 168 h, whereas the AUC0-168 h of the radioactivity concentration in every tissue examined except the treated site was statistically lower than that after the oral administration (p < 0.05). 4. The trans-OH form was observed at high levels in the treated skin site at 0.5 h. Metabolite profiles in plasma, non-treated skin site and urine after the dermal application were comparable with those after the oral administration. 5. Renal excretion was the main route of elimination after the dermal application. 6. In conclusion, compared to the oral administration, the dermal application of [(14)C]LX-G showed lower systemic and tissue exposure with higher exposure in the therapeutic target site. The radioactivity revealed similar metabolite profiles in both administration routes.

Decreased absorption as a possible cause for the lower bioavailability of a sustained-release propranolol.

PubMed

Takahashi, H; Ogata, H; Warabioka, R; Kashiwada, K; Ohira, M; Someya, K

1990-03-01

The influence of sustained absorption on the oral availability of propranolol (P) and the metabolic disposition of P were investigated by obtaining the partial metabolic clearances (CLm) following long-acting P (LA) dosing in comparison with the conventional propranolol tablet (CP). Ten healthy volunteers were given a single oral dose of an LA capsule (60 mg) and CP (20 mg x 3) using a crossover design. Blood and urine samples were collected over 24- and 48-h postdose periods, respectively. Concentrations of P, propranolol glucuronide (PG), 4-hydroxypropranolol (4P), 4-hydroxypropranolol glucuronide (4PG), 4-hydroxypropranolol sulfate (4PS), and naphthoxylactic acid (NLA) were determined by HPLC with fluorescence and UV detection. Significant differences were observed between LA and CP in the area under the plasma concentration-time curves (AUCs) for P, PG, and NLA and in the amounts excreted into urine (Ae) for all measured metabolites (i.e., PG, 4P, 4PG, 4PS, and NLA). The parallel decrease of the AUC for P and the excreted amounts of all measured metabolites following LA dosing resulted in partial metabolic clearances (CLm) and renal clearances (CL) for P and its metabolites that were similar to those observed for CP. Therefore, the hepatic metabolism of P would not be affected by the slower absorption at a single oral dose of 60 mg. These results indicate that the poor absorption of P from the gastrointestinal tract might be one of the factors causing the low bioavailability of P observed after administration of the sustained-release formulation.

From Technique of Tattooing to Biokinetics and Toxicology of Injected Tattoo Ink Particles and Chemicals.

PubMed

Serup, Jørgen

2017-01-01

Tattoo colourants are colourful nano- and microparticles, which are practically insoluble and thus permanent once installed in the dermis by the tattooist. Tattoo ink also has soluble ingredients and contaminants. Pigments can distribute via the lymph and possibly also directly to the blood, and a minute fraction may over time undergo metabolic breakdown and as hapten(s) induce allergic reactions of red tattoos. Carbon black of black tattoos has a tendency to agglomerate and form larger bodies that can elicit foreign body reactions in black tattoos and even granuloma formation with overlap to sarcoidosis in the clinic. Very little is known about the biokinetics and safety profile of the many tattoo pigments in use, and no specific pigment-related chemical of tattoo ink causing identified adverse reactions in humans has been depicted. Inks have many ingredients and contaminants. Insoluble and soluble ingredients of inks supposedly have very different characteristics of absorption, distribution, metabolism, and excretion, with pigments being extremely slowly excreted, contrasting soluble ingredients with fast elimination. Tattoos are a single-dose exposure. Controlling the safety of tattoo inks by banning potentially critical chemicals hitherto has been unsuccessful due to lacking documentation of clinical and epidemiological relevance and because the tattoo industry is already internationally established, free, and in the ownership of the people. Doctors treating patients with tattoo complications consequently have a key role in identifying risk situations and local outbreaks, which needs clarification, therapy, and the intervention of authorities. In the treatment of complications, as seen in general practice and in other specialties, basic insight into the fate of tattoo pigments in the body is necessary. Tattoo complications are complicated and facetted with many entities and disease mechanisms; they are a new subspecialty in medicine and dermatology. © 2017 S. Karger AG, Basel.

Tissue distribution, metabolism and hepatic tissue injury in Chinese lizards (Eremias argus) after a single oral administration of lambda-cyhalothrin.

PubMed

Chang, Jing; Li, Jitong; Wang, Huili; Wang, Yinghuan; Guo, Baoyuan; Yin, Jing; Hao, Weiyu; Li, Wei; Li, Jianzhong; Xu, Peng

2016-11-01

Lambda-cyhalothrin (LCT) is a widely used pyrethroid with neurotoxicity. However, little is known about the toxicokinetics of LCT in reptiles. In this study, the absorption, distribution, metabolism and excretion of LCT in Chinese lizards (Eremias Argus) were determined following a single dose (10 mg kg -1 ) treatment. In the liver, brain, gonads and skin, LCT levels peaked within several hours and then decreased rapidly. However, the concentration of LCT gradually increased in the fat tissue. More than 90% of the LCT dose was excreted in the faeces. One LCT metabolite, 3-phenoxybenzoic acid (PBA), was detected in lizard plasma and tissues. PBA preferentially accumulates in the brain and plasma. The half-life of PBA in the brain was 3.2 days, which was 35.4-fold greater than that of LCT. In the plasma, the concentration of PBA was significantly higher than that of LCT. The bioaccumulation of LCT in tissues was enantioselective, and the enantiomeric fractions (EF) ranged from 0.72 to 0.26. The preferential accumulation of enantiomers changed according to exposure time, but the reasons behind this phenomenon were not clear. For pathological analysis, vacuolation of the cytoplasm and large areas of necrosis were observed in the liver sections after 168 h of dosing. The liver tissues exhibited both decreases in the hepatosomatic index and histopathological lesions during the exposure period. In this study, the effect concentration of LCT in lizards was 200-fold lower than its LD 50 value used in risk assessments for birds. These results may provide additional information for the risk assessment of LCT for reptiles and indicate that birds may not be an ideal surrogate for reptile toxicity evaluation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Correlation of arsenic exposure through drinking groundwater and urinary arsenic excretion among adults in Pakistan.

PubMed

Ahmed, Mubashir; Fatmi, Zafar; Ali, Arif

2014-01-01

Long-term exposure to arsenic has been associated with manifestation of skin lesions (melanosis/keratosis) and increased risk of internal cancers (lung/bladder). The objective of the study described here was to determine the relationship between exposure of arsenic through drinking groundwater and urinary arsenic excretion among adults > or =15 years of age living in Khairpur district, Pakistan. Total arsenic was determined in drinking groundwater and in spot urine samples of 465 randomly selected individuals through hydride generation-atomic absorption spectrometry. Spearman's rank correlation coefficient was calculated between arsenic in drinking groundwater and arsenic excreted in urine. The median arsenic concentration in drinking water was 2.1 microg/L (range: 0.1-350), and in urine was 28.5 microg/L (range: 0.1-848). Positive correlation was found between total arsenic in drinking water and in urine (r = .52, p < .01). Urinary arsenic may be used as a biomarker of arsenic exposure through drinking water.

In silico prediction of cytochrome P450-mediated drug metabolism.

PubMed

Zhang, Tao; Chen, Qi; Li, Li; Liu, Limin Angela; Wei, Dong-Qing

2011-06-01

The application of combinatorial chemistry and high-throughput screening technique enables the large number of chemicals to be generated and tested simultaneously, which will facilitate the drug development and discovery. At the same time, it brings about a challenge of how to efficiently identify the potential drug candidates from thousands of compounds. A way used to deal with the challenge is to consider the drug pharmacokinetic properties, such as absorption, distribution, metabolism and excretion (ADME), in the early stage of drug development. Among ADME properties, metabolism is of importance due to the strong association with efficacy and safety of drug. The review will focus on in silico approaches for prediction of Cytochrome P450-mediated drug metabolism. We will describe these predictive methods from two aspects, structure-based and data-based. Moreover, the applications and limitations of various methods will be discussed. Finally, we provide further direction toward improving the predictive accuracy of these in silico methods.

Cell-based medicinal chemistry optimization of high-throughput screening (HTS) hits for orally active antimalarials. Part 1: challenges in potency and absorption, distribution, metabolism, excretion/pharmacokinetics (ADME/PK).

PubMed

Chatterjee, Arnab K

2013-10-24

Malaria represents a significant health issue, and novel and effective drugs are needed to address parasite resistance that has emerged to the current drug arsenal. Antimalarial drug discovery has historically benefited from a whole-cell (phenotypic) screening approach to identify lead molecules. This approach has been utilized by several groups to optimize weakly active antimalarial pharmacophores, such as the quinolone scaffold, to yield potent and highly efficacious compounds that are now poised to enter clinical trials. More recently, GNF/Novartis, GSK, and others have employed the same approach in high-throughput screening (HTS) of large compound libraries to find novel scaffolds that have also been optimized to clinical candidates by GNF/Novartis. This perspective outlines some of the inherent challenges in cell-based medicinal chemistry optimization, including optimization of oral exposure and hERG activity.

Pharmacomicrobiomics: a novel route towards personalized medicine?

PubMed

Doestzada, Marwah; Vila, Arnau Vich; Zhernakova, Alexandra; Koonen, Debby P Y; Weersma, Rinse K; Touw, Daan J; Kuipers, Folkert; Wijmenga, Cisca; Fu, Jingyuan

2018-05-01

Inter-individual heterogeneity in drug response is a serious problem that affects the patient's wellbeing and poses enormous clinical and financial burdens on a societal level. Pharmacogenomics has been at the forefront of research into the impact of individual genetic background on drug response variability or drug toxicity, and recently the gut microbiome, which has also been called the second genome, has been recognized as an important player in this respect. Moreover, the microbiome is a very attractive target for improving drug efficacy and safety due to the opportunities to manipulate its composition. Pharmacomicrobiomics is an emerging field that investigates the interplay of microbiome variation and drugs response and disposition (absorption, distribution, metabolism and excretion). In this review, we provide a historical overview and examine current state-of-the-art knowledge on the complex interactions between gut microbiome, host and drugs. We argue that combining pharmacogenomics and pharmacomicrobiomics will provide an important foundation for making major advances in personalized medicine.

Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors

NASA Astrophysics Data System (ADS)

Lagorce, David; Douguet, Dominique; Miteva, Maria A.; Villoutreix, Bruno O.

2017-04-01

The modulation of PPIs by low molecular weight chemical compounds, particularly by orally bioavailable molecules, would be very valuable in numerous disease indications. However, it is known that PPI inhibitors (iPPIs) tend to have properties that are linked to poor Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and in some cases to poor clinical outcomes. Previously reported in silico analyses of iPPIs have essentially focused on physicochemical properties but several other ADMET parameters would be important to assess. In order to gain new insights into the ADMET properties of iPPIs, computations were carried out on eight datasets collected from several databases. These datasets involve compounds targeting enzymes, GPCRs, ion channels, nuclear receptors, allosteric modulators, oral marketed drugs, oral natural product-derived marketed drugs and iPPIs. Several trends are reported that should assist the design and optimization of future PPI inhibitors, either for drug discovery endeavors or for chemical biology projects.

Mercury study report to Congress. Volume 5. Health effects of mercury and mercury compounds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hassett-Sipple, B.; Swartout, J.; Schoeny, R.

1997-12-01

This volume summarizes the available information on human health effects and animal data for hazard identification and dose-response assessment for three forms of mercury: elemental mercury, mercury chloride (inorganic mercury), and methylmercury (organic mercury). Effects are summarized by endpoint. The risk assessment evaluates carcinogenicity, mutagenicity, developmental toxicity and general systemic toxicity of these chemical species of mercury. Toxicokinetics (absorption, distribution, metabolism and excretion) are described for each of the three mercury species. Reference doses are calculated for inorganic and methylmercury; a reference concentrations for inhaled elemental mercury is provided. A quantitative analysis of factors contributing to variability and uncertainty inmore » the methylmercury RfD is provided in an appendix. Interactions and sensitive populations are described. the draft volume assesses ongoing research and research needs to reduce uncertainty surrounding adverse human health consequences of methylmercury exposure.« less

Mercury study report to Congress. Volume 4. Health effects of mercury and mercury compounds. Sab review draft

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schoeny, R.

1996-06-01

This volume of the draft Mercury Study Report to Congress summarizes the available information on human health effects and animal data for hazard identification and dose-response assessment for three forms of mercury: elemental mercury, mercury chloride (inorganic mercury), and methylmercury (organic mercury). Effects are summarized by endpoint. The risk assessment evaluates carcinogenicity, mutagenicity, developmental toxicity and general systemic toxicity of these chemical species of mercury. Toxicokinetics (absorption, distribution, metabolism and excretion) are described for each of the three mercury species. PBPK models are described, but not applied in risk assessment. Reference doses are calculated for inorganic and methylmercury; a referencemore » concentration for inhaled elemental mercury is provided. A quantitiative analysis of factors contributing to variability and uncertainty in the methylmercury RfD is provided in an appendix. Interations and sensitive populations are described.« less

5-((3-Amidobenzyl)oxy)nicotinamides as Sirtuin 2 Inhibitors.

PubMed

Ai, Teng; Wilson, Daniel J; More, Swati S; Xie, Jiashu; Chen, Liqiang

2016-04-14

Derived from our previously reported human sirtuin 2 (SIRT2) inhibitors that were based on a 5-aminonaphthalen-1-yloxy nicotinamide core structure, 5-((3-amidobenzyl)oxy)nicotinamides offered excellent activity against SIRT2 and high isozyme selectivity over SIRT1 and SIRT3. Selected compounds also exhibited generally favorable in vitro absorption, distribution, metabolism, and excretion properties. Kinetic studies revealed that a representative SIRT2 inhibitor acted competitively against both NAD(+) and the peptide substrate, an inhibitory modality that was supported by our computational study. More importantly, two selected compounds exhibited significant protection against α-synuclein aggregation-induced cytotoxicity in SH-SY5Y cells. Therefore, 5-((3-amidobenzyl)oxy)nicotinamides represent a new class of SIRT2 inhibitors that are attractive candidates for further lead optimization in our continued effort to explore selective inhibition of SIRT2 as a potential therapy for Parkinson's disease.

Pharmacogenomic implications of the evolutionary history of infectious diseases in Africa

PubMed Central

Baker, J L; Shriner, D; Bentley, A R; Rotimi, C N

2017-01-01

As the common birthplace of all human populations, modern humans have lived longer on the African continent than in any other geographical region of the world. This long history, along with the evolutionary need to adapt to environmental challenges such as exposure to infectious agents, has led to greater genetic variation in Africans. The vast genetic variation in Africans also extends to genes involved in the absorption, distribution, metabolism and excretion of pharmaceuticals. Ongoing cataloging of these clinically relevant variants reveals huge allele-frequency differences within and between African populations. Here, we examine Africa's large burden of infectious disease, discuss key examples of known genetic variation modulating disease risk, and provide examples of clinically relevant variants critical for establishing dosing guidelines. We propose that a more systematic characterization of the genetic diversity of African ancestry populations is required if the current benefits of precision medicine are to be extended to these populations. PMID:27779243

The Significance of Acid/Base Properties in Drug Discovery

PubMed Central

Manallack, David T.; Prankerd, Richard J.; Yuriev, Elizabeth; Oprea, Tudor I.; Chalmers, David K.

2013-01-01

While drug discovery scientists take heed of various guidelines concerning drug-like character, the influence of acid/base properties often remains under-scrutinised. Ionisation constants (pKa values) are fundamental to the variability of the biopharmaceutical characteristics of drugs and to underlying parameters such as logD and solubility. pKa values affect physicochemical properties such as aqueous solubility, which in turn influences drug formulation approaches. More importantly, absorption, distribution, metabolism, excretion and toxicity (ADMET) are profoundly affected by the charge state of compounds under varying pH conditions. Consideration of pKa values in conjunction with other molecular properties is of great significance and has the potential to be used to further improve the efficiency of drug discovery. Given the recent low annual output of new drugs from pharmaceutical companies, this review will provide a timely reminder of an important molecular property that influences clinical success. PMID:23099561

Human biokinetic data and a new compartmental model of zirconium--a tracer study with enriched stable isotopes.

PubMed

Greiter, Matthias B; Giussani, Augusto; Höllriegl, Vera; Li, Wei Bo; Oeh, Uwe

2011-09-01

Biokinetic models describing the uptake, distribution and excretion of trace elements are an essential tool in nutrition, toxicology, or internal dosimetry of radionuclides. Zirconium, especially its radioisotope (95)Zr, is relevant to radiation protection due to its production in uranium fission and neutron activation of nuclear fuel cladding material. We present a comprehensive set of human data from a tracer study with stable isotopes of zirconium. The data are used to refine a biokinetic model of zirconium. Six female and seven male healthy adult volunteers participated in the study. It includes 16 complete double tracer investigations with oral ingestion and intravenous injection, and seven supplemental investigations. Tracer concentrations were measured in blood plasma and urine collected up to 100 d after tracer administration. The four data sets (two chemical tracer forms in plasma and urine) each encompass 105-240 measured concentration values above detection limits. Total fractional absorption of ingested zirconium was found to be 0.001 for zirconium in citrate-buffered drinking solution and 0.007 for zirconium oxalate solution. Biokinetic models were developed based on the linear first-order kinetic compartmental model approach used by the International Commission on Radiological Protection (ICRP). The main differences of the optimized systemic model of zirconium to the current ICRP model are (1) recycling into the transfer compartment made necessary by the observed tracer clearance from plasma, (2) different parameters related to fractional absorption for each form of the ingested tracer, and (3) a physiologically based excretion pathway to urine. The study considerably expands the knowledge on the biokinetics of zirconium, which was until now dominated by data from animal studies. The proposed systemic model improves the existing ICRP model, yet is based on the same principles and fits well into the ICRP radiation protection approach. Copyright © 2011 Elsevier B.V. All rights reserved.

Determination of cadmium in urine by extraction and flameless atomic-absorption spectrophotometry Comparison of urine from smokers and non-smokers of different sex and age.

PubMed

Jawaid, M; Lind, B; Elinder, C G

1983-07-01

A method is presented for determining cadmium in urine by nameless atomic-absorption spectrophotometry after extraction. The sample is dried, ashed in the presence of nitric acid, and then the residue is dissolved in hydrochloric acid. Cadmium is extracted as its tetrahexylammonium iodide complex into methyl isobutyl ketone. The organic phase is analysed for cadmium by atomic-absorption spectrophotometry with electrothermal atomization. The median urinary excretion of cadmium for smokers aged 50-64 has been found to be 0.7 and 0.75 mug l . for males and females respectively, the values for non-smokers being 0.25 and 0.4mug l .

Distribution of creatinine following intravenous and oral administration to rats.

PubMed

Watanabe, J; Hirate, J; Iwamoto, K; Ozeki, S

1981-05-01

To evaluate the distribution of creatinine in rats, urinary, fecal and expiratory excretion, plasma levels and whole-body autoradiography following intravenous or oral administration of [carbonyl-14C]creatinine was investigated. More than 90% of the exogeneous creatinine was excreted in the urine in 24 hr following intravenous administration, and both fecal and expiratory excretion were only about 1%. In case of oral administration, however, it was found that expiratory excretion could not be neglected, ranging from about 1 to 30%. Plasma creatinine concentration-time curves following the intravenous administration (70.4 micrograms/kg or 400 mg/kg as creatinine) were analyzed according to a two-compartment open model. There were significant but very small differences in the pharmacokinetic parameters for these two doses. When these parameters were compared with those of urea, k12 and k21, which are transfer rate constants between compartment 1 and 2, for creatinine were significantly smaller than those of urea. On the other hand, k10 was larger in creatinine. Furthermore, (V'd)extrap for creatinine was about three times that of urea. Whole-body autoradiograms at 5 minutes following intravenous administration showed that exogeneous creatinine distributes with higher concentrations in liver, lung and kidney than in muscle and fat. This results was remarkably different from that of urea which distributes almost uniformly throughout the body at the same time. This difference observed in the autoradiograms would be the consequence of the fact that urea has larger k12 and k21 than creatinine.

Origin of Urinary Oxalate

NASA Astrophysics Data System (ADS)

Holmes, Ross P.; Knight, John; Assimos, Dean G.

2007-04-01

Urinary oxalate is mostly derived from the absorption of ingested oxalate and endogenous synthesis. The breakdown of vitamin C may also contribute small amounts to the urinary oxalate pool. The amount of oxalate absorbed is influenced by the oxalate content of the diet, the concentrations of divalent cations in the gut, the presence of oxalate-degrading organisms, transport characteristics of the intestinal epithelium, and other factors associated with the intestinal environment. Knowledge of pathways associated with endogenous oxalate synthesis is limited. Urinary oxalate excretion can be modified using strategies that limit dietary oxalate absorption and the ingestion of oxalogenic substrates such as hydroxyproline.

Mono- and biphasic plasma concentration-time curves of mesalazine from a 500 mg suppository in healthy male volunteers controlled by the time of defecation before dosing.

PubMed

Vree, T B; Dammers, E; Exler, P S; Maes, R A

2000-06-01

This study was based on data from a bioequivalence study (n=24) of two different formulations of suppositories containing 500 mg mesalazine (formulation I and II), with a similar dissolution profile in phosphate buffer pH 6.8. There was a large intra- and intersubject variability in the plasma concentration-time curves of mesalazine from both suppositories. The aim of the investigation was to identify the parameters that caused the observed large variations in release and absorption of mesalazine in the rectum. Plasma mesalazine and acetylmesalazine, and urine acetylmesalazine concentrations were determined according to validated methods involving HPLC analysis with coulometric detection. Lower limit of quantitation values were respectively 10.4 and 19.4 ng mL(-1) in plasma and 0.96 microg mL(-1) in urine. The time of defecation before and after insertion was recorded. There was a clear distinction between subjects who showed monophasic mesalazine release/absorption and those who showed biphasic and more extended release/absorption. With formulation I there was a correlation between time of defecation before dosing and the type of absorption, monophasic and biphasic absorbers showed a significant difference in the time of defecation, e.g. 9.7+/-5.6 h vs 18.8+/-11.9 h (P = 0.0218). The impact of time of defecation before dosing was non-significant with formulation II, 16.7+/-7.2 h vs 15.1+/-4.2 h (P = 0.67). The impact of the time elapsed between administration and time of defecation after the insertion of the suppository was not significant for the type of release/absorption. The plasma concentration-time curves of the metabolite ran parallel to that of the parent drug, the more parent drug was released/absorbed, the more was acetylated (P = 0.0013) and excreted into the urine (P = 0.0004). After absorption the compound was metabolized into acetylmesalazine, and renally excreted (12-13% of the dose). Monophasic release/ absorption resulted in 7.1% metabolite with I and 10.3% with II (P = 0.0004), while biphasic release/absorption gave 16.8% metabolite with I and 15.5% with II. The renal clearance of the metabolite acetylmesalazine was independent of the observed defecation patterns (300 mL min(-1), P > 0.8), stool composition, and type of absorption.

Urinary excretion of Citrus flavanones and their major catabolites after consumption of fresh oranges and pasteurized orange juice: A randomized cross-over study.

PubMed

Aschoff, Julian K; Riedl, Ken M; Cooperstone, Jessica L; Högel, Josef; Bosy-Westphal, Anja; Schwartz, Steven J; Carle, Reinhold; Schweiggert, Ralf M

2016-12-01

Orange juice contains flavanones including hesperidin and narirutin, albeit at lower concentrations as compared to orange fruit. Therefore, we compared bioavailability and colonic catabolism of flavanones from orange juice to a 2.4-fold higher dose from fresh oranges. Following a randomized two-way cross-over design, 12 healthy subjects consumed a test meal comprising either fresh oranges or pasteurized orange juice, delivering 1774 and 751 μmol of total Citrus flavanones, respectively. Deglucuronidated and desulfated hesperetin, naringenin, and the flavanone catabolites 3-(3'-hydroxy-4'-methoxyphenyl)propionic acid, 3-(3'-hydroxyphenyl)hydracrylic acid, 4-hydroxyhippuric acid, and hippuric acid were quantitated in 24-h urine by UHPLC-MS/MS. Differences in urinary hesperetin excretion were found to be nonsignificant (p = 0.5209) both after consumption of orange fruit (21.6 ± 8.0 μmol) and juice (18.3 ± 7.2 μmol). By analogy, postprandial flavanone catabolite excretions were highly similar between treatments. Excretion of 3-(3'-hydroxy-4'-methoxyphenyl)propionic acid was inversely related to that of hesperetin, illustrating the catabolite/precursor relationship. Despite 2.4-fold higher doses, excretion of flavanones from ingested fresh orange fruit did not differ from that following orange juice consumption, possibly due to a saturation of absorption or their entrapment in the fiber-rich matrix of the fruit. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Development of In Vitro-In Vivo Correlation for Potassium Chloride Extended Release Tablet Formulation Using Urinary Pharmacokinetic Data.

PubMed

Mittapalli, Rajendar K; Marroum, Patrick; Qiu, Yihong; Apfelbaum, Kathleen; Xiong, Hao

2017-07-01

To develop and validate a Level A in vitro-in vivo correlation (IVIVC) for potassium chloride extended-release (ER) formulations. Three prototype ER formulations of potassium chloride with different in vitro release rates were developed and their urinary pharmacokinetic profiles were evaluated in healthy subjects. A mathematical model between in vitro dissolution and in vivo urinary excretion, a surrogate for measuring in vivo absorption, was developed using time-scale and time-shift parameters. The IVIVC model was then validated based on internal and external predictability. With the established IVIVC model, there was a good correlation between the observed fraction of dose excreted in urine and the time-scaled and time-shifted fraction of the drug dissolved, and between the in vitro dissolution time and the in vivo urinary excretion time for the ER formulations. The percent prediction error (%PE) on cumulative urinary excretion over the 24 h interval (A e0-24h ) and maximum urinary excretion rate (R max ) was less than 15% for the individual formulations and less than 10% for the average of the two formulations used to develop the model. Further, the %PE values using external predictability were below 10%. A novel Level A IVIVC was successfully developed and validated for the new potassium chloride ER formulations using urinary pharmacokinetic data. This successful IVIVC may facilitate future development or manufacturing changes to the potassium chloride ER formulation.

Bioaccessibility and excretion of arsenic in Niu Huang Jie Du Pian pills

DOE Office of Scientific and Technical Information (OSTI.GOV)

Koch, Iris; Sylvester, Steven; Lai, Vivian W.-M.

2007-08-01

Traditional Chinese medicines (TCMs) often contain significant levels of potentially toxic elements, including arsenic. Niu Huang Jie Du Pian pills were analyzed to determine the concentration, bioaccessibility (arsenic fraction soluble in the human gastrointestinal system) and chemical form (speciation) of arsenic. Arsenic excretion in urine (including speciation) and facial hair were studied after a one-time ingestion. The pills contained arsenic in the form of realgar, and although the total arsenic that was present in a single pill was high (28 mg), the low bioaccessibility of this form of arsenic predicted that only 4% of it was available for absorption intomore » the bloodstream (1 mg of arsenic per pill). The species of arsenic that were solubilized were inorganic arsenate (As(V)) and arsenite (As(III)) but DMAA and MMAA were detected in urine. Two urinary arsenic excretion peaks were observed: an initial peak several (4-8) hours after ingestion corresponding to the excretion of predominantly As(III), and a larger peak at 14 h corresponding predominantly to DMAA and MMAA. No methylated As(III) species were observed. Facial hair analysis revealed that arsenic concentrations did not increase significantly as a result of the ingestion. Arsenic is incompletely soluble under human gastrointestinal conditions, and is metabolized from the inorganic to organic forms found in urine. Bioaccessible arsenic is comparable to the quantity excreted. Facial hair as a bio-indicator should be further tested.« less

Infant Nutritional Status, Feeding Practices, Enteropathogen Exposure, Socioeconomic Status, and Illness Are Associated with Gut Barrier Function As Assessed by the Lactulose Mannitol Test in the MAL-ED Birth Cohort.

PubMed

Lee, Gwenyth O; McCormick, Benjamin J J; Seidman, Jessica C; Kosek, Margaret N; Haque, Rashidul; Olortegui, Maribel Paredes; Lima, Aldo A M; Bhutta, Zulfiqar A; Kang, Gagandeep; Samie, Amidou; Amour, Caroline; Mason, Carl J; Ahmed, Tahmeed; Yori, Pablo Peñataro; Oliveira, Domingos B; Alam, Didar; Babji, Sudhir; Bessong, Pascal; Mduma, Estomih; Shrestha, Sanjaya K; Ambikapathi, Ramya; Lang, Dennis R; Gottlieb, Michael; Guerrant, Richard L; Caulfield, Laura E; For The Mal-Ed Network Investigators

2017-07-01

The lactulose mannitol (LM) dual sugar permeability test is the most commonly used test of environmental enteropathy in developing countries. However, there is a large but conflicting literature on its association with enteric infection and host nutritional status. We conducted a longitudinal cohort using a single field protocol and comparable laboratory procedures to examine intestinal permeability in multiple, geographically diverse pediatric populations. Using a previously published systematic review to guide the selection of factors potentially associated with LM test results, we examined the relationships between these factors and mucosal breach, represented by percent lactulose excretion; absorptive area, represented by percent mannitol excretion; and gut barrier function, represented by the L/M ratio. A total of 6,602 LM tests were conducted in 1,980 children at 3, 6, 9, and 15 months old; percent lactulose excretion, percent mannitol excretion, and the L/M ratio were expressed as age- and sex-specific normalized values using the Brazil cohort as the reference population. Among the factors considered, recent severe diarrhea, lower socioeconomic status, and recent asymptomatic enteropathogen infections were associated with decreased percent mannitol excretion and higher L/M ratios. Poorer concurrent weight-for-age, infection, and recent breastfeeding were associated with increased percent lactulose excretion and increased L/M ratios. Our results support previously reported associations between the L/M ratio and factors related to child nutritional status and enteropathogen exposure. These results were remarkably consistent across sites and support the hypothesis that the frequency of these exposures in communities living in poverty leads to alterations in gut barrier function.

Infant Nutritional Status, Feeding Practices, Enteropathogen Exposure, Socioeconomic Status, and Illness Are Associated with Gut Barrier Function As Assessed by the Lactulose Mannitol Test in the MAL-ED Birth Cohort

PubMed Central

Lee, Gwenyth O.; McCormick, Benjamin J. J.; Seidman, Jessica C.; Kosek, Margaret N.; Haque, Rashidul; Olortegui, Maribel Paredes; Lima, Aldo A. M.; Bhutta, Zulfiqar A.; Kang, Gagandeep; Samie, Amidou; Amour, Caroline; Mason, Carl J.; Ahmed, Tahmeed; Yori, Pablo Peñataro; Oliveira, Domingos B.; Alam, Didar; Babji, Sudhir; Bessong, Pascal; Mduma, Estomih; Shrestha, Sanjaya K.; Ambikapathi, Ramya; Lang, Dennis R.; Gottlieb, Michael; Guerrant, Richard L.; Caulfield, Laura E.

2017-01-01

Abstract. The lactulose mannitol (LM) dual sugar permeability test is the most commonly used test of environmental enteropathy in developing countries. However, there is a large but conflicting literature on its association with enteric infection and host nutritional status. We conducted a longitudinal cohort using a single field protocol and comparable laboratory procedures to examine intestinal permeability in multiple, geographically diverse pediatric populations. Using a previously published systematic review to guide the selection of factors potentially associated with LM test results, we examined the relationships between these factors and mucosal breach, represented by percent lactulose excretion; absorptive area, represented by percent mannitol excretion; and gut barrier function, represented by the L/M ratio. A total of 6,602 LM tests were conducted in 1,980 children at 3, 6, 9, and 15 months old; percent lactulose excretion, percent mannitol excretion, and the L/M ratio were expressed as age- and sex-specific normalized values using the Brazil cohort as the reference population. Among the factors considered, recent severe diarrhea, lower socioeconomic status, and recent asymptomatic enteropathogen infections were associated with decreased percent mannitol excretion and higher L/M ratios. Poorer concurrent weight-for-age, infection, and recent breastfeeding were associated with increased percent lactulose excretion and increased L/M ratios. Our results support previously reported associations between the L/M ratio and factors related to child nutritional status and enteropathogen exposure. These results were remarkably consistent across sites and support the hypothesis that the frequency of these exposures in communities living in poverty leads to alterations in gut barrier function. PMID:28719336

Gastric decontamination performed 5 min after the ingestion of temazepam, verapamil and moclobemide: charcoal is superior to lavage

PubMed Central

Lapatto-reiniluoto, O; Kivistö, K T; Neuvonen, P J

2000-01-01

Aims The aim was to study the efficacy of gastric lavage and activated charcoal in preventing the absorption of temazepam, verapamil and moclobemide when gastric decontamination was performed immediately after ingestion of the drugs. Methods Nine healthy volunteers took part in a randomized cross-over study with three phases. The subjects were administered single oral doses of 10 mg temazepam, 80 mg verapamil and 150 mg moclobemide. Five minutes later, they were assigned to one of the following treatments: 200 ml water (control), 25 g activated charcoal as a suspension in 200 ml water or gastric lavage. Plasma concentrations and the cumulative excretion into urine of the three drugs were determined up to 24 h. Results The mean AUC(0,24 h) of temazepam, verapamil and moclobemide was reduced by 95.2% (P < 0.01), 92.8% (P < 0.01) and 99.7% (P < 0.01), respectively, by activated charcoal compared with control. Gastric lavage did not reduce significantly the AUC(0,24 h) of these drugs. The 24 h cumulative excretion of temazepam, verapamil and moclobemide into urine was reduced significantly (P < 0.05) by charcoal but not by gastric lavage. Charcoal reduced the AUC(0,24 h), Cmax and urinary excretion of all three drugs significantly more than lavage. Conclusions Activated charcoal is very effective and gastric lavage can be rather ineffective in preventing the absorption of temazepam, verapamil and moclobemide when the treatment is given very rapidly after ingestion of the drugs, before tablet disintegration has occurred. PMID:10718784

High-fiber rye diet increases ileal excretion of energy and macronutrients compared with low-fiber wheat diet independent of meal frequency in ileostomy subjects

PubMed Central

Isaksson, Hanna; Landberg, Rikard; Sundberg, Birgitta; Lundin, Eva; Hallmans, Göran; Zhang, Jie-Xian; Tidehag, Per; Erik Bach Knudsen, Knud; Moazzami, Ali A.; Åman, Per

2013-01-01

Background Whole-grain foods and cereal dietary fiber intake is associated with lower body weight. This may partly result from lower energy utilization of high-fiber diets. Objective In the present study, the impact on ileal excretion of energy and macronutrients in response to a rye bread high-fiber diet compared to a refined wheat low-fiber diet was investigated. Furthermore, the effect of meal frequency on apparent absorption of nutrients was studied for the first time. Design Ten participants that had undergone ileostomy consumed standardized iso-caloric diets, including low-fiber wheat bread (20 g dietary fiber per day) for 2 weeks followed by high-fiber rye bread (52 g dietary fiber per day) for 2 weeks. The diets were consumed in an ordinary (three meals per day) and a nibbling (seven meals per day) meal frequency in a cross-over design. Ileal effluents were collected during 24 h at the third day of each of the four dietary periods and analyzed for gross energy and nutrient contents. Results The results showed that intake of rye bread high-fiber diet compared to the refined wheat low-fiber diet caused an increase in ileal excretion of energy and macronutrients. The effect was independent of meal frequency. This suggests that a high intake of rye may result in lower availability of macronutrients for small intestinal digestion and absorption. A regular intake of rye may therefore have implications for weight management. PMID:24358035

Guar gum does not impair the absorption and utilization of dietary nitrogen but affects early endogenous urea kinetics in humans.

PubMed

Mariotti, F; Pueyo, M E; Tomé, D; Benamouzig, R; Mahé, S

2001-10-01

Viscous gums enhance viscosity in the upper gastrointestinal lumen, quickly disturbing motility and promoting fluid secretion. We sought to determine whether guar gum could acutely affect the absorption and utilization of dietary nitrogen and whether these luminal effects could also perturb the kinetics of urea. We studied the short-term effect of adding 1% of highly viscous guar gum to a (15)N-labeled protein meal (30 g soy protein isolate in 500 mL water) during the postprandial phase in humans. The effects on bioavailability were studied by using the [(13)C]glycine breath test (to assess gastric emptying) and (15)N enrichment in plasma amino acids (for systemic amino acid bioavailability). The kinetics of dietary and endogenous urea were assessed in plasma and urine. Guar gum modulated the gastric emptying kinetics of the liquid phase of the meal slightly (P < 0.05), but had no significant effect on either the systemic appearance of dietary amino acids or plasma and urinary dietary urea kinetics. Without significantly affecting plasma urea concentrations, guar gum reduced by approximately 40% the urinary excretion of endogenous urea for the first 2-h period after the meal (P < 0.01), although endogenous urinary excretion was similar at later stages. Guar gum did not significantly affect the bioavailability or utilization of dietary protein. We showed an early effect of guar gum on endogenous urea kinetics, which most probably arose from very early, short-term stimulation of the intestinal disposal of endogenous urea, at the expense of its urinary excretion.

Spectrophotometric determination of pyrrole-like substances in urine of rat and man: an assay for the evaluation of 2,5-hexanedione formed from n-hexane.

PubMed

Kessler, W; Heilmaier, H; Kreuzer, P; Shen, J H; Filser, M; Filser, J G

1990-01-01

Male Wistar rats exposed to atmospheric n-hexane excreted in their urine substances which gave rise to absorption spectra like those of pyrroles after the reaction with Ehrlich's reagent. A simple spectrophotometric assay was developed to determine these "pyrrole-like substances" in urine. Their excretion kinetics were evaluated by exposing rats for 8 h to atmospheric n-hexane concentrations between 50 and 3000 ppm. The dose-response curve revealed saturation kinetics according to Michaelis-Menten, Vmax being 1.12 [delta E526.ml urine/8 h n-hexane exposure] and "Km", the atmospheric n-hexane concentration at Vmax/2, being 250 ppm. The excretion of pyrrole-like substances closely correlated with that of 2,5-hexanedione measured by Fedtke and Bolt (1987). Pyrrole-like substances were also found in the urine of a male volunteer. When exposing the person for 3 h to atmospheric n-hexane at a concentration of 146 ppm (equivalent to 55 ppm/8 h) the excreted amount was twice the background value. Due to the sensitivity of this assay it is possible to determine pyrrole-like substances in urine according to the present German MAK or US TLV conditions for n-hexane (50 ppm/8 h).

Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima-Media Thickness in Humans.

PubMed

Lin, Xiaobo; Racette, Susan B; Ma, Lina; Wallendorf, Michael; Dávila-Román, Victor G; Ostlund, Richard E

2017-12-01

Epidemiological studies strongly suggest that lipid factors independent of low-density lipoprotein cholesterol contribute significantly to cardiovascular disease risk. Because circulating lipoproteins comprise only a small fraction of total body cholesterol, the mobilization and excretion of cholesterol from plasma and tissue pools may be an important determinant of cardiovascular disease risk. Our hypothesis is that fecal excretion of endogenous cholesterol is protective against atherosclerosis. Cholesterol metabolism and carotid intima-media thickness were quantitated in 86 nondiabetic adults. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d 7 solubilized in a lipid emulsion and dietary cholesterol by cholesterol-d 5 and the nonabsorbable stool marker sitostanol-d 4 . Plasma and stool samples were collected while subjects consumed a cholesterol- and phytosterol-controlled metabolic kitchen diet and were analyzed by mass spectrometry. Carotid intima-media thickness was negatively correlated with fecal excretion of endogenous cholesterol ( r =-0.426; P <0.0001), total cholesterol ( r =-0.472; P ≤0.0001), and daily percent excretion of cholesterol from the rapidly mixing cholesterol pool ( r =-0.343; P =0.0012) and was positively correlated with percent cholesterol absorption ( r =+0.279; P =0.0092). In a linear regression model controlling for age, sex, systolic blood pressure, hemoglobin A1c, low-density lipoprotein, high-density lipoprotein cholesterol, and statin drug use, fecal excretion of endogenous cholesterol remained significant ( P =0.0008). Excretion of endogenous cholesterol is strongly, independently, and negatively associated with carotid intima-media thickness. The reverse cholesterol transport pathway comprising the intestine and the rapidly mixing plasma, and tissue cholesterol pool could be an unrecognized determinant of cardiovascular disease risk not reflected in circulating lipoproteins. Further work is needed to relate measures of reverse cholesterol transport to atherosclerotic disease. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758. © 2017 American Heart Association, Inc.

Effect of the amino acid histidine on the uptake of cadmium from the digestive system of the blue crab, Callinectes sapidus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pecon, J.; Powell, E.N.

1981-07-01

The digestive tract functions in the storage, metabolism, and excretion of heavy metals in invertebrates. The importance of the digestive tract and the processes governing digestion and absorption of nutrients in heavy metal uptake is becoming increasingly clear. The results of this study suggest that in order to understand the processes controlling heavy metal uptake in invertebrates, it will be necessary to investigate the role that digestion and absorption play in determining the transport rate of metals across the gut wall into the blood. For example, some amino acids increase metal absorption rates, whereas other compounds, such as phytate, decreasemore » metal absorption rates. The results also suggest that experimental designs to investigate metal absorption must include an appreciation of the significant role that the feeding state of the animal (e.g. fed or starved) and the role chelators, particularly those produced by the organisms themselves during digestion, may play in the observed uptake rates of metal ions.« less

Zinc metabolism in genetically obese (ob/ob) mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kennedy, M.L.; Failla, M.L.

1987-05-01

Recent reports indicate that the concentrations and total amounts of several essential trace metals in various tissues of genetically obese rodents differ markedly from those in lean controls. In the present studies the absorption, retention and tissue distribution of zinc and constitutive levels of zinc-metallothionein (Zn-MT) in selected tissues were compared in obese (ob/ob) and lean (+/.) C57BL/6J mice. When 5-, 10- and 22-wk-old mice were administered 1.2 mumol /sup 65/Zn by stomach tube the apparent absorption of /sup 65/Zn by obese mice was 1.5, 2.2 and 3.9 times higher, respectively, than that in age-matched lean mice. Retention of orallymore » administered /sup 65/Zn after 96 h was also substantially higher in obese mice than in lean mice. To assess the possible influences of hyperphagia and intestinal hypertrophy on the enhanced apparent absorption of /sup 65/Zn by obese mice food intake by an additional group of obese mice was restricted to that of age-matched lean controls. When actual absorption of zinc was determined according to the method of Heth and Hoekstra, groups of ad libitum--fed obese, pair-fed obese and lean mice absorbed 38, 32 and 18% of administered /sup 65/Zn, respectively. In contrast, the rate of /sup 65/Zn excretion 2-6 d after oral or subcutaneous administration of the metal was similar for obese and lean mice. Unrestricted and pair-fed obese mice had significantly lower percentages of carcass /sup 65/Zn present in skin, muscle plus bone, spleen and testes and higher percentages present in liver, small intestine and adipose tissue than lean mice.« less

E. coli infection modulates the pharmacokinetics of oral enrofloxacin by targeting P-glycoprotein in small intestine and CYP450 3A in liver and kidney of broilers.

PubMed

Guo, Mengjie; Sun, Yong; Zhang, Yu; Bughio, Shamsuddin; Dai, Xiaohua; Ren, Weilong; Wang, Liping

2014-01-01

P-glycoprotein (P-gp) expression determines the absorption, distribution, metabolism and excretion of many drugs in the body. Also, up-regulation of P-gp acts as a defense mechanism against acute inflammation. This study examined expression levels of abcb1 mRNA and localization of P-gp protein in the liver, kidney, duodenum, jejunum and ileum in healthy and E. coli infected broilers by real time RT-PCR and immunohistochemistry. Meanwhile, pharmacokinetics of orally administered enrofloxacin was also investigated in healthy and infected broilers by HPLC. The results indicated that E. coli infection up-regulated expression of abcb1 mRNA levels significantly in the kidney, jejunum and ileum (P<0.05), but not significantly in the liver and duodenum (P>0.05). However, the expression level of CYP 3A37 mRNA were observed significantly decreased only in liver and kidney of E. coli infected broilers (P<0.05) compared with healthy birds. Furthermore, the infection reduced absorption of orally administered enrofloxacin, significantly decreased Cmax (0.34 vs 0.98 µg mL(-1), P = 0.000) and AUC0-12h (4.37 vs 8.88 µg mL(-1) h, P = 0.042) of enrofloxacin, but increased Tmax (8.32 vs 3.28 h, P = 0.040), T1/2a(2.66 vs 1.64 h(-1), P = 0.050) and V/F (26.7 vs 5.2 L, P = 0.040). Treatment with verapamil, an inhibitor of P-gp, significantly improved the absorption of enrofloxacin in both healthy and infected broilers. The results suggest that the E. coli infection induces intestine P-gp expression, altering the absorption of orally administered enrofloxacin in broilers.

Dietary Plant Sterol Esters Must Be Hydrolyzed to Reduce Intestinal Cholesterol Absorption in Hamsters123

PubMed Central

Carden, Trevor J; Hang, Jiliang; Dussault, Patrick H; Carr, Timothy P

2015-01-01

Background: Elevated concentrations of LDL cholesterol are associated with the development of atherosclerosis and therefore are considered an important target for intervention to prevent cardiovascular diseases. The inhibition of cholesterol absorption in the small intestine is an attractive approach to lowering plasma cholesterol, one that is addressed by drug therapy as well as dietary supplementation with plant sterols and plant sterol esters (PSEs). Objective: This study was conducted to test the hypothesis that the cholesterol-lowering effects of PSE require hydrolysis to free sterols (FSs). Methods: Male Syrian hamsters were fed atherogenic diets (AIN-93M purified diet containing 0.12% cholesterol and 8% coconut oil) to which one of the following was added: no PSEs or ethers (control), 5% sterol stearate esters, 5% sterol palmitate esters (PEs), 5% sterol oleate esters (OEs), 5% sterol stearate ethers (STs; to mimic nonhydrolyzable PSE), or 3% FSs plus 2% sunflower oil. The treatments effectively created a spectrum of PSE hydrolysis across which cholesterol metabolism could be compared. Metabolic measurements included cholesterol absorption, plasma and liver lipid concentration, and fecal neutral sterol and bile acid excretion. Results: The STs and the PEs and SEs were poorly hydrolyzed (1.69–4.12%). In contrast, OEs were 88.3% hydrolyzed. The percent hydrolysis was negatively correlated with cholesterol absorption (r = −0.85; P < 0.0001) and positively correlated with fecal cholesterol excretion (r = 0.92; P < 0.0001), suggesting that PSE hydrolysis plays a central role in the cholesterol-lowering properties of PSE. Conclusions: Our data on hamsters suggest that PSE hydrolysis and the presence of FSs is necessary to induce an optimum cholesterol-lowering effect and that poorly hydrolyzed PSEs may lower cholesterol through an alternative mechanism than that of competition with cholesterol for micelle incorporation. PMID:25972524

Dietary Plant Sterol Esters Must Be Hydrolyzed to Reduce Intestinal Cholesterol Absorption in Hamsters.

PubMed

Carden, Trevor J; Hang, Jiliang; Dussault, Patrick H; Carr, Timothy P

2015-07-01

Elevated concentrations of LDL cholesterol are associated with the development of atherosclerosis and therefore are considered an important target for intervention to prevent cardiovascular diseases. The inhibition of cholesterol absorption in the small intestine is an attractive approach to lowering plasma cholesterol, one that is addressed by drug therapy as well as dietary supplementation with plant sterols and plant sterol esters (PSEs). This study was conducted to test the hypothesis that the cholesterol-lowering effects of PSE require hydrolysis to free sterols (FSs). Male Syrian hamsters were fed atherogenic diets (AIN-93M purified diet containing 0.12% cholesterol and 8% coconut oil) to which one of the following was added: no PSEs or ethers (control), 5% sterol stearate esters, 5% sterol palmitate esters (PEs), 5% sterol oleate esters (OEs), 5% sterol stearate ethers (STs; to mimic nonhydrolyzable PSE), or 3% FSs plus 2% sunflower oil. The treatments effectively created a spectrum of PSE hydrolysis across which cholesterol metabolism could be compared. Metabolic measurements included cholesterol absorption, plasma and liver lipid concentration, and fecal neutral sterol and bile acid excretion. The STs and the PEs and SEs were poorly hydrolyzed (1.69-4.12%). In contrast, OEs were 88.3% hydrolyzed. The percent hydrolysis was negatively correlated with cholesterol absorption (r = -0.85; P < 0.0001) and positively correlated with fecal cholesterol excretion (r = 0.92; P < 0.0001), suggesting that PSE hydrolysis plays a central role in the cholesterol-lowering properties of PSE. Our data on hamsters suggest that PSE hydrolysis and the presence of FSs is necessary to induce an optimum cholesterol-lowering effect and that poorly hydrolyzed PSEs may lower cholesterol through an alternative mechanism than that of competition with cholesterol for micelle incorporation. © 2015 American Society for Nutrition.

Interaction between Bisphosphonates and Mineral Water: Study of Oral Risedronate Absorption in Rats.

PubMed

Itoh, Akihisa; Akagi, Yuuki; Shimomura, Hitoshi; Aoyama, Takao

2016-01-01

Bisphosphonates are antiosteoporotic agents prescribed for patients with osteoporosis. Drug package inserts for bisphosphonate supplements indicate that their bioavailability is reduced by high levels of metal cations (Ca(2+), Mg(2+), etc.). However, standards for these cations in water used for taking risedronate have not been defined. Here, we examined the effect of calcium and magnesium in mineral waters on the bioavailability of the third-generation bisphosphonate, risedronate, following oral administration in rats. As risedronate is unchanged and eliminated renally, risedronate absorption was estimated from the amount excreted in the urine. Risedronate was dissolved in mineral water samples and administered orally at 0.35 mg/kg. Urine samples were collected for 24 h after dosing. Risedronate was extracted from urine using ion-pair solid-phase cartridges and quantified by HPLC with UV detection (262 nm). Cumulative recovery of risedronate was calculated from the amount excreted in the urine. The 24-h recovery of risedronate from evian® (0.32±0.02% [mean±standard deviation (S.D.)], n=4) and Contrex(®) (0.22±0.05%) mineral waters was significantly lower than that from tap water (0.47±0.04%, p<0.01). Absorption of risedronate in calcium chloride and magnesium chloride aqueous solutions of the same hardness (822 mg/L) was 54% (0.27±0.04%) and 12% (0.51±0.08%) lower, respectively, compared with ultrapure water; suggesting that absorption of risedronate declines as the calcium concentration of mineral waters increases. Consumption of mineral waters containing high levels of calcium (80 mg/L or above), such as evian® and Contrex(®), is therefore not recommended when taking risedronate.

Secondary contributors to bone loss in osteoporosis related hip fractures.

PubMed

Edwards, B J; Langman, C B; Bunta, A D; Vicuna, M; Favus, M

2008-07-01

Osteoporosis treatment of patients with hip fractures is necessary to prevent subsequent fractures. Secondary causes for bone loss are present in more than 80% of patients with hip fractures, and therefore, assessment of Vitamin D status, disorders in calcium absorption and excretion, monoclonal gammopathies, and renal function should be performed. Identifying and managing these disorders will improve detection and enhance treatment aimed at reducing the risk of recurrent fractures in older adults. The purpose of this study was to determine the prevalence of disorders affecting bone and mineral metabolism in individuals with osteoporotic hip fractures. Community dwelling individuals with hip fractures (HFx) 50 years of age and older. Assessment for vitamin D, renal and parathyroid status, calcium absorption, and plasma cell disorders. Of 157 HFx, mean age 70 +/- 10 years, HFx had higher creatinine (p = 0.002, 95% C.I. -0.09, 0.05); lower 25 OH vitamin D (p = 0.019, 95% C.I. 6.5, 2.7), albumin (p = 0.007, 95% C.I. 0.36, 0.009), and 24-h urine calcium (p = 0.024, 95% CI 51, 21) as compared to controls. More than 80% of HFx had at least one previously undiagnosed condition, with vitamin D insufficiency (61%), chronic kidney disease (16%) (CKD), monoclonal gammopathy (6%), and low calcium absorption (5%) being the most common. One case each of multiple myeloma and solitary plasmocytoma were identified. Osteoporosis treatment of HFx is necessary to prevent subsequent fractures. Secondary causes for bone loss are remarkably common in HFx; therefore, assessment of vitamin D status, disorders in calcium absorption and excretion, protein electrophoresis, and renal function should be performed. Identifying and correcting these disorders will improve detection and enhance treatment aimed at reducing the risk of recurrent fractures in older adults.

The effect of ingested lactulose on absorption of L-rhamnose, D-xylose, and 3-O-methyl-D-glucose in subjects with ileostomies.

PubMed

Jenkins, A P; Menzies, I S; Nukajam, W S; Creamer, B

1994-09-01

We have previously shown that small oral doses of poorly absorbed solute can significantly reduce absorption of test sugars in normal volunteers. To confirm these results and investigate the underlying mechanism, the effects of lactulose on absorption of three test sugars in subjects with ileostomies were studied. Ten fasted subjects with ileostomies ingested an isosmolar test solution containing 2.5 g 3-O-methyl-D-glucose, 5.0 g D-xylose, 1.0 g L-rhamnose, and 50 microCi 51Cr-labelled ethylenediaminetetraacetic acid together with a blue dye transit marker. Urine was collected for time periods of 0-5 h and 5-24 h, to measure excretion of absorbed sugars, and ileostomy effluent was saved from 0-5 h and from 5 h until blue dye transit marker was no longer present, to measure small-bowel output of unabsorbed sugars. After 1 week the test was repeated, including 5 g lactulose in the test solution. Inclusion of lactulose in the test solution significantly reduced the 5 h and 24 h urine excretion of L-rhamnose and D-xylose but not that of 3-O-methyl-D-glucose and increased 0- to 5-h and total ileostomy output of L-rhamnose and D-xylose but not of 3-O-methyl-D-glucose. The presence of lactulose also reduced the time for first appearance of the blue dye transit marker in the effluent and increased effluent volume together with output of electrolyte. Poorly absorbed solute reduces intestinal absorption by retention of fluid and electrolyte, with subsequent intraluminal dilution and acceleration of transit.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Metivier, H.; Bourges, J.; Fritsch, P.

Absorption and retention of neptunium were determined in baboons after intragastric administration of neptunium nitrate solutions at pH 1. The effects of mass, diet, and fasting on absorption were studied. At higher mass levels (400-800 micrograms Np/kg), absorption was about 1%; at lower mass intakes (0.0009-0.005 micrograms Np/kg), absorption was reduced by 10- to 20-fold. The addition of an oxidizing agent (Fe3+) increased gastrointestinal absorption and supported the hypothesis of a reduction of Np (V) when loss masses were ingested. Diets depleted of or enriched with hydroxy acids did not modify retention of neptunium but increased urinary excretion with increasingmore » hydroxy acid content. The diet enriched with milk components reduced absorption by a factor of 5. Potatoes increased absorption and retention by a factor 5, not necessarily due to the effect of phytate. Fasting for 12 or 24 h increased retention and absorption by factors of about 3 and 10, respectively. Data obtained in baboons when low masses of neptunium were administered suggest that the f1 factor used by ICRP should be decreased. However, fasting as encountered in certain nutritional habits is a factor to be taken into consideration.« less

Nutritional Biochemistry of Space Flight

NASA Technical Reports Server (NTRS)

Smith, Scott M.

2000-01-01

Adequate nutrition is critical for maintenance of crew health during and after extended-duration space flight. The impact of weightlessness on human physiology is profound, with effects on many systems related to nutrition, including bone, muscle, hematology, fluid and electrolyte regulation. Additionally, we have much to learn regarding the impact of weightlessness on absorption, mtabolism , and excretion of nutrients, and this will ultimately determine the nutrient requirements for extended-duration space flight. Existing nutritional requirements for extended-duration space flight have been formulated based on limited flight research, and extrapolation from ground-based research. NASA's Nutritional Biochemistry Laboratory is charged with defining the nutritional requirements for space flight. This is accomplished through both operational and research projects. A nutritional status assessment program is included operationally for all International Space Station astronauts. This medical requirement includes biochemical and dietary assessments, and is completed before, during, and after the missions. This program will provide information about crew health and nutritional status, and will also provide assessments of countermeasure efficacy. Ongoing research projects include studies of calcium and bone metabolism, and iron absorption and metabolism. The calcium studies include measurements of endocrine regulation of calcium homeostasis, biochemical marker of bone metabolism, and tracer kinetic studies of calcium movement in the body. These calcium kinetic studies allow for estimation of intestinal absorption, urinary excretion, and perhaps most importantly - deposition and resorption of calcium from bone. The Calcium Kinetics experiment is currently being prepared for flight on the Space Shuttle in 2001, and potentially for subsequent Shuttle and International Space Station missions. The iron study is intended to assess whether iron absorption is down-regulated dUl1ng space flight. This is critical due to the red blood cell changes which occur, and the increase in iron storage that has been observed after space flight. The Iron Absorption and Metabolism experiment is currently planned for long-term flights on the International Space Station.

A workflow to investigate exposure and pharmacokinetic ...

EPA Pesticide Factsheets

Adverse outcome pathways (AOP) link known population outcomes to a molecular initiating event (MIE) that can be quantified using high-throughput in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires consideration of exposure and absorption, distribution, metabolism, excretion (ADME) properties of chemicals. We developed a conceptual workflow to consider exposure and ADME properties in relationship to an MIE and demonstrated the utility of this workflow using a previously established AOP, acetylcholinesterase (AChE) inhibition. Thirty active chemicals found to inhibit AChE in the ToxCastTM assay were examined with respect to their exposure and absorption potentials, and their ability to cross the blood-brain barrier. Structural similarities of active compounds were compared against structures of inactive compounds to detect possible non-active parents that might have active metabolites. Fifty-two of the 1,029 inactive compounds exhibited a similarity threshold above 75% with their nearest active neighbors. Excluding compounds that may not be absorbed, 22 could be potentially toxic following metabolism. The incorporation of exposure and ADME properties into the conceptual workflow resulted in prioritization of 20 out of 30 active compounds identified in an AChE inhibition assay for further analysis, along with identification of several inactive parent compounds of active metabolites. This qualitative approach can minimize co

Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle

PubMed Central

Vernetti, Lawrence; Gough, Albert; Baetz, Nicholas; Blutt, Sarah; Broughman, James R.; Brown, Jacquelyn A.; Foulke-Abel, Jennifer; Hasan, Nesrin; In, Julie; Kelly, Edward; Kovbasnjuk, Olga; Repper, Jonathan; Senutovitch, Nina; Stabb, Janet; Yeung, Catherine; Zachos, Nick C.; Donowitz, Mark; Estes, Mary; Himmelfarb, Jonathan; Truskey, George; Wikswo, John P.; Taylor, D. Lansing

2017-01-01

Organ interactions resulting from drug, metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements. PMID:28176881

Stereoselective bioaccumulation of syn- and anti-Dechlorane plus isomers in different tissues of common carp (Cyprinus carpio).

PubMed

Tang, Bin; Luo, Xiao-Jun; Huang, Chen-Chen; Sun, Run-Xia; Wang, Tao; Zeng, Yan-Hong; Mai, Bi-Xian

2018-03-01

Common carps (Cyprinus carpio) were exposed to syn- and anti-Dechlorane Plus (DP) isomers to investigate absorption, tissue distribution, and stereoselective bioaccumulation of DP isomers. The absorption efficiencies of anti-DP in the gastrointestinal system were higher than those of syn-DP. A linear accumulation was found for both isomers in all fish tissues except for serum; and the liver and gill exhibited the highest and lowest DP assimilation efficiency, respectively. The elimination of DP isomers in all tissues followed first-order kinetics, with the fastest depuration rate occurring in the liver and serum. The biomagnification factors (BMFs) of both isomers were less than one in all tissues, except for serum. Anti-DP was preferably accumulated in the liver, gill, and serum, whereas syn-DP was selectively accumulated in the carcass and gastrointestinal tract. As a whole, fish did not show selective accumulation of the syn- or anti-DP isomer in the uptake stage, whereas a selective accumulation of syn-DP in fish was observed during the depuration period, which could be due to a selective excretion of anti-DP. Metabolism cannot be ruled out as a possible reason considering the high f anti values and the high elimination rate of DPs in the liver. Copyright © 2017 Elsevier B.V. All rights reserved.

Loss of Vitamin D Receptor Produces Polyuria by Increasing Thirst

PubMed Central

Kong, Juan; Zhang, Zhongyi; Li, Dongdong; Wong, Kari E.; Zhang, Yan; Szeto, Frances L.; Musch, Mark W.; Li, Yan Chun

2008-01-01

Vitamin D receptor (VDR)-null mice develop polyuria, but the underlying mechanism remains unknown. In this study, we investigated the relationship between vitamin D and homeostasis of water and electrolytes. VDR-null mice had polyuria, but the urine osmolarity was normal as a result of high salt excretion. The urinary responses to water restriction and to vasopressin were similar between wild-type and VDR-null mice, suggesting intact fluid-handling capacity in VDR-null mice. Compared with wild-type mice, however, renin and angiotensin II were dramatically upregulated in the kidney and brain of VDR-null mice, leading to a marked increase in water intake and salt appetite. Angiotensin II–mediated upregulation of intestinal NHE3 expression partially explained the increased salt absorption and excretion in VDR-null mice. In the brain of VDR-null mice, expression of c-Fos, which is known to associate with increased water intake, was increased in the hypothalamic paraventricular nucleus and the subfornical organ. Treatment with an angiotensin II type 1 receptor antagonist normalized water intake, urinary volume, and c-Fos expression in VDR-null mice. Furthermore, despite a salt-deficient diet to reduce intestinal salt absorption, VDR-null mice still maintained the increased water intake and urinary output. Together, these data indicate that the polyuria observed in VDR-null mice is not caused by impaired renal fluid handling or increased intestinal salt absorption but rather is the result of increased water intake induced by the increase in systemic and brain angiotensin II. PMID:18832438

Loss of vitamin D receptor produces polyuria by increasing thirst.

PubMed

Kong, Juan; Zhang, Zhongyi; Li, Dongdong; Wong, Kari E; Zhang, Yan; Szeto, Frances L; Musch, Mark W; Li, Yan Chun

2008-12-01

Vitamin D receptor (VDR)-null mice develop polyuria, but the underlying mechanism remains unknown. In this study, we investigated the relationship between vitamin D and homeostasis of water and electrolytes. VDR-null mice had polyuria, but the urine osmolarity was normal as a result of high salt excretion. The urinary responses to water restriction and to vasopressin were similar between wild-type and VDR-null mice, suggesting intact fluid-handling capacity in VDR-null mice. Compared with wild-type mice, however, renin and angiotensin II were dramatically upregulated in the kidney and brain of VDR-null mice, leading to a marked increase in water intake and salt appetite. Angiotensin II-mediated upregulation of intestinal NHE3 expression partially explained the increased salt absorption and excretion in VDR-null mice. In the brain of VDR-null mice, expression of c-Fos, which is known to associate with increased water intake, was increased in the hypothalamic paraventricular nucleus and the subfornical organ. Treatment with an angiotensin II type 1 receptor antagonist normalized water intake, urinary volume, and c-Fos expression in VDR-null mice. Furthermore, despite a salt-deficient diet to reduce intestinal salt absorption, VDR-null mice still maintained the increased water intake and urinary output. Together, these data indicate that the polyuria observed in VDR-null mice is not caused by impaired renal fluid handling or increased intestinal salt absorption but rather is the result of increased water intake induced by the increase in systemic and brain angiotensin II.

Distribution and excretion of BisGMA in guinea pigs.

PubMed

Reichl, F X; Seiss, M; Kleinsasser, N; Kehe, K; Kunzelmann, K H; Thomas, P; Spahl, W; Hickel, R

2008-04-01

Bisphenol-A-glycidyldimethacrylate (BisGMA) is used in many resin-based dental materials. It was shown in vitro that BisGMA was released into the adjacent biophase from such materials during the first days after placement. In this study, the uptake, distribution, and excretion of [(14)C]BisGMA applied via gastric and intravenous administration (at dose levels well above those encountered in dental care) were examined in vivo in guinea pigs to test the hypothesis that BisGMA reaches cytotoxic levels in mammalian tissues. [(14)C]BisGMA was taken up rapidly from the stomach and intestine after gastric administration and was widely distributed in the body following administration by each route. Most [(14)C] was excreted within one day as (14)CO(2). The peak equivalent BisGMA levels in guinea pig tissues examined were at least 1000-fold less than known toxic levels. The peak urine level in guinea pigs that received well in excess of the body-weight-adjusted dose expected in humans was also below known toxic levels. The study therefore did not support the hypothesis.

The influence of age on the distribution, metabolism and excretion of methoxyflurane in Fischer 344 rats: a possible relationship to nephrotoxicity.

PubMed

Bell, L E; Hitt, B A; Mazze, R I

1975-10-01

Age as a factor in methoxyflurane nephrotoxicity was evaluated in Fischer 344 rats of various ages by determination of: 1) serum inorganic fluoride and methoxyflurane concentrations, and urinary inorganic fluoride excretion in methoxyflurane-exposed rats; 2) liver microsomal methoxyflurane defluorinase activity; and 3) distribution of injected sodium fluoride. Only rats in the youngest age group (6 weeks) did not develop nephrotoxicity after anesthesia. Older rats had a biphasic rather than a monophasic decay in serum methoxyflurane concentration and also had increased serum inorganic fluoride concentration and urinary inorganic fluoride excretion. Older rats also excreted a greater proportion of an injected dose of sodium fluoride compared to young rats. Microsomal methoxyflurane defluorinase specific activity was similar among rats of all ages. It is likely that increased availability of methoxyflurane due to its greater storage in fat led to more inorganic fluoride production in older compared to younger rats. Bone sequestration of inorganic fluoride in younger rats probably accounts for decreased serum inorganic fluoride levels in that group. Both factors cause significant differences in renal exposure to inorganic fluoride; thus the risk of nephrotoxicity is less in younger animals.

Historical exposure to inorganic mercury at the smelter works of Abbadia San Salvatore, Italy.

PubMed

Bellander, T; Merler, E; Ceccarelli, F; Boffetta, P

1998-02-01

Metallic mercury production from cinnabar ore may result in high exposures to inorganic mercury, that are difficult to assess separately from the exposures originating from underground extraction, and previously have only been scantily described. We retrieved and analysed the air and biological mercury determinations on workers involved in the smelting process of the Abbadia San Salvatore mine (Monte Amiata, Italy). Native mercury was not present in the ore, and the exposure in the underground extraction was low. The smelter operated from 1897 to 1983. Blood and urine (24/h urine collections and concentration samples) had been sampled in 1968 to 1982, and analysed for mercury by atomic absorption spectrophotometry, and relate to all subjects. Exposure to mercury in air had been determined in a small set of personal samples in 1982. The data relate to all jobs in the smelter process, and all jobs entailed substantial exposure to mercury. The overall distribution of breathing zone air, blood and urinary levels is right-skewed and similar to the log-normal distribution (air, median 48 micrograms/m3, n = 49; blood, arithmetic mean AM 49 micrograms/L; geometric mean GM 26 micrograms/L, n = 192; urinary excretion, AM 140 micrograms/24 h, GM 78 micrograms/24 h, n = 839; and urinary concentration, AM 160 micrograms/L, GM 83 micrograms/L, n = 632). Air, blood and urinary values show a high ratio of the between- and within-job variance, indicating differences in exposure by job. Cinnabar pigment production, of which the exposure has not been characterised previously, was the job with the highest air (AM 160 micrograms/m3) and urinary levels (excretion AM 690 micrograms/24 h; concentration AM 1100 micrograms/L). Other jobs with high urinary levels were soot purification, laboratory work, and bottling. Cleaning of condensers showed the highest blood level (AM 280 micrograms/L). There is a downwards time trend in mercury concentration in blood and in urine. The corresponding trend is not seen for urinary excretion levels, the reason for this being unclear. Roasters, which is the most frequently monitored group, show however a decreasing trend in all sets of data (e.g. the mean of urinary excretion decreased from 300 micrograms/24 h in 1968/69 to 50 micrograms/24 h in 1980/81). The mercury exposure experienced by the smelters of Abbadia San Salvatore is in line with the few available data on workers from other mercury mines and smelters, and our data confirm the high exposure levels in this occupational group, in particular at cinnabar pigment production, soot purification, and condenser cleaning.

Bifidobacterium animalis subsp. lactis decreases urinary oxalate excretion in a mouse model of primary hyperoxaluria

PubMed Central

Whittamore, Jonathan M.; Hatch, Marguerite

2015-01-01

Hyperoxaluria significantly increases the risk of calcium oxalate kidney stone formation. Since several bacteria have been shown to metabolize oxalate in vitro, including probiotic bifidobacteria, we focused on the efficiency and possible mechanisms by which bifidobacteria can infuence oxalate handling in vivo, especially in the intestines, and compared these results with the reported effects of Oxalobacter formigenes. Bifidobacterium animalis subsp. lactis DSM 10140 and B. adolescentis ATCC 15703 were administered to wild-type (WT) mice and to mice defcient in the hepatic enzyme alanine-glyoxylate aminotransferase (Agxt−/−, a mouse model of Primary Hyperoxaluria) that were fed an oxalate-supplemented diet. The administration of B. animalis subsp. lactis led to a significant decrease in urinary oxalate excretion in WT and Agxt−/− mice when compared to treatment with B. adolescent-is. Detection of B. animalis subsp. lactis in feces revealed that 3 weeks after oral gavage with the bacteria 64 % of WT mice, but only 37 % of Agxt−/− mice were colonized. Examining intestinal oxalate fuxes showed there were no significant changes to net oxalate secretion in colonized animals and were therefore not associated with the changes in urinary oxalate excretion. These results indicate that colonization with B. animalis subsp. lactis decreased urinary oxalate excretion by degrading dietary oxalate thus limiting its absorption across the intestine but it did not promote enteric oxalate excretion as reported for O. formigenes. Preventive or therapeutic administration of B. animalis subsp. lactis appears to have some potential to beneficially infuence dietary hyperoxaluria in mice. PMID:25269440

Substituting milk for apple juice does not increase kidney stone risk in most normocalciuric adults who form calcium oxalate stones.

PubMed

Massey, L K; Kynast-Gales, S A

1998-03-01

Increasing intake of dietary calcium from less than 400 mg to 800 mg daily may decrease the absorption of dietary oxalate, which in turn would decrease urinary oxalate excretion. The effect of substituting milk for apple juice on urine composition and risk of calcium oxalate precipitability was studied. Twenty-one normocalciuric adults with a history of at least 1 calcium oxalate stone and urinary oxalate excretion exceeding 275 micromol/day on their self-selected diet. Randomized crossover trial. Each participant consumed two moderate-oxalate (2,011 micromol/day) study diets, which were identical except that one contained 360 mL milk and the other contained 540 mL apple juice as the beverage with meals. Four days free-living then 2 days in the metabolic unit of a university nutrition department. Tiselius risk index for calcium oxalate precipitability calculated from urine composition. Paired t tests. Twenty-four hour urinary oxalate excretion was 18% lower (P<.0001) on the milk diet vs the juice diet: 423 vs 514 micromol, respectively. Calcium excretion was 17% higher (P<.05) on the milk vs juice diet: 4.7 vs 3.9 mmol, respectively. Urinary magnesium and citrate excretion, volume, and Tiselius risk index did not differ between diets. Substituting 360 mL milk daily for apple juice with meals in a diet containing moderate amounts of dietary oxalate from whole grains, legumes, fruits, and vegetables does not increase the risk index of calcium oxalate precipitability in most normocalciuric adults who form stones.

Nickel absorption and kinetics in human volunteers.

PubMed

Sunderman, F W; Hopfer, S M; Sweeney, K R; Marcus, A H; Most, B M; Creason, J

1989-05-01

Mathematical modeling of the kinetics of nickel absorption, distribution, and elimination was performed in healthy human volunteers who ingested NiSO4 drinking water (Experiment 1) or added to food (Experiment 2). Nickel was analyzed by electrothermal atomic absorption spectrophotometry in serum, urine, and feces collected during 2 days before and 4 days after a specified NiSO4 dose (12 micrograms of nickel/kg, n = 4; 18 micrograms of nickel/kg, n = 4; or 50 micrograms of nickel/kg, n = 1). In Experiment 1, each of the subjects fasted 12 hr before and 3 hr after drinking one of the specified NiSO4 doses dissolved in water; in Experiment 2, the respective subjects fasted 12 hr before consuming a standard American breakfast that contained the identical dose of NiSO4 added to scrambled eggs. Kinetic analyses, using a compartmental model, provided excellent goodness-of-fit for paired data sets from all subjects. Absorbed nickel averaged 27 +/- 17% (mean +/- SD) of the dose ingested in water vs 0.7 +/- 0.4% of the same dose ingested in food (a 40-fold difference); rate constants for nickel absorption, transfer, and elimination were not significantly influenced by the oral vehicle. The elimination half-time for absorbed nickel averaged 28 +/- 9 hr. Renal clearance of nickel averaged 8.3 +/- 2.0 ml/min/1.73 m2 in Experiment 1 and 5.8 +/- 4.3 ml/min/1.73 m2 in Experiment 2. This study confirms that dietary constituents profoundly reduce the bioavailability of Ni2+ for alimentary absorption; approximately one-quarter of nickel ingested in drinking water after an over-night fast is absorbed from the human intestine and excreted in urine, compared with only 1% of nickel ingested in food. The compartmental model and kinetic parameters provided by this study will reduce the uncertainty of toxicologic risk assessments of human exposures to nickel in drinking water and food.

METABOLISM OF RUTHENIUM IN THE RAT. Technical Documentary Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Traynor, J.E.; Leeper, S.W.

1961-12-01

Seventeen Sprague-Dawley rats were injected intramuscularly and intraperitoneally with ruthenium-106. The amount of this isotope was determined daily for 5 weeks in the urine and feces. Animals were sacrificed at intervals and the various organs were analyzed for ruthenium. It was noted from this experiment that the pathways of absorption, metabolism, and excretion are dependent on the route of administration of ruthenium. (auth)

Disruption of Calcium Homeostasis During Exercise as a Mediator of Bone Metabolism

DTIC Science & Technology

2015-10-01

Meeting of the American College of Sports Medicine (Appendix A). 15. SUBJECT TERMS calcium homeostasis, exercise, bone resorption, parathyroid hormone ... hormone (PTH). PTH can defend serum Ca by reducing urinary Ca excretion, increasing intestinal Ca absorption, and increasing mobilization of skeletal Ca...certain conditions. It is our contention that disruptions in calcium homeostasis during exercise lead to increases in parathyroid hormone (PTH) and

Effect of age and lactose on sup 67 Cu utilization in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Link, J.; Dowdy, R.; Michelmann, E.

1991-03-15

Young and old male Fischer 344 rats were fed a control diet or a lactose diet. After four weeks rats were gavaged with approximately 6.24 uCl {sup 67}Cu, placed in metabolism cages, and fed their respective diets for an additional two weeks. Daily whole body, urine and fecal radioactivity measurements were made. Rats were killed on day 42 and livers removed for radioactivity determination. Diet had no effect on whole body retention of {sup 67}Cu in the old rats; approximately 20% of the initial dose was retained by the end of the study. In the young rats, however, lactose appearedmore » to enhance initial {sup 67}Cu retention; by day three young control rats retained only 30% of the initial dose, while the young lactose rats retained about 50%. Retention of {sup 67}Cu at the end of the study was approximately 15% and 20% for young control and young lactose rats, respectively. During the first four days post dosing, cumulative fecal {sup 67}Cu excretion was approximately 83% for young control rats and 69% for young lactose rats indicating enhancement of {sup 67}Cu absorption by lactose in the young rats. For old rats cumulative {sup 67}Cu excretion in feces was about 50% regardless of diet. Cumulative urinary {sup 67}Cu excretion was approximately 6% and 8% for young control and lactose rats, respectively vs about 11% for old rats. {sup 67}Cu retention in liver was greater in old rats regardless of diet. The early increase in {sup 67}Cu absorption after a bolus dose may have therapeutic implications. In light of current concern regarding Cu-carbohydrate interactions, the apparent enhancement Cu retention by lactose in young rats deserves further attention.« less

Klotho Prevents Renal Calcium Loss

PubMed Central

Alexander, R. Todd; Woudenberg-Vrenken, Titia E.; Buurman, Jan; Dijkman, Henry; van der Eerden, Bram C. J.; van Leeuwen, Johannes P.T.M.; Bindels, René J.

2009-01-01

Disturbed calcium (Ca2+) homeostasis, which is implicit to the aging phenotype of klotho-deficient mice, has been attributed to altered vitamin D metabolism, but alternative possibilities exist. We hypothesized that failed tubular Ca2+ absorption is primary, which causes increased urinary Ca2+ excretion, leading to elevated 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and its sequelae. Here, we assessed intestinal Ca2+ absorption, bone densitometry, renal Ca2+ excretion, and renal morphology via energy-dispersive x-ray microanalysis in wild-type and klotho−/− mice. We observed elevated serum Ca2+ and fractional excretion of Ca2+ (FECa) in klotho−/− mice. Klotho−/− mice also showed intestinal Ca2+ hyperabsorption, osteopenia, and renal precipitation of calcium-phosphate. Duodenal mRNA levels of transient receptor potential vanilloid 6 (TRPV6) and calbindin-D9K increased. In the kidney, klotho−/− mice exhibited increased expression of TRPV5 and decreased expression of the sodium/calcium exchanger (NCX1) and calbindin-D28K, implying a failure to absorb Ca2+ through the distal convoluted tubule/connecting tubule (DCT/CNT) via TRPV5. Gene and protein expression of the vitamin D receptor (VDR), 25-hydroxyvitamin D-1-α-hydroxylase (1αOHase), and calbindin-D9K excluded renal vitamin D resistance. By modulating the diet, we showed that the renal Ca2+ wasting was not secondary to hypercalcemia and/or hypervitaminosis D. In summary, these findings illustrate a primary defect in tubular Ca2+ handling that contributes to the precipitation of calcium-phosphate in DCT/CNT. This highlights the importance of klotho to the prevention of renal Ca2+ loss, secondary hypervitaminosis D, osteopenia, and nephrocalcinosis. PMID:19713312

Ezetimibe Increases Endogenous Cholesterol Excretion in Humans

PubMed Central

Lin, Xiaobo; Racette, Susan B; Ma, Lina; Wallendorf, Michael; Ostlund, Richard E

2017-01-01

Objective Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers LDL cholesterol and percent intestinal cholesterol absorption, but the exact cardioprotective mechanism is unknown. We tested the hypothesis that the dominant effect of ezetimibe is to increase the reverse transport of cholesterol from rapidly-mixing endogenous cholesterol pool into the stool. Approach and Results In a randomized, placebo-controlled, double-blind parallel trial in 24 healthy subjects with LDL cholesterol 100–200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/day or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 in a lipid emulsion and dietary cholesterol with cholesterol-d5 and sitostanol-d4 solubilized in oil. Plasma and stool samples collected during a cholesterol- and phytosterol-controlled metabolic kitchen diet were analyzed by mass spectrometry. Ezetimibe reduced intestinal cholesterol absorption efficiency 30 ± 4.3% (SE, P < 0.0001) and LDL cholesterol 19.8 ± 1.9% (P = 0.0001). Body cholesterol pool size was unchanged, but fecal endogenous cholesterol excretion increased 66.6 ± 12.2% (P < 0.0001) and percent cholesterol excretion from body pools into the stool increased 74.7 ± 14.3% (P < 0.0001) while plasma cholesterol turnover rose 26.2 ± 3.6% (P = 0.0096). Fecal bile acids were unchanged. Conclusions Ezetimibe increased the efficiency of reverse cholesterol transport from rapidly-mixing plasma and tissue pools into the stool. Further work is needed to examine the potential relation of reverse cholesterol transport and whole body cholesterol metabolism to coronary events and the treatment of atherosclerosis. PMID:28279967

Ezetimibe Increases Endogenous Cholesterol Excretion in Humans.

PubMed

Lin, Xiaobo; Racette, Susan B; Ma, Lina; Wallendorf, Michael; Ostlund, Richard E

2017-05-01

Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers low-density lipoprotein cholesterol and percent intestinal cholesterol absorption, but the exact cardioprotective mechanism is unknown. We tested the hypothesis that the dominant effect of ezetimibe is to increase the reverse transport of cholesterol from rapidly mixing endogenous cholesterol pool into the stool. In a randomized, placebo-controlled, double-blind parallel trial in 24 healthy subjects with low-density lipoprotein cholesterol 100 to 200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/d or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d 7 in a lipid emulsion and dietary cholesterol with cholesterol-d 5 and sitostanol-d 4 solubilized in oil. Plasma and stool samples collected during a cholesterol- and phytosterol-controlled metabolic kitchen diet were analyzed by mass spectrometry. Ezetimibe reduced intestinal cholesterol absorption efficiency 30±4.3% (SE, P <0.0001) and low-density lipoprotein cholesterol 19.8±1.9% ( P =0.0001). Body cholesterol pool size was unchanged, but fecal endogenous cholesterol excretion increased 66.6±12.2% ( P <0.0001) and percent cholesterol excretion from body pools into the stool increased 74.7±14.3% ( P <0.0001), whereas plasma cholesterol turnover rose 26.2±3.6% ( P =0.0096). Fecal bile acids were unchanged. Ezetimibe increased the efficiency of reverse cholesterol transport from rapidly mixing plasma and tissue pools into the stool. Further work is needed to examine the potential relation of reverse cholesterol transport and whole body cholesterol metabolism to coronary events and the treatment of atherosclerosis. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758. © 2017 American Heart Association, Inc.

Studies on the Presence of Mycotoxins in Biological Samples: An Overview

PubMed Central

Escrivá, Laura; Font, Guillermina; Manyes, Lara

2017-01-01

Mycotoxins are fungal secondary metabolites with bioaccumulation levels leading to their carry-over into animal fluids, organs, and tissues. As a consequence, mycotoxin determination in biological samples from humans and animals has been reported worldwide. Since most mycotoxins show toxic effects at low concentrations and considering the extremely low levels present in biological samples, the application of reliable detection methods is required. This review summarizes the information regarding the studies involving mycotoxin determination in biological samples over the last 10 years. Relevant data on extraction methodology, detection techniques, sample size, limits of detection, and quantitation are presented herein. Briefly, liquid-liquid extraction followed by LC-MS/MS determination was the most common technique. The most analyzed mycotoxin was ochratoxin A, followed by zearalenone and deoxynivalenol—including their metabolites, enniatins, fumonisins, aflatoxins, T-2 and HT-2 toxins. Moreover, the studies were classified by their purpose, mainly focused on the development of analytical methodologies, mycotoxin biomonitoring, and exposure assessment. The study of tissue distribution, bioaccumulation, carry-over, persistence and transference of mycotoxins, as well as, toxicokinetics and ADME (absorption, distribution, metabolism and excretion) were other proposed goals for biological sample analysis. Finally, an overview of risk assessment was discussed. PMID:28820481

Evaluation of transporters in drug development: Current status and contemporary issues.

PubMed

Lee, Sue-Chih; Arya, Vikram; Yang, Xinning; Volpe, Donna A; Zhang, Lei

2017-07-01

Transporters govern the access of molecules to cells or their exit from cells, thereby controlling the overall distribution of drugs to their intracellular site of action. Clinically relevant drug-drug interactions mediated by transporters are of increasing interest in drug development. Drug transporters, acting alone or in concert with drug metabolizing enzymes, can play an important role in modulating drug absorption, distribution, metabolism and excretion, thus affecting the pharmacokinetics and/or pharmacodynamics of a drug. The drug interaction guidance documents from regulatory agencies include various decision criteria that may be used to predict the need for in vivo assessment of transporter-mediated drug-drug interactions. Regulatory science research continues to assess the prediction performances of various criteria as well as to examine the strength and limitations of each prediction criterion to foster discussions related to harmonized decision criteria that may be used to facilitate global drug development. This review discusses the role of transporters in drug development with a focus on methodologies in assessing transporter-mediated drug-drug interactions, challenges in both in vitro and in vivo assessments of transporters, and emerging transporter research areas including biomarkers, assessment of tissue concentrations, and effect of diseases on transporters. Published by Elsevier B.V.

Urinary metabolites from mango (Mangifera indica L. cv. Keitt) galloyl derivatives and in vitro hydrolysis of gallotannins in physiological conditions.

PubMed

Barnes, Ryan C; Krenek, Kimberly A; Meibohm, Bernd; Mertens-Talcott, Susanne U; Talcott, Stephen T

2016-03-01

The absorption, metabolism, and excretion of mango galloyl derivatives (GD) has not yet been investigated in humans, and studies investigating repeated dosages of polyphenols are limited. In this human pilot trial, healthy volunteers (age = 21-38 y, n = 11) consumed 400 g/day of mango-pulp (cv. Keitt) for 10 days, and seven metabolites of gallic acid (GA) were characterized and quantified in urine excreted over a 12 h period. Pyrogallol-O-sulfate and deoxypyrogallol-O-sulfate were found to be significantly more excreted between days 1 and 10 (p < 0.05) from 28.5 to 55.4 mg and 23.6 to 47.7 mg, respectively. Additionally, the in vitro hydrolysis of gallotannins (GTs) was monitored at physiological pH and temperature conditions, and after 4 h a significant (p < 0.05) shift in composition from relativity high to low molecular weight GTs was observed. Seven metabolites of GA were identified in the urine of healthy volunteers, and two microbial metabolites were found to be significantly more excreted following 10 days of mango consumption. Mango GTs were also found to release free GA in conditions similar to the intestines. GTs may serve as a pool of pro-GA compounds that can be absorbed or undergo microbial metabolism. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effect of animal and vegetable protein intake on oxalate excretion in idiopathic calcium stone disease.

PubMed

Marangella, M; Bianco, O; Martini, C; Petrarulo, M; Vitale, C; Linari, F

1989-04-01

Oxalate excretion was measured in healthy subjects and idiopathic calcium stone-formers on dietary regimens which differed in the type and amount of protein allowed; 24-h urine collections were obtained from 41 practising vegetarians and 40 normal persons on a free, mixed, "mediterranean" diet. Twenty idiopathic calcium stone-formers were also studied while on two low calcium, low oxalate diets which differed in that animal protein was high in one and restricted in the other. Vegetarians had higher urinary oxalate levels than controls and although the calcium levels were markedly lower, urinary saturation with calcium/oxalate was significantly higher. This mild hypercalciuria was interpreted as being secondary to both a higher intake and increased fractional intestinal absorption of oxalate. Changing calcium stone-formers from a high to a low animal protein intake produced a significant decrease in calcium excretion but there was no variation in urinary oxalate. As a result, the decrease in calcium oxalate saturation was only marginal and not significant. It was concluded that dietary animal protein has a minimal effect on oxalate excretion. Mild hyperoxaluria of idiopathic calcium stone disease is likely to be intestinal in origin. Calcium stone-formers should be advised to avoid an excess of animal protein but the risks of a vegetable-rich diet should also be borne in mind.

Simultaneous administration of lactulose and 51Cr-ethylenediaminetetraacetic acid. A test to distinguish colonic from small-intestinal permeability change.

PubMed

Jenkins, A P; Nukajam, W S; Menzies, I S; Creamer, B

1992-09-01

In normal adults intestinal permeation of ingested 51Cr-ethylenediaminetetraacetic acid (EDTA) is greater than that of lactulose. This difference is abolished in patients with ileostomies, suggesting that it results from colonic permeation of 51Cr-EDTA, which, unlike lactulose, resists bacterial degradation. To investigate the effect of an increase in colonic permeability on absorption of the two molecules, lactulose (5 g) and 51Cr-EDTA (50 microCi) were given orally in isosmolar solution to 11 patients with colitis, and their 24-h urinary excretion measured. By comparison the effect of an increase in small-intestinal permeability induced by ingestion of a hyperosmolar solution (4240 mosm/l) was measured in 10 healthy adults. Hyperosmolar stress increased the 24-h urinary excretion of 51Cr-EDTA above the normal mean + 2 standard deviations (3.31%) in all 10 healthy subjects, and in all of these excretion of lactulose was also increased (greater than 1.06%). In contrast, although seven colitics had a urinary excretion of 51Cr-EDTA above the normal mean + 2 SD, in only two of these patients was recovery of lactulose increased. This suggests that simultaneous administration of lactulose and 51Cr-EDTA may enable permeability changes affecting the colon alone to be distinguished from those involving the small intestine.

Inorganic mercury poisoning associated with skin-lightening cosmetic products.

PubMed

Chan, Thomas Y K

2011-12-01

Mercury and mercury salts, including mercurous chloride and mercurous oxide, are prohibited for use in cosmetic products as skin-lightening agents because of their high toxicity. Yet, the public continue to have access to these products. Reports of skin-lightening cosmetic products containing mercury and cases of mercury poisoning following the use of such products were identified using Medline (1950 - 28 March 2011) with mercury, mercury compounds, mercury poisoning, cosmetics and skin absorption as the subject headings. These searches identified 118 citations of which 31 were relevant. The rate of dermal absorption increases with the concentration of mercury and prior hydration of the skin. The degree of dermal absorption varies with the skin integrity and lipid solubility of the vehicle in the cosmetic products. Ingestion may occur after topical application around the mouth and hand-to-mouth contact. After absorption, inorganic mercury is distributed widely and elimination occurs primarily through the urine and feces. With long-term exposure, urinary excretion is the major route of elimination. The half-life is approximately 1-2 months. The kidneys are the major site of inorganic mercury deposition; renal damage includes reversible proteinuria, acute tubular necrosis and nephrotic syndrome. Gastrointestinal symptoms include a metallic taste, gingivostomatitis, nausea and hypersalivation. Although penetration of the blood-brain barrier by inorganic mercury is poor, prolonged exposure can result in central nervous system (CNS) accumulation and neurotoxicity. Inorganic mercury poisoning following the use of skin-lightening creams has been reported from Africa, Europe, USA, Mexico, Australia and Hong Kong. Nephrotic syndrome (mainly due to minimal change or membranous nephropathy) and neurotoxicity were the most common presenting features. As mercury-containing cosmetic products can contaminate the home, some close household contacts were also reported to have elevated urine mercury concentrations. Prevention from further exposure is the first step. Cream users and their close contacts should be evaluated for evidence of mercury exposure, the presence of target organ damage and the need for chelation treatment. Laboratory evaluation of affected subjects should include a complete blood count, serum electrolytes, liver and renal function tests, urinalysis, urine and blood mercury concentrations. Since blood mercury concentrations tend to return to normal within days of exposure, blood samples are useful primarily in short-term, higher-level exposures. Estimation of the urine mercury concentration is the best marker of exposure to inorganic mercury and indicator of body burden. A 24-hour urine for measurement of mercury excretion is preferred; a spot urine mercury concentration should be corrected for creatinine output. Chelation therapy is indicated in patients with features of mercury poisoning and elevated blood and/or urine mercury concentrations. Unithiol (2,3-dimercapto-1-propanesulfonic acid, DMPS) is the preferred antidote though succimer (dimercaptosuccinic acid, DMSA) has also been employed. The use of mercury in cosmetic products should be strictly prohibited. The public should be warned not to use such products as their use can result in systemic absorption and accumulation of mercury causing renal, gastrointestinal and CNS toxicity.

Intestinal Calcium Absorption among Hypercalciuric Patients with or without Calcium Kidney Stones.

PubMed

Vezzoli, Giuseppe; Macrina, Lorenza; Rubinacci, Alessandro; Spotti, Donatella; Arcidiacono, Teresa

2016-08-08

Idiopathic hypercalciuria is a frequent defect in calcium kidney stone formers that is associated with high intestinal calcium absorption and osteopenia. Characteristics distinguishing hypercalciuric stone formers from hypercalciuric patients without kidney stone history (HNSFs) are unknown and were explored in our study. We compared 172 hypercalciuric stone formers with 36 HNSFs retrospectively selected from patients referred to outpatient clinics of the San Raffaele Hospital in Milan from 1998 to 2003. Calcium metabolism and lumbar bone mineral density were analyzed in these patients. A strontium oral load test was performed: strontium was measured in 240-minute urine and serum 30, 60, and 240 minutes after strontium ingestion; serum strontium concentration-time curve and renal strontium clearance were evaluated to estimate absorption and excretion of divalent cations. Serum strontium concentration-time curve (P<0.001) and strontium clearance (4.9±1.3 versus 3.5±2.7 ml/min; P<0.001) were higher in hypercalciuric stone formers than HNSFs, respectively. The serum strontium-time curve was also higher in hypercalciuric stone formers with low bone mineral density (n=42) than in hypercalciuric stone formers with normal bone mineral density (n=130; P=0.03) and HNSFs with low (n=22; P=0.01) or normal bone mineral density (n=14; P=0.02). Strontium clearance was greater in hypercalciuric stone formers with normal bone mineral density (5.3±3.4 ml/min) than in hypercalciuric stone formers and HNSFs with low bone mineral density (3.6±2.5 and 3.1±2.5 ml/min, respectively; P=0.03). Multivariate regression analyses displayed that strontium absorption at 30 minutes was positively associated calcium excretion (P=0.03) and negatively associated with lumbar bone mineral density z score (P=0.001) in hypercalciuric stone formers; furthermore, hypercalciuric patients in the highest quartile of strontium absorption had increased stone production risk (odds ratio, 5.06; 95% confidence interval, 1.2 to 20.9; P=0.03). High calcium absorption in duodenum and jejunum may expose hypercalciuric patients to the risk of stones because of increased postprandial calcium concentrations in urine and tubular fluid. High calcium absorption may identify patients at risk of bone loss among stone formers. Copyright © 2016 by the American Society of Nephrology.

Copper-65-absorption by men fed intrinsically and extrinsically labeled whole wheat bread

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, P.E.; Lykken, G.I.

Six men were fed a diet composed of conventional foods with all bread as whole wheat bread. Intrinsically labeled /sup 65/Cu bread (containing 6.5 ppm Cu and 48 atom % /sup 65/Cu) was substituted for unlabeled bread for 3 days, and stools were collected for 24 days. Extrinsically labeled bread was then substituted for 3 days and another 24-day stool collection made. /sup 65/Cu excretion was measured by mass spectrometry. Mean Cu intake was 1.10 mg of Cu/day. Average Cu balance was /minus/0.06 /+-/ 0.08 mg/day. Average absorption of the intrinsic copper was 72.2 /+-/ 9.3% and of extrinsic Cumore » 64.2 /+-/ 5.8%. The ratio of extrinsic to intrinsic absorption was 0.906 /+-/ 0.164. Absorption of intrinsic and extrinsic tracers did not differ significantly (p > 0.05) by a paired t-test, and the ratio (E/I) was not significantly different from 1. Use of extrinsic Cu tracers to assess Cu absorption is supported by these results.« less

In silico discovery and in vitro activity of inhibitors against Mycobacterium tuberculosis 7,8-diaminopelargonic acid synthase (Mtb BioA).

PubMed

Billones, Junie B; Carrillo, Maria Constancia O; Organo, Voltaire G; Sy, Jamie Bernadette A; Clavio, Nina Abigail B; Macalino, Stephani Joy Y; Emnacen, Inno A; Lee, Alexandra P; Ko, Paul Kenny L; Concepcion, Gisela P

2017-01-01

Computer-aided drug discovery and development approaches such as virtual screening, molecular docking, and in silico drug property calculations have been utilized in this effort to discover new lead compounds against tuberculosis. The enzyme 7,8-diaminopelargonic acid aminotransferase (BioA) in Mycobacterium tuberculosis ( Mtb ), primarily involved in the lipid biosynthesis pathway, was chosen as the drug target due to the fact that humans are not capable of synthesizing biotin endogenously. The computational screening of 4.5 million compounds from the Enamine REAL database has ultimately yielded 45 high-scoring, high-affinity compounds with desirable in silico absorption, distribution, metabolism, excretion, and toxicity properties. Seventeen of the 45 compounds were subjected to bioactivity validation using the resazurin microtiter assay. Among the 4 actives, compound 7 (( Z )- N -(2-isopropoxyphenyl)-2-oxo-2-((3-(trifluoromethyl)cyclohexyl)amino)acetimidic acid) displayed inhibitory activity up to 83% at 10 μg/mL concentration against the growth of the Mtb H37Ra strain.

In silico discovery and in vitro activity of inhibitors against Mycobacterium tuberculosis 7,8-diaminopelargonic acid synthase (Mtb BioA)

PubMed Central

Billones, Junie B; Carrillo, Maria Constancia O; Organo, Voltaire G; Sy, Jamie Bernadette A; Clavio, Nina Abigail B; Macalino, Stephani Joy Y; Emnacen, Inno A; Lee, Alexandra P; Ko, Paul Kenny L; Concepcion, Gisela P

2017-01-01

Computer-aided drug discovery and development approaches such as virtual screening, molecular docking, and in silico drug property calculations have been utilized in this effort to discover new lead compounds against tuberculosis. The enzyme 7,8-diaminopelargonic acid aminotransferase (BioA) in Mycobacterium tuberculosis (Mtb), primarily involved in the lipid biosynthesis pathway, was chosen as the drug target due to the fact that humans are not capable of synthesizing biotin endogenously. The computational screening of 4.5 million compounds from the Enamine REAL database has ultimately yielded 45 high-scoring, high-affinity compounds with desirable in silico absorption, distribution, metabolism, excretion, and toxicity properties. Seventeen of the 45 compounds were subjected to bioactivity validation using the resazurin microtiter assay. Among the 4 actives, compound 7 ((Z)-N-(2-isopropoxyphenyl)-2-oxo-2-((3-(trifluoromethyl)cyclohexyl)amino)acetimidic acid) displayed inhibitory activity up to 83% at 10 μg/mL concentration against the growth of the Mtb H37Ra strain. PMID:28280303

Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds.

PubMed

Loh, Yong Yao; Nagao, Kazunori; Hoover, Andrew J; Hesk, David; Rivera, Nelo R; Colletti, Steven L; Davies, Ian W; MacMillan, David W C

2017-12-01

Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp 3 carbon-hydrogen bonds in a single step, using isotopically labeled water (D 2 O or T 2 O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T 2 O from T 2 , providing access to high-specific-activity T 2 O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Analytical Techniques and Pharmacokinetics of Gastrodia elata Blume and Its Constituents.

PubMed

Wu, Jinyi; Wu, Bingchu; Tang, Chunlan; Zhao, Jinshun

2017-07-08

Gastrodia elata Blume ( G. elata ), commonly called Tianma in Chinese, is an important and notable traditional Chinese medicine (TCM), which has been used in China as an anticonvulsant, analgesic, sedative, anti-asthma, anti-immune drug since ancient times. The aim of this review is to provide an overview of the abundant efforts of scientists in developing analytical techniques and performing pharmacokinetic studies of G. elata and its constituents, including sample pretreatment methods, analytical techniques, absorption, distribution, metabolism, excretion (ADME) and influence factors to its pharmacokinetics. Based on the reported pharmacokinetic property data of G. elata and its constituents, it is hoped that more studies will focus on the development of rapid and sensitive analytical techniques, discovering new therapeutic uses and understanding the specific in vivo mechanisms of action of G. elata and its constituents from the pharmacokinetic viewpoint in the near future. The present review discusses analytical techniques and pharmacokinetics of G. elata and its constituents reported from 1985 onwards.

It takes a team: reflections on insecticide discoveries, toxicological problems and enjoying the unexpected.

PubMed

Wing, Keith D

2017-04-01

Absorption/distribution/metabolism/excretion (ADME)-related studies are mandatory in agrochemical development/registration, but can also play a valuable role in the discovery process. In combination with target-site potency, bioavailability/ADME characteristics determine agrochemical bioactivity and selectivity, and these concerns can dictate the fate of a discovery lead area. Bioavailability/ADME research was critical to the eventual commercialization of three different insecticide chemistries examined in this paper. In one situation, improved systemicity in anthranilic diamides was required to expand pest spectrum. In another, ADME tools were needed to improve the selective toxicity and non-target safety of sodium channel blocker insecticides. Finally, differential ADME characteristics of two classes of hormone agonists dictated differential insecticidal activity, and were useful in optimizing the dibenzoylhydrazine ecdysone agonists. ADME discovery research will help companies to advance novel, efficacious and selective agrochemicals, but organizational patience and a desire to understand lead areas in depth are required. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

COMPUTER-AIDED DRUG DISCOVERY AND DEVELOPMENT (CADDD): in silico-chemico-biological approach

PubMed Central

Kapetanovic, I.M.

2008-01-01

It is generally recognized that drug discovery and development are very time and resources consuming processes. There is an ever growing effort to apply computational power to the combined chemical and biological space in order to streamline drug discovery, design, development and optimization. In biomedical arena, computer-aided or in silico design is being utilized to expedite and facilitate hit identification, hit-to-lead selection, optimize the absorption, distribution, metabolism, excretion and toxicity profile and avoid safety issues. Commonly used computational approaches include ligand-based drug design (pharmacophore, a 3-D spatial arrangement of chemical features essential for biological activity), structure-based drug design (drug-target docking), and quantitative structure-activity and quantitative structure-property relationships. Regulatory agencies as well as pharmaceutical industry are actively involved in development of computational tools that will improve effectiveness and efficiency of drug discovery and development process, decrease use of animals, and increase predictability. It is expected that the power of CADDD will grow as the technology continues to evolve. PMID:17229415

In Silico Approaches for Predicting Adme Properties

NASA Astrophysics Data System (ADS)

Madden, Judith C.

A drug requires a suitable pharmacokinetic profile to be efficacious in vivo in humans. The relevant pharmacokinetic properties include the absorption, distribution, metabolism, and excretion (ADME) profile of the drug. This chapter provides an overview of the definition and meaning of key ADME properties, recent models developed to predict these properties, and a guide as to how to select the most appropriate model(s) for a given query. Many tools using the state-of-the-art in silico methodology are now available to users, and it is anticipated that the continual evolution of these tools will provide greater ability to predict ADME properties in the future. However, caution must be exercised in applying these tools as data are generally available only for "successful" drugs, i.e., those that reach the marketplace, and little supplementary information, such as that for drugs that have a poor pharmacokinetic profile, is available. The possibilities of using these methods and possible integration into toxicity prediction are explored.

Sex differences in the pharmacokinetics of antidepressants: influence of female sex hormones and oral contraceptives.

PubMed

Damoiseaux, Valérie A; Proost, Johannes H; Jiawan, Vincent C R; Melgert, Barbro N

2014-06-01

Women are twice as likely to develop depression as men. Moreover, the symptoms they experience also show sex differences: women tend to develop depression at an earlier age and show more severe symptoms than men. Likewise, the response to antidepressant pharmacotherapy appears to have sex differences. These differences can partially be explained by differences in pharmacokinetic properties (i.e., absorption, distribution, metabolism, and excretion) of drugs in males and females. More recent research has shown that sex hormones may influence all these previously named pharmacokinetic processes. As concentrations of sex hormones vary throughout the female lifespan, these hormonal variations can have effects on therapeutic responses to antidepressants as well as the occurrence of adverse events. The purpose of this paper is therefore to review the literature reporting on the effects of female sex hormones on the pharmacokinetics of antidepressants and to discuss and evaluate the implications of changes in levels of sex hormones throughout life for the treatment of depression.

Metabolism of adiphenine. I. Absorption, distribution and excretion in rats and mice.

PubMed

Michelot, J; Madelmont, J C; Jordan, D; Mornex, R; Meyniel, G

1981-02-01

1. The disposition of adiphenine labelled with 14C in two positions has been investigated in rats and mice after i.v. administration, and has been compared with that of the [14C]diethylethanolamine HCl and of the [14C]diphenylacetic acid. 2. Radioactivity in the blood declined in a biphasic manner. Biliary elimination depended upon the 14C-labelled compound administered: less than 5% dose for the diethylethanolamine moiety, 100% dose for the carboxylic moiety. Of the radioactivity appearing in rat bile, less than 1% is associated with unchanged adiphenine. 3. In preliminary metabolic studies, three major metabolites have been identified: diphenylacetic acid, diethylethanolamine and a diphenylacetic acid glucuronide. 4. Uptake by the brain of [14C]adiphenine shortly after dosing is 15 times greater than that of blood. Radioactivity is also found in the hypophysis, the adrenals and melanoid pigments, with a concn. up to 30 times greater than that found in the blood.

Modeling and Experimental Studies of Obeticholic Acid Exposure and the Impact of Cirrhosis Stage

PubMed Central

LaCerte, C; Peyret, T; Gosselin, NH; Marier, JF; Hofmann, AF; Shapiro, D

2016-01-01

Obeticholic acid (OCA), a semisynthetic bile acid, is a selective and potent farnesoid X receptor (FXR) agonist in development for the treatment of chronic nonviral liver diseases. Physiologic pharmacokinetic models have been previously used to describe the absorption, distribution, metabolism, and excretion (ADME) of bile acids. OCA plasma levels were measured in healthy volunteers and cirrhotic subjects. A physiologic pharmacokinetic model was developed to quantitatively describe the ADME of OCA in patients with and without hepatic impairment. There was good agreement between predicted and observed increases in systemic OCA exposure in subjects with mild, moderate, and severe hepatic impairment, which were 1.4‐, 8‐, and 13‐fold relative to healthy volunteers. Predicted liver exposure for subjects with mild, moderate, and severe hepatic impairment were increased only 1.1‐, 1.5‐, and 1.7‐fold. In subjects with cirrhosis, OCA exposure in the liver, the primary site of pharmacological activity along with the intestine, is increased marginally (∼2‐fold). PMID:27743502

The combined effects of oxygen availability and salinity on physiological responses and scope for growth in the green-lipped mussel Perna viridis.

PubMed

Wang, Youji; Hu, Menghong; Wong, Wai Hing; Shin, Paul K S; Cheung, Siu Gin

2011-01-01

Mussels were maintained for 4 weeks under different combinations of dissolved oxygen concentration (1.5, 3.0 and 6.0 mg O2 l(-1)) and salinity (15, 20, 25 and 30) in a 3×4 factorial design experiment. Clearance rate (CR), absorption efficiency (AE), respiration rate (RR) and scope for growth (SFG) decreased with decreasing salinity and dissolved oxygen concentration (DO), while excretion rate (ER) increased with decreasing salinity and increasing DO. The O:N ratio was <10 at salinities of 15 and 20, irrespective of DO levels. SFG was negative in most of the treatments, except for those under 6.0 mg O2 l(-1) or at a salinity of 30 when DO was lower. The results may help explain the distribution pattern of Perna viridis in Hong Kong waters and provide guidelines for mussel culture site selection. Copyright © 2011 Elsevier Ltd. All rights reserved.

Pharmacokinetics and pharmacodynamics of sofosbuvir and ledipasvir for the treatment of hepatitis C.

PubMed

Cuenca-Lopez, Francisca; Rivero, Antonio; Rivero-Juárez, Antonio

2017-01-01

The sofosbuvir (SOF) plus ledipasvir (LDV) fixed dose combination is the first direct action antiviral (DAA) single-treatment regimen (STR) to be commercialized. It is approved for the treatment of Hepatitis C virus (HCV) genotypes 1,3,4,5 and 6. Following approval in 2014, new pharmacokinetics and pharmacodynamics data were reported, which led to important clinical applications. Areas covered: This article reviews the pharmacokinetic and pharmacodynamic properties of the SOF/LDV fixed dose combination for the treatment of HCV. The topics covered include data regarding the drug´s absorption, distribution, metabolism and excretion and antiviral activity strategies such as the clinical dose selection and treatment duration. Expert opinion: The SOF/LDV fixed dose combination has good pharmacological properties that lead to a high sustained virological response after 12 or 24 weeks of treatment; there is minimal interference with other drugs or associated renal or hepatic impairment, such that dose adjustment is not necessary.

Pharmacokinetic properties and in silico ADME modeling in drug discovery.

PubMed

Honório, Kathia M; Moda, Tiago L; Andricopulo, Adriano D

2013-03-01

The discovery and development of a new drug are time-consuming, difficult and expensive. This complex process has evolved from classical methods into an integration of modern technologies and innovative strategies addressed to the design of new chemical entities to treat a variety of diseases. The development of new drug candidates is often limited by initial compounds lacking reasonable chemical and biological properties for further lead optimization. Huge libraries of compounds are frequently selected for biological screening using a variety of techniques and standard models to assess potency, affinity and selectivity. In this context, it is very important to study the pharmacokinetic profile of the compounds under investigation. Recent advances have been made in the collection of data and the development of models to assess and predict pharmacokinetic properties (ADME--absorption, distribution, metabolism and excretion) of bioactive compounds in the early stages of drug discovery projects. This paper provides a brief perspective on the evolution of in silico ADME tools, addressing challenges, limitations, and opportunities in medicinal chemistry.

New Thiazolyl-triazole Schiff Bases: Synthesis and Evaluation of the Anti-Candida Potential.

PubMed

Stana, Anca; Enache, Alexandra; Vodnar, Dan Cristian; Nastasă, Cristina; Benedec, Daniela; Ionuț, Ioana; Login, Cezar; Marc, Gabriel; Oniga, Ovidiu; Tiperciuc, Brîndușa

2016-11-22

In the context of the dangerous phenomenon of fungal resistance to the available therapies, we present here the chemical synthesis of a new series of thiazolyl-triazole Schiff bases B1 - B15 , which were in vitro assessed for their anti- Candida potential. Compound B10 was found to be more potent against Candida spp. when compared with the reference drugs Fluconazole and Ketoconazole. A docking study of the newly synthesized Schiff bases was performed, and results showed good binding affinity in the active site of co-crystallized Itraconazole-lanosterol 14α-demethylase isolated from Saccharomyces cerevisiae . An in silico ADMET (absorption, distribution, metabolism, excretion, toxicity) study was done in order to predict some pharmacokinetic and pharmacotoxicological properties. The Schiff bases showed good drug-like properties. The results of in vitro anti- Candida activity, a docking study and ADMET prediction revealed that the newly synthesized compounds have potential anti- Candida activity and evidenced the most active derivative, B10 , which can be further optimized as a lead compound.

Fatty Acids as Therapeutic Auxiliaries for Oral and Parenteral Formulations

PubMed Central

Hackett, Michael J.; Zaro, Jennica L.; Shen, Wei-Chiang; Guley, Patrick C.; Cho, Moo J.

2012-01-01

Many drugs have decreased therapeutic activity due to issues with absorption, distribution, metabolism and excretion. The co-formulation or covalent attachment of drugs with fatty acids has demonstrated some capacity to overcome these issues by improving intestinal permeability, slowing clearance and binding serum proteins for selective tissue uptake and metabolism. For orally administered drugs, albeit at low level of availability, the presence of fatty acids and triglycerides in the intestinal lumen may promote intestinal uptake of small hydrophilic molecules. Small lipophilic drugs or acylated hydrophilic drugs also show increased lymphatic uptake and enhanced passive diffusional uptake. Fatty acid conjugation of small and large proteins or peptides have exhibited protracted plasma half-lives, site-specific delivery and sustained release upon parenteral administration. These improvements are most likely due to associations with lipid-binding serum proteins, namely albumin, LDL and HDL. These molecular interactions, although not fully characterized, could provide the ability of using the endogenous carrier systems for improving therapeutic outcomes. PMID:22921839

Methods in Clinical Pharmacology Series

PubMed Central

Beaumont, Claire; Young, Graeme C; Cavalier, Tom; Young, Malcolm A

2014-01-01

Human radiolabel studies are traditionally conducted to provide a definitive understanding of the human absorption, distribution, metabolism and excretion (ADME) properties of a drug. However, advances in technology over the past decade have allowed alternative methods to be employed to obtain both clinical ADME and pharmacokinetic (PK) information. These include microdose and microtracer approaches using accelerator mass spectrometry, and the identification and quantification of metabolites in samples from classical human PK studies using technologies suitable for non-radiolabelled drug molecules, namely liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. These recently developed approaches are described here together with relevant examples primarily from experiences gained in support of drug development projects at GlaxoSmithKline. The advantages of these study designs together with their limitations are described. We also discuss special considerations which should be made for a successful outcome to these new approaches and also to the more traditional human radiolabel study in order to maximize knowledge around the human ADME properties of drug molecules. PMID:25041729

Pharmacometrics in pregnancy: An unmet need.

PubMed

Ke, Alice Ban; Rostami-Hodjegan, Amin; Zhao, Ping; Unadkat, Jashvant D

2014-01-01

Pregnant women and their fetuses are orphan populations with respect to the safety and efficacy of drugs. Physiological and absorption, distribution, metabolism, and excretion (ADME) changes during pregnancy can significantly affect drug pharmacokinetics (PK) and may necessitate dose adjustment. Here, the specific aspects related to the design, execution, and analysis of clinical studies in pregnant women are discussed, underlining the unmet need for top-down pharmacometrics analyses and bottom-up modeling approaches. The modeling tools that support data analysis for the pregnancy population are reviewed, with a focus on physiologically based pharmacokinetics (PBPK) and population pharmacokinetics (POP-PK). By integrating physiological data, preclinical data, and clinical data (e.g., via POP-PK) to quantify anticipated changes in the PK of drugs during pregnancy, the PBPK approach allows extrapolation beyond the previously studied model drugs to other drugs with well-characterized ADME characteristics. Such a systems pharmacology approach can identify drugs whose PK may be altered during pregnancy, guide rational PK study design, and support dose adjustment for pregnant women.

Altered Transport and Metabolism of Phenolic Compounds in Obesity and Diabetes: Implications for Functional Food Development and Assessment.

PubMed

Redan, Benjamin W; Buhman, Kimberly K; Novotny, Janet A; Ferruzzi, Mario G

2016-11-01

Interest in the application of phenolic compounds from the diet or supplements for the prevention of chronic diseases has grown substantially, but the efficacy of such approaches in humans is largely dependent on the bioavailability and metabolism of these compounds. Although food and dietary factors have been the focus of intense investigation, the impact of disease states such as obesity or diabetes on their absorption, metabolism, and eventual efficacy is important to consider. These factors must be understood in order to develop effective strategies that leverage bioactive phenolic compounds for the prevention of chronic disease. The goal of this review is to discuss the inducible metabolic systems that may be influenced by disease states and how these effects impact the bioavailability and metabolism of dietary phenolic compounds. Because current studies generally report that obesity and/or diabetes alter the absorption and excretion of these compounds, this review includes a description of the absorption, conjugation, and excretion pathways for phenolic compounds and how they are potentially altered in disease states. A possible mechanism that will be discussed related to the modulation of phenolic bioavailability and metabolism may be linked to increased inflammatory status from increased amounts of adipose tissue or elevated plasma glucose concentrations. Although more studies are needed, the translation of benefits derived from dietary phenolic compounds to individuals with obesity or diabetes may require the consideration of dosing strategies or be accompanied by adjunct therapies to improve the bioavailability of these compounds. © 2016 American Society for Nutrition.

Altered Transport and Metabolism of Phenolic Compounds in Obesity and Diabetes: Implications for Functional Food Development and Assessment12

PubMed Central

Redan, Benjamin W; Buhman, Kimberly K; Novotny, Janet A; Ferruzzi, Mario G

2016-01-01

Interest in the application of phenolic compounds from the diet or supplements for the prevention of chronic diseases has grown substantially, but the efficacy of such approaches in humans is largely dependent on the bioavailability and metabolism of these compounds. Although food and dietary factors have been the focus of intense investigation, the impact of disease states such as obesity or diabetes on their absorption, metabolism, and eventual efficacy is important to consider. These factors must be understood in order to develop effective strategies that leverage bioactive phenolic compounds for the prevention of chronic disease. The goal of this review is to discuss the inducible metabolic systems that may be influenced by disease states and how these effects impact the bioavailability and metabolism of dietary phenolic compounds. Because current studies generally report that obesity and/or diabetes alter the absorption and excretion of these compounds, this review includes a description of the absorption, conjugation, and excretion pathways for phenolic compounds and how they are potentially altered in disease states. A possible mechanism that will be discussed related to the modulation of phenolic bioavailability and metabolism may be linked to increased inflammatory status from increased amounts of adipose tissue or elevated plasma glucose concentrations. Although more studies are needed, the translation of benefits derived from dietary phenolic compounds to individuals with obesity or diabetes may require the consideration of dosing strategies or be accompanied by adjunct therapies to improve the bioavailability of these compounds. PMID:28140326

Association of mRNA expression of iron metabolism-associated genes and progression of non-alcoholic steatohepatitis in rats.

PubMed

Higuchi, Teruhisa; Moriyama, Mitsuhiko; Fukushima, Akiko; Matsumura, Hiroshi; Matsuoka, Shunichi; Kanda, Tatsuo; Sugitani, Masahiko; Tsunemi, Akiko; Ueno, Takahiro; Fukuda, Noboru

2018-05-25

Excess iron is associated with non-alcoholic steatohepatitis (NASH). mRNA expression of duodenal cytochrome b, divalent metal transporter 1, ferroportin 1, hepcidin, hephaestin and transferrin receptor 1 in liver were higher in high fat, high cholesterol-containing diet (HFCD) group than in normal diet (ND) group. mRNA levels of divalent metal transporter 1 and transferrin receptor 1, which stimulate iron absorption and excretion, were enhanced in small intestine. Epithelial mucosa of small intestine in HFCD group was characterized by plasma cell and eosinophil infiltration and increased vacuoles. Iron absorption was enhanced in this NASH model in the context of chronic inflammation of small intestinal epithelial cells, consequences of intestinal epithelial cell impairment caused by HFCD. Iron is transported to hepatocytes via portal blood, and abnormalities in iron absorption and excretion occur in small intestine from changes in iron transporter expression, which also occurs in NASH liver. Knockdown of hepcidin antimicrobial peptide led to enhanced heavy chain of ferritin expression in human hepatocytes, indicating association between hepcidin production and iron storage in hepatocytes. Iron-related transporters in liver and lower/upper portions of small intestine play critical roles in NASH development. Expression of iron metabolism-related genes in liver and small intestine was analyzed in stroke-prone spontaneously hypertensive rats (SHR-SP), which develop NASH. Five-week-old SHR-SP fed ND or HFCD were examined. mRNA and protein levels of iron metabolism-related genes in liver and small intestine from 12- and 19-week-old rats were evaluated by real-time RT-PCR and immunohistochemistry or Western blot.

Effect and mechanism of dioscin from Dioscorea spongiosa on uric acid excretion in animal model of hyperuricemia.

PubMed

Zhang, Yi; Jin, Lijun; Liu, Jinchang; Wang, Wei; Yu, Haiyang; Li, Jian; Chen, Qian; Wang, Tao

2018-03-25

Dioscin, a spirostane glycoside, the rhizoma of Dioscorea septemloba (Diocoreacea) is used for diuresis, rheumatism, and joints pain. Given the poor solubility and stability of Dioscin, we proposed a hypothesis that Dioscin's metabolite(s) are the active substance(s) in vivo to contribute to the reducing effects on serum uric acid levels. The aim of this study is to identify the active metabolite(s) of Dioscin in vivo and to explore the mechanism of its antihyperuricemic activity. After oral administration of Dioscin in potassium oxonate (PO) induced hyperuricemia rats and adenine-PO induced hyperuricemia mice models, serum uric acid and creatinine levels, clearance of uric acid and creatinine, fractional excretion of uric acid, and renal pathological lesions were determined were used to evaluate the antihyperuricemic effects. Renal glucose transporter-9 (GLUT-9) and organic anion transporter-1 (OAT-1) expressions were analyzed by western blotting method. Renal uric acid excretion was evaluated using stably urate transporter-1 (URAT-1) transfected human epithelial kidney cell line. Intestinal uric acid excretion was evaluated by measuring the transcellular transport of uric acid in HCT116 cells. In hyperuricemia rats, both 25 and 50mg/kg of oral Dioscin decreased serum uric acid levels over 4h. In the hyperuricemia mice, two weeks treatment of Dioscin significantly decreased serum uric acid and creatinine levels, increased clearance of uric acid and creatinine, increased fractional excretion of uric acid, and reduced renal pathological lesions caused by hyperuricemia. In addition, renal GLUT -9 was significantly down-regulated and OAT-1 was up-regulated in Dioscin treated hyperuricemia mice. Dioscin's metabolite Tigogenin significantly inhibited uric acid re-absorption via URAT1 from 10 to 100μM. Diosgenin and Tigogenin increased uric acid excretion via ATP binding cassette subfamily G member 2 (ABCG2). Decreasing effect of Dioscin on serum uric acid level and enhancing effect on urate excretion were confirmed in hyperuricemia animal models. Tigogenin, a metabolite of Dioscin, was identified as an active substance with antihyperuricemic activity in vivo, through inhibition of URAT1 and promotion of ABCG2. Copyright © 2017 Elsevier B.V. All rights reserved.

Comparative effects of hawthorn (Crataegus pinnatifida Bunge) pectin and pectin hydrolyzates on the cholesterol homeostasis of hamsters fed high-cholesterol diets.

PubMed

Zhu, Ru-Gang; Sun, Yan-Di; Li, Tuo-Ping; Chen, Gang; Peng, Xue; Duan, Wen-Bin; Zheng, Zheng-Zheng; Shi, Shu-Lei; Xu, Jing-Guo; Liu, Yan-Hua; Jin, Xiao-Yi

2015-08-05

This study aims to compare the effects of feeding haw pectin (HP), haw pectin hydrolyzates (HPH), and haw pectin pentasaccharide (HPPS) on the cholesterol metabolism of hypercholesterolemic hamsters induced by high-cholesterol diets. The animals were fed a standard diet (SD), high-cholesterol diet (HCD), or HCD plus HP, HPH, or HPPS at a dose of 300mg/kg body weight for 4weeks. Results showed that HPPS was more effective than HP and HPH in decreasing the body weight gain (by 38.2%), liver weight (by 16.4%), and plasma and hepatic total cholesterol (TC; by 23.6% and 27.3%, respectively) of hamsters. In addition, the bile acid levels in the feces were significantly higher by 39.8% and 132.8% in the HPH and HPPS groups than in the HCD group. Such changes were not noted in the HP group. However, the HP group had higher cholesterol excretion capacities than the HPH and HPPS groups by inhibiting cholesterol absorption in the diet, with a 21.7% increase in TC excretion and a 31.1% decrease in TC absorption. Thus, HPPS could be a promising anti-atherogenic dietary ingredient for the development of functional food to improve cholesterol metabolism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Phytosterol glycosides reduce cholesterol absorption in humans

PubMed Central

Lin, Xiaobo; Ma, Lina; Racette, Susan B.; Anderson Spearie, Catherine L.; Ostlund, Richard E.

2009-01-01

Dietary phytosterols inhibit intestinal cholesterol absorption and regulate whole body cholesterol excretion and balance. However, they are biochemically heterogeneous and a portion is glycosylated in some foods with unknown effects on biological activity. We tested the hypothesis that phytosterol glycosides reduce cholesterol absorption in humans. Phytosterol glycosides were extracted and purified from soy lecithin in a novel two-step process. Cholesterol absorption was measured in a series of three single-meal tests given at intervals of 2 wk to each of 11 healthy subjects. In a randomized crossover design, participants received ∼300 mg of added phytosterols in the form of phytosterol glycosides or phytosterol esters, or placebo in a test breakfast also containing 30 mg cholesterol-d7. Cholesterol absorption was estimated by mass spectrometry of plasma cholesterol-d7 enrichment 4–5 days after each test. Compared with the placebo test, phytosterol glycosides reduced cholesterol absorption by 37.6 ± 4.8% (P < 0.0001) and phytosterol esters 30.6 ± 3.9% (P = 0.0001). These results suggest that natural phytosterol glycosides purified from lecithin are bioactive in humans and should be included in methods of phytosterol analysis and tables of food phytosterol content. PMID:19246636

Percutaneous absorption of topically applied DTIC-14C (NSC-45388) in Yorkshire white pigs. Final report, 14 September-14 November 1976

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skierkowski, P.; Murphy, J.C.; Watson, E.S.

1978-03-01

The absorption of topically applied DTIC (5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide-2-14C) (NSC-45388) was studied in female, weanling, Yorkshire white pigs. After 48 hours, an average of 9.61% of the topically applied dose was excreted in the urine of the test animals. Liver and kidney showed the most consistent uptake of radioactivity with heart and adrenal samples also showing significant uptake. Radioactivity was detected in random muscle samples at 6 hours after application, and in bone after 48 hours. A significant percentage of the applied dose was generally detected at and near the site of application.

Drug-nutrient interactions.

PubMed

Trovato, A; Nuhlicek, D N; Midtling, J E

1991-11-01

Drug-nutrient interactions are a commonly overlooked aspect of the prescribing practices of physicians. As more pharmaceutical agents become available, attention should be focused on interactions of drugs with foods and nutrients. Although drug-nutrient interactions are not as common as drug-drug interactions, they can have an impact on therapeutic outcome. Drugs can affect nutritional status by altering nutrient absorption, metabolism, utilization or excretion. Food, beverages and mineral or vitamin supplements can affect the absorption and effectiveness of drugs. Knowledge of drug-nutrient interactions can help reduce the incidence of these effects. Physicians should question patients about their dietary habits so that patients can be informed about possible interactions between a prescribed drug and foods and nutrients.

Studies on absorption and elimination of dietary maillard reaction products.

PubMed

Förster, Anke; Kühne, Yvonne; Henle, Thomas

2005-06-01

A nine-day dietary study involving 18 healthy volunteers was performed in order to investigate the influence of nutrition on the urinary excretion of the Maillard reaction products (MRPs) fructoselysine, pyrraline, and pentosidine. From day two through day eight, most types of Maillard product-containing food had to be avoided. On day five, participants were divided into four groups, three of them receiving a test meal (pretzel sticks, brewed coffee, or custard) containing defined amounts of MRPs. The fourth group served as a control. Urine samples taken over a 24-h period were analyzed for MRPs using chromatographic means. As a result of the MRP-free diet, urinary excretion of free pyrraline and fructoselysine, which was calculated from furosine analysis, were lowered about 90%. Excretion of pentosidine decreased about 40%. Consumption of pretzel sticks and coffee on day five resulted in increased amounts of pyrraline and pentosidine in urine samples on days five to seven. Related to the supplied amounts of pyrraline, about 50% were recovered in the urine samples after ingestion of the pretzel sticks. For pentosidine, 60% of the ingested free derivative from coffee brew and 2% of the peptide-bound amino acid ingested with the bakery product were recovered in the urine samples, indicating a better bioavailability for free pentosidine compared to the protein-bound form. For peptide-bound Amadori products, no influence on the excretion was observed after ingestion of the test foods, indicating degradation in the intestine or plasma to yet-unknown metabolites. In conclusion, differences concerning the excretion rate of individual MRPs point to individual resorption and metabolic pathways. These results are of importance for the discussion of a possible (patho)physiological role of dietary advanced glycation end products (AGEs).

Consumption of retrograded (RS3) but not uncooked (RS2) resistant starch shifts nitrogen excretion from urine to feces in cannulated piglets.

PubMed

Heijnen, M L; Beynen, A C

1997-09-01

To study the effect of resistant starch (RS) on the route of nitrogen excretion, we fed three groups of six cannulated piglets each a diet containing either uncooked resistant starch (RS2 ), retrograded resistant starch (RS3 ) or glucose. The use of piglets with a cannula at the end of the ileum allowed measurement of the amount of nitrogen that entered the colon. Ileal digesta, urine and feces were collected quantitatively and weighed, and dry matter, starch and nitrogen content were determined. We hypothesized that RS2 would lower colonic absorption of nitrogen when compared with RS3 , because RS2 may be more fermentable than RS3 , thus trapping more nitrogen in bacteria. The piglets fed RS3 had a significantly higher production of ileal digesta and feces than the piglets fed glucose or RS2 . In the piglets fed RS2 , 44% of the amount of RS fed was recovered in the ileal digesta; in the piglets fed RS3 , 71% was recovered. Thus, more fermentable material entered the colon in the RS3 -fed piglets than in the RS2 -fed piglets. Virtually no starch was recovered in the feces of any dietary group. Replacement of glucose by either RS2 or RS3 did not affect nitrogen retention but increased fecal nitrogen excretion. Compared with glucose, RS3 but not RS2 reduced urinary nitrogen excretion, mainly in the form of urea, and reduced the amount of nitrogen absorbed by the colon when expressed as a percentage of the amount of nitrogen entering the colon. This study provides evidence that RS3 , but not RS2 , shifts nitrogen excretion from urine to feces in cannulated piglets.

Hepatoselective Nitric Oxide (NO) Donors, V-PYRRO/NO and V-PROLI/NO, in Nonalcoholic Fatty Liver Disease: A Comparison of Antisteatotic Effects with the Biotransformation and Pharmacokinetics.

PubMed

Kus, Kamil; Walczak, Maria; Maslak, Edyta; Zakrzewska, Agnieszka; Gonciarz-Dytman, Anna; Zabielski, Piotr; Sitek, Barbara; Wandzel, Krystyna; Kij, Agnieszka; Chabowski, Adrian; Holland, Ryan J; Saavedra, Joseph E; Keefer, Larry K; Chlopicki, Stefan

2015-07-01

V-PYRRO/NO [O(2)-vinyl-1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate] and V-PROLI/NO (O2-vinyl-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate), two structurally similar diazeniumdiolate derivatives, were designed as liver-selective prodrugs that are metabolized by cytochrome P450 isoenzymes, with subsequent release of nitric oxide (NO). Yet, their efficacy in the treatment of nonalcoholic fatty liver disease (NAFLD) and their comparative pharmacokinetic and metabolic profiles have not been characterized. The aim of the present work was to compare the effects of V-PYRRO/NO and V-PROLI/NO on liver steatosis, glucose tolerance, and liver fatty acid composition in C57BL/6J mice fed a high-fat diet, as well as to comprehensively characterize the ADME (absorption, distribution, metabolism and excretion) profiles of both NO donors. Despite their similar structure, V-PYRRO/NO and V-PROLI/NO showed differences in pharmacological efficacy in the murine model of NAFLD. V-PYRRO/NO, but not V-PROLI/NO, attenuated liver steatosis, improved glucose tolerance, and favorably modified fatty acid composition in the liver. Both compounds were characterized by rapid absorption following i.p. administration, rapid elimination from the body, and incomplete bioavailability. However, V-PYRRO/NO was eliminated mainly by the liver, whereas V-PROLI/NO was excreted mostly in unchanged form by the kidney. V-PYRRO/NO was metabolized by CYP2E1, CYP2C9, CYP1A2, and CYP3A4, whereas V-PROLI/NO was metabolized mainly by CYP1A2. Importantly, V-PYRRO/NO was a better NO releaser in vivo and in the isolated, perfused liver than V-PROLI/NO, an effect compatible with the superior antisteatotic activity of V-PYRRO/NO. In conclusion, V-PYRRO/NO displayed a pronounced antisteatotic effect associated with liver-targeted NO release, whereas V-PROLI/NO showed low effectiveness, was not taken up by the liver, and was eliminated mostly in unchanged form by the kidney. U.S. Government work not protected by U.S. copyright.

Absorption of zinc from lupin (Lupinus angustifolius)-based foods.

PubMed

Petterson, D S; Sandström, B; Cederblad, A

1994-12-01

The absorption of Zn from a lupin (Lupinus angustifolius) milk fortified with Ca, a bread containing lupin flour (230 g/kg), a sauce containing lupin flour and a sauce containing a lupin-protein isolate was determined in humans by measuring the whole-body retention of radioisotope from meals labelled with 0.02 MBq 65Zn, allowing for endogenous excretion of Zn, after 14 d. The absorption of Zn from the Ca-enriched milk (16.2%) and the bread made with lupin flour (27.0%) was similar to literature figures for comparable soya-bean products. The absorption from composite meals made with lupin flour (28.2%) and protein isolate (32.7%) was significantly higher than that reported for comparable soya-bean products. In a second experiment the absorption of Zn from a lupin-milk base and a soya-bean-milk base was compared with that from Ca-supplemented bases. The absorption of Zn from the lupin-milk base (26.3%) was significantly higher than from the soya-bean-milk base (17.6%), and neither was significantly altered by the addition of Ca. Overall the absorption of Zn from lupin-protein foods was found to be higher than from comparable soya-bean products. Lupin milk could be an attractive alternative to soya-bean milk for infant formulas.

Carbohydrate derived energy and gross energy absorption in preterm infants fed human milk or formula.

PubMed

De Curtis, M; Senterre, J; Rigo, J; Putet, G

1986-09-01

Significant production of breath hydrogen has been shown in premature infants, suggesting limited intestinal capacity for digestion of carbohydrate. To evaluate net absorption of carbohydrate 24 three day balance studies were carried out in seven preterm infants fed pasteurised banked human milk and in 17 preterm infants fed a formula containing 75% lactose and 25% glucose polymers. Because carbohydrate reaching the colon may be converted to organic acids by bacterial flora, carbohydrate net absorption was determined by quantitating the faecal excretion of energy derived from carbohydrate. The carbohydrate derived energy content of milk and stools was calculated as the difference between the measured gross energy and the sum of energy related to nitrogen and fat. Faecal loss of carbohydrate derived energy was lower in the group fed formula (1.9 (SD 1.2) kcal/kg/day) than in the group fed human milk (4.0 (SD 1.8) kcal/kg/day). Net absorption of carbohydrate derived energy was 97.0 (SD 1.9)% as opposed to 92.6 (SD 3.9)%, respectively. Within each group there was no significant relation between carbohydrate energy absorption and fat, nitrogen, or gross energy absorption. Thus, although less complete with human milk than with formula, apparent absorption of energy derived from carbohydrate seemed quite satisfactory in these preterm infants.

Cinnamaldehyde, Cinnamic Acid, and Cinnamyl Alcohol, the Bioactives of Cinnamomum cassia Exhibit HDAC8 Inhibitory Activity: An In vitro and In silico Study

PubMed Central

Patil, Mangesh; Choudhari, Amit S.; Pandita, Savita; Islam, Md Ataul; Raina, Prerna; Kaul-Ghanekar, Ruchika

2017-01-01

Background: The altered expression of histone deacetylase family member 8 (HDAC8) has been found to be linked with various cancers, thereby making its selective inhibition a potential strategy in cancer therapy. Recently, plant secondary metabolites, particularly phenolic compounds, have been shown to possess HDAC inhibitory activity. Objective: In the present work, we have evaluated the potential of cinnamaldehyde (CAL), cinnamic acid (CA), and cinnamyl alcohol (CALC) (bioactives of Cinnamomum) as well as aqueous cinnamon extract (ACE), to inhibit HDAC8 activity in vitro and in silico. Materials and Methods: HDAC8 inhibitory activity of ACE and cinnamon bioactives was determined in vitro using HDAC8 inhibitor screening kit. Trichostatin A (TSA), a well-known anti-cancer agent and HDAC inhibitor, was used as a positive control. In silico studies included molecular descriptor Analysis molecular docking absorption, distribution, metabolism, excretion, and toxicity prediction, density function theory calculation and synthetic accessibility program. Results: Pharmacoinformatics studies implicated that ACE and its Bioactives (CAL, CA, and CALC) exhibited comparable activity with that of TSA. The highest occupied molecular orbitals and lowest unoccupied molecular orbitals along with binding energy of cinnamon bioactives were comparable with that of TSA. Molecular docking results suggested that all the ligands maintained two hydrogen bond interactions within the active site of HDAC8. Finally, the synthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA. Conclusion: It was evident from both the experimental and computational data that cinnamon bioactives exhibited significant HDAC8 inhibitory activity, thereby suggesting their potential therapeutic implications against cancer. SUMMARY Pharmacoinformatics studies revealed that cinnamon bioactives bound to the active site of HDAC8 enzyme in a way similar to that of TSAThe molecular descriptors of cinnamon compounds successfully correlated with TSA values. The binding interactions and energies were also found to be close to TSASynthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA. Abbreviations used: ACE: Aqueous Cinnamon Extract; DFT: Density Function Theory; CAL: Cinnamaldehyde; CA: Cinnamic Acid; CALC: Cinnamyl Alcohol; MW: Molecular Weight; ROTBs: Rotatable Bonds; ROF: Lipinski's Rule of Five; TSA: Trichostatin A; PDB: Protein Data Bank; RMSD: Root Mean Square Deviation; HBA: Hydrogen Bond Acceptor; HBD: Hydrogen Bond Donor; ADMET: Absorption, Distribution, Metabolism, Excretion and Toxicity; FO: Frontier Orbital; HOMOs: Highest Occupied Molecular Orbitals; LUMOs: Lowest Unoccupied Molecular Orbitals; BE: Binding Energy. PMID:29142427

Revisiting the physiological roles of SGLTs and GLUTs using positron emission tomography in mice

PubMed Central

Sala‐Rabanal, Monica; Hirayama, Bruce A.; Ghezzi, Chiara; Liu, Jie; Huang, Sung‐Cheng; Kepe, Vladimir; Koepsell, Hermann; Yu, Amy; Powell, David R.; Thorens, Bernard; Barrio, Jorge R.

2016-01-01

Key points Glucose transporters are central players in glucose homeostasis.There are two major classes of glucose transporters in the body, the passive facilitative glucose transporters (GLUTs) and the secondary active sodium‐coupled glucose transporters (SGLTs).In the present study, we report the use of a non‐invasive imaging technique, positron emission tomography, in mice aiming to evaluate the role of GLUTs and SGLTs in controlling glucose distribution and utilization.We show that GLUTs are most significant for glucose uptake into the brain and liver, whereas SGLTs are important in glucose recovery in the kidney.This work provides further support for the use of SGLT imaging in the investigation of the role of SGLT transporters in human physiology and diseases such as diabetes and cancer. Abstract The importance of sodium‐coupled glucose transporters (SGLTs) and facilitative glucose transporters (GLUTs) in glucose homeostasis was studied in mice using fluorine‐18 labelled glucose molecular imaging probes and non‐invasive positron emission tomography (PET) imaging. The probes were: α‐methyl‐4‐[F‐18]‐fluoro‐4‐deoxy‐d‐glucopyranoside (Me‐4FDG), a substrate for SGLTs; 4‐deoxy‐4‐[F‐18]‐fluoro‐d‐glucose (4‐FDG), a substrate for SGLTs and GLUTs; and 2‐deoxy‐2‐[F‐18]‐fluoro‐d–glucose (2‐FDG), a substrate for GLUTs. These radiolabelled imaging probes were injected i.v. into wild‐type, Sglt1–/–, Sglt2–/– and Glut2–/– mice and their dynamic whole‐body distribution was determined using microPET. The distribution of 2‐FDG was similar to that reported earlier (i.e. it accumulated in the brain, heart, liver and kidney, and was excreted into the urinary bladder). There was little change in the distribution of 2‐FDG in Glut2–/– mice, apart from a reduction in the rate of uptake into liver. The major differences between Me‐4FDG and 2‐FDG were that Me‐4FDG did not enter the brain and was not excreted into the urinary bladder. There was urinary excretion of Me‐4FDG in Sglt1–/– and Sglt2–/– mice. However, Me‐4FDG was not reabsorbed in the kidney in Glut2–/– mice. There were no differences in Me‐4FDG uptake into the heart of wild‐type, Sglt1–/– and Sglt2–/– mice. We conclude that GLUT2 is important in glucose liver transport and reabsorption of glucose in the kidney along with SGLT2 and SGLT1. Complete reabsorption of Me‐4FDG from the glomerular filtrate in wild‐type mice and the absence of reabsorption in the kidney in Glut2–/– mice confirm the importance of GLUT2 in glucose absorption across the proximal tubule. PMID:27018980

A theoretical and experimental study of calcium, iron, zinc, cadmium, and sodium ions absorption by aspartame.

PubMed

Mahnam, Karim; Raisi, Fatame

2017-03-01

Aspartame (L-Aspartyl-L-phenylalanine methyl ester) is a sweet dipeptide used in some foods and beverages. Experimental studies show that aspartame causes osteoporosis and some illnesses, which are similar to those of copper and calcium deficiency. This raises the issue that aspartame in food may interact with cations and excrete them from the body. This study aimed to study aspartame interaction with calcium, zinc, iron, sodium, and cadmium ions via molecular dynamics simulation (MD) and spectroscopy. Following a 480-ns molecular dynamics simulation, it became clear that the aspartame is able to sequester Fe 2+ , Ca 2+ , Cd 2+ , and Zn 2+ ions for a long time. Complexation led to increasing UV-Vis absorption spectra and emission spectra of the complexes. This study suggests a potential risk of cationic absorption of aspartame. This study suggests that purification of cadmium-polluted water by aspartame needs a more general risk assessment.

Digestion and absorption ofEucalyptus essential oils in greater glider (Petauroide svolans) and brushtail possum (Trichosurus vulpecula).

PubMed

Foley, W J; Lassak, E V; Brophy, J

1987-11-01

Measurements were made of the quantity and composition of the steam-volatile essential oils in gastrointestinal tract contents of greater gliders fedEucalyptus radiata foliage and brushtail possums fedE. melliodora foliage. In both species, there was less oil in the stomach contents than in an equivalent mass of foliage. Only minor losses of leaf oils occurred during mastication by greater gliders, and absorption from the stomach appeared to be the major reason for the difference in the oil content of ingested leaves and of stomach contents. The apparent digestibility of oils over the whole gut was 96-97 %, although oils from the cecum and feces of both species contained compounds not present in the original leaf oils. Absorption of oils before they reach the hindgut should reduce the severity of antimicrobial effects but may involve a metabolic cost to the animal in detoxification and excretion.

The study of trace metal absoption using stable isotopes and mass spectrometry

NASA Astrophysics Data System (ADS)

Fennessey, P. V.; Lloyd-Kindstrand, L.; Hambidge, K. M.

1991-12-01

The absorption and excretion of zinc stable isotopes have been followed in more than 120 human subjects. The isotope enrichment determinations were made using a standard VG 7070E HF mass spectrometer. A fast atom gun (FAB) was used to form the ions from a dry residue on a pure silver probe tip. Isotope ratio measurements were found to have a precision of better than 2% (relative standard deviation) and required a sample size of 1-5 [mu]g. The average true absorption of zinc was found to be 73 ± 12% (2[sigma]) when the metal was taken in a fasting state. This absorption figure was corrected for tracer that had been absorbed and secreted into the gastrointestinal (GI) tract over the time course of the study. The average time for a majority of the stable isotope tracer to pass through the GI tract was 4.7 ± 1.9 (2[sigma]) days.

Computational Design of Apolipoprotein E4 Inhibitors for Alzheimer's Disease Therapy from Traditional Chinese Medicine

PubMed Central

Huang, Hung-Jin; Chen, Hsin-Yi; Lee, Cheng-Chun

2014-01-01

Apolipoprotein E4 (Apo E4) is the major genetic risk factor in the causation of Alzheimer's disease (AD). In this study we utilize virtual screening of the world's largest traditional Chinese medicine (TCM) database and investigate potential compounds for the inhibition of ApoE4. We present the top three TCM candidates: Solapalmitine, Isodesacetyluvaricin, and Budmunchiamine L5 for further investigation. Dynamics analysis and molecular dynamics (MD) simulation were used to simulate protein-ligand complexes for observing the interactions and protein variations. Budmunchiamine L5 did not have the highest score from virtual screening; however, the dynamics pose is similar to the initial docking pose after MD simulation. Trajectory analysis reveals that Budmunchiamine L5 was stable over all simulation times. The migration distance of Budmunchiamine L5 illustrates that docked ligands are not variable from the initial docked site. Interestingly, Arg158 was observed to form H-bonds with Budmunchiamine L5 in the docking pose and MD snapshot, which indicates that the TCM compounds could stably bind to ApoE4. Our results show that Budmunchiamine L5 has good absorption, blood brain barrier (BBB) penetration, and less toxicity according to absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction and could, therefore, be safely used for developing novel ApoE4 inhibitors. PMID:24967370

Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease.

PubMed

Wiczling, Paweł; Liem, Robert I; Panepinto, Julie A; Garg, Uttam; Abdel-Rahman, Susan M; Kearns, Gregory L; Neville, Kathleen A

2014-09-01

The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2)  = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure. © 2014, The American College of Clinical Pharmacology.

Predictive framework for estimating exposure of birds to pharmaceuticals

USGS Publications Warehouse

Bean, Thomas G.; Arnold, Kathryn E.; Lane, Julie M.; Bergström, Ed; Thomas-Oates, Jane; Rattner, Barnett A.; Boxall, Allistair B.A.

2017-01-01

We present and evaluate a framework for estimating concentrations of pharmaceuticals over time in wildlife feeding at wastewater treatment plants (WWTPs). The framework is composed of a series of predictive steps involving the estimation of pharmaceutical concentration in wastewater, accumulation into wildlife food items, and uptake by wildlife with subsequent distribution into, and elimination from, tissues. Because many pharmacokinetic parameters for wildlife are unavailable for the majority of drugs in use, a read-across approach was employed using either rodent or human data on absorption, distribution, metabolism, and excretion. Comparison of the different steps in the framework against experimental data for the scenario where birds are feeding on a WWTP contaminated with fluoxetine showed that estimated concentrations in wastewater treatment works were lower than measured concentrations; concentrations in food could be reasonably estimated if experimental bioaccumulation data are available; and read-across from rodent data worked better than human to bird read-across. The framework provides adequate predictions of plasma concentrations and of elimination behavior in birds but yields poor predictions of distribution in tissues. The approach holds promise, but it is important that we improve our understanding of the physiological similarities and differences between wild birds and domesticated laboratory mammals used in pharmaceutical efficacy/safety trials, so that the wealth of data available can be applied more effectively in ecological risk assessments.

Predictive framework for estimating exposure of birds to pharmaceuticals.

PubMed

Bean, Thomas G; Arnold, Kathryn E; Lane, Julie M; Bergström, Ed; Thomas-Oates, Jane; Rattner, Barnett A; Boxall, Alistair B A

2017-09-01

We present and evaluate a framework for estimating concentrations of pharmaceuticals over time in wildlife feeding at wastewater treatment plants (WWTPs). The framework is composed of a series of predictive steps involving the estimation of pharmaceutical concentration in wastewater, accumulation into wildlife food items, and uptake by wildlife with subsequent distribution into, and elimination from, tissues. Because many pharmacokinetic parameters for wildlife are unavailable for the majority of drugs in use, a read-across approach was employed using either rodent or human data on absorption, distribution, metabolism, and excretion. Comparison of the different steps in the framework against experimental data for the scenario where birds are feeding on a WWTP contaminated with fluoxetine showed that estimated concentrations in wastewater treatment works were lower than measured concentrations; concentrations in food could be reasonably estimated if experimental bioaccumulation data are available; and read-across from rodent data worked better than human to bird read-across. The framework provides adequate predictions of plasma concentrations and of elimination behavior in birds but yields poor predictions of distribution in tissues. The approach holds promise, but it is important that we improve our understanding of the physiological similarities and differences between wild birds and domesticated laboratory mammals used in pharmaceutical efficacy/safety trials, so that the wealth of data available can be applied more effectively in ecological risk assessments. Environ Toxicol Chem 2017;36:2335-2344. © 2017 SETAC. © 2017 SETAC.

Comparative metabolism as a key driver of wildlife species sensitivity to human and veterinary pharmaceuticals

PubMed Central

Hutchinson, Thomas H.; Madden, Judith C.; Naidoo, Vinny; Walker, Colin H.

2014-01-01

Human and veterinary drug development addresses absorption, distribution, metabolism, elimination and toxicology (ADMET) of the Active Pharmaceutical Ingredient (API) in the target species. Metabolism is an important factor in controlling circulating plasma and target tissue API concentrations and in generating metabolites which are more easily eliminated in bile, faeces and urine. The essential purpose of xenobiotic metabolism is to convert lipid-soluble, non-polar and non-excretable chemicals into water soluble, polar molecules that are readily excreted. Xenobiotic metabolism is classified into Phase I enzymatic reactions (which add or expose reactive functional groups on xenobiotic molecules), Phase II reactions (resulting in xenobiotic conjugation with large water-soluble, polar molecules) and Phase III cellular efflux transport processes. The human–fish plasma model provides a useful approach to understanding the pharmacokinetics of APIs (e.g. diclofenac, ibuprofen and propranolol) in freshwater fish, where gill and liver metabolism of APIs have been shown to be of importance. By contrast, wildlife species with low metabolic competency may exhibit zero-order metabolic (pharmacokinetic) profiles and thus high API toxicity, as in the case of diclofenac and the dramatic decline of vulture populations across the Indian subcontinent. A similar threat looms for African Cape Griffon vultures exposed to ketoprofen and meloxicam, recent studies indicating toxicity relates to zero-order metabolism (suggesting P450 Phase I enzyme system or Phase II glucuronidation deficiencies). While all aspects of ADMET are important in toxicity evaluations, these observations demonstrate the importance of methods for predicting API comparative metabolism as a central part of environmental risk assessment. PMID:25405970

Effect of cinnamon and turmeric on urinary oxalate excretion, plasma lipids, and plasma glucose in healthy subjects.

PubMed

Tang, Minghua; Larson-Meyer, D Enette; Liebman, Michael

2008-05-01

High oxalate intake resulting from consuming supplemental doses of cinnamon and turmeric may increase risk of hyperoxaluria, a significant risk factor for urolithiasis. This study assessed urinary oxalate excretion from supplemental doses of cinnamon and turmeric as well as changes in fasting plasma glucose, cholesterol, and triacylglycerol concentrations. Eleven healthy subjects, aged 21-38 y, participated in an 8-wk, randomly assigned, crossover study that involved the ingestion of supplemental doses of cinnamon and turmeric for 4-wk periods that provided 55 mg oxalate/d. Oxalate load tests, which entailed the ingestion of a 63-mg dose of oxalate from the test spices, were performed after each 4-wk experimental period and at the study onset with water only (control treatment). Fasting plasma glucose and lipid concentrations were also assessed at these time points. Compared with the cinnamon and control treatments, turmeric ingestion led to a significantly higher urinary oxalate excretion during the oxalate load tests. There were no significant changes in fasting plasma glucose or lipids in conjunction with the 4-wk periods of either cinnamon or turmeric supplementation. The percentage of oxalate that was water soluble differed markedly between cinnamon (6%) and turmeric (91%), which appeared to be the primary cause of the greater urinary oxalate excretion/oxalate absorption from turmeric. The consumption of supplemental doses of turmeric, but not cinnamon, can significantly increase urinary oxalate levels, thereby increasing risk of kidney stone formation in susceptible individuals.

Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes

PubMed Central

Kontoghiorghe, Christina N; Kontoghiorghes, George J

2016-01-01

The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30–40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO–L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption. PMID:26893541

Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes.

PubMed

Kontoghiorghe, Christina N; Kontoghiorghes, George J

2016-01-01

The prevalence rate of thalassemia, which is endemic in Southeast Asia, the Middle East, and the Mediterranean, exceeds 100,000 live births per year. There are many genetic variants in thalassemia with different pathological severity, ranging from a mild and asymptomatic anemia to life-threatening clinical effects, requiring lifelong treatment, such as regular transfusions in thalassemia major (TM). Some of the thalassemias are non-transfusion-dependent, including many thalassemia intermedia (TI) variants, where iron overload is caused by chronic increase in iron absorption due to ineffective erythropoiesis. Many TI patients receive occasional transfusions. The rate of iron overloading in TI is much slower in comparison to TM patients. Iron toxicity in TI is usually manifested by the age of 30-40 years, and in TM by the age of 10 years. Subcutaneous deferoxamine (DFO), oral deferiprone (L1), and DFO-L1 combinations have been effectively used for more than 20 years for the treatment of iron overload in TM and TI patients, causing a significant reduction in morbidity and mortality. Selected protocols using DFO, L1, and their combination can be designed for personalized chelation therapy in TI, which can effectively and safely remove all the excess toxic iron and prevent cardiac, liver, and other organ damage. Both L1 and DF could also prevent iron absorption. The new oral chelator deferasirox (DFX) increases iron excretion and decreases liver iron in TM and TI. There are drawbacks in the use of DFX in TI, such as limitations related to dose, toxicity, and cost, iron load of the patients, and ineffective removal of excess iron from the heart. Furthermore, DFX appears to increase iron and other toxic metal absorption. Future treatments of TI and related iron-loading conditions could involve the use of the iron-chelating drugs and other drug combinations not only for increasing iron excretion but also for preventing iron absorption.

Urine sodium excretion increased slightly among U.S. adults between 1988 and 2010.

PubMed

Pfeiffer, Christine M; Hughes, Jeffery P; Cogswell, Mary E; Burt, Vicki L; Lacher, David A; Lavoie, Donna J; Rabinowitz, Daniel J; Johnson, Clifford L; Pirkle, James L

2014-05-01

Little information is available on temporal trends in sodium intake in the U.S. population using urine sodium excretion as a biomarker. Our aim was to assess 1988-2010 trends in estimated 24-h urine sodium (24hUNa) excretion among U.S. adults (age 20-59 y) participating in the cross-sectional NHANES. We used subsamples from a 1988-1994 convenience sample, a 2003-2006 one-third random sample, and a 2010 one-third random sample to comply with resource constraints. We estimated 24hUNa excretion from measured sodium concentrations in spot urine samples by use of calibration equations (for men and women) derived from the International Cooperative Study on Salt, Other Factors, and Blood Pressure study. Estimated 24hUNa excretion increased over the 20-y period [1988-1994, 2003-2006, and 2010; means ± SEMs (n): 3160 ± 38.4 mg/d (1249), 3290 ± 29.4 mg/d (1235), and 3290 ± 44.4 mg/d (525), respectively; P-trend = 0.022]. We observed significantly higher mean estimated 24hUNa excretion in each survey period (P < 0.001) for men compared with women (31-33%) and for persons with a higher body mass index (BMI; 32-35% for obese vs. normal weight) or blood pressure (17-26% for hypertensive vs. normal blood pressure). After adjusting for age, sex, and race-ethnicity, temporal trends in mean estimated 24hUNa excretion remained significant (P-trend = 0.004). We observed no temporal trends in mean estimated 24hUNa excretion among BMI subgroups, nor after adjusting for BMI. Although several limitations apply to this analysis (the use of a convenience sample in 1988-1994 and using estimated 24hUNa excretion as a biomarker of sodium intake), these first NHANES data suggest that mean estimated 24hUNa excretion increased slightly in U.S. adults over the past 2 decades, and this increase may be explained by a shift in the distribution of BMI.

Effects of diet on plasma concentrations of oral anthelmintics for cattle and sheep.

PubMed

Taylor, S M; Mallon, T R; Blanchflower, W J; Kennedy, D G; Green, W P

1992-03-28

Groups of parasite-free lambs and calves which were either housed and fed hay and concentrates or were grazing on pasture were dosed separately with the oral anthelmintics fenbendazole and ivermectin (lambs only). The plasma concentrations of the drugs and their major metabolites were monitored during the period of their metabolism and excretion. The peak plasma concentrations and the availability of the drugs, as estimated by the areas under the plasma concentration-time curves, were significantly less in the grazing animals. When similar groups of lambs were dosed orally with the inert marker chromium EDTA, which has a particle size similar to the anthelmintics, it was observed that a higher percentage of chromium was excreted by the grazing lambs during the first 40 hours after dosing, suggesting that the extent of absorption in the grazing animals was less than in the housed animals.

Evaluation of the anti-hyperglycemic effect and safety of microorganism 1-deoxynojirimycin.

PubMed

Takasu, Soo; Parida, Isabella Supardi; Onose, Shinji; Ito, Junya; Ikeda, Ryoichi; Yamagishi, Kenji; Higuchi, Oki; Tanaka, Fukuyo; Kimura, Toshiyuki; Miyazawa, Teruo; Nakagawa, Kiyotaka

2018-01-01

1-Deoxynojirimycin (DNJ) is a potent α-glucosidase inhibitor and thus beneficial for prevention of diabetes. While we have succeeded in obtaining the culture supernatant extract (CSE) rich in DNJ from microorganism source, information regarding its anti-hyperglycemic effect and safety were still limited. Therefore, this study was aimed to evaluate the anti-hyperglycemic effect and safety of microorganism DNJ. Oral sucrose tolerance test was performed, and the result showed that CSE was able to significantly suppress the blood glucose elevation and suggested DNJ as the main active compound. To determine its safety, the absorption and excretion of microorganism DNJ were evaluated using 15N labeling method. Our findings investigated the recovery rate of 15N from DNJ reached 80% up to 48 hours after oral administration, suggesting its rapid excretion, suggesting the safety of DNJ. This study verified the functional properties and safety of DNJ from microorganisms, suggesting its potential use for functional purpose.

Quantitation of calcium metabolism in postmenopausal osteoporosis and in scoliosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bronner, F.; Richelle, L. J.; Saville, P. D.

1963-06-01

By a combination of balance and isotope techniques, the following parameters of Ca metabolism were measured: pool size, rate of loss from pool, urinary excretion, fecal excretion, intake, endogenous fecal Ca, absorption, balance, bone formation, and bone resorption. The subjects were two normal women and five women with postmenopausal osteoporosis, aged 41 to 74 years, and four patients with scoliosis, aged 12 to 22 years. The latter were studied before, shortly after, and many months after immobilization in plaster casts. On the basis of observed relationships, it appeared that the negative Ca balance observed in the older women was duemore » to the low intensity of the various vectors of Ca metabolism, without clearcut distinction between the subjects with and without osteoporosis. Conversely, in the young patients with scoliosis, the negative balance incident to treatment by immobilization was associated with vectors of relatively high intensity whose relationships were altered temporarily.« less

E. coli Infection Modulates the Pharmacokinetics of Oral Enrofloxacin by Targeting P-Glycoprotein in Small Intestine and CYP450 3A in Liver and Kidney of Broilers

PubMed Central

Guo, Mengjie; Sun, Yong; Zhang, Yu; Bughio, Shamsuddin; Dai, Xiaohua; Ren, Weilong; Wang, Liping

2014-01-01

P-glycoprotein (P-gp) expression determines the absorption, distribution, metabolism and excretion of many drugs in the body. Also, up-regulation of P-gp acts as a defense mechanism against acute inflammation. This study examined expression levels of abcb1 mRNA and localization of P-gp protein in the liver, kidney, duodenum, jejunum and ileum in healthy and E. coli infected broilers by real time RT-PCR and immunohistochemistry. Meanwhile, pharmacokinetics of orally administered enrofloxacin was also investigated in healthy and infected broilers by HPLC. The results indicated that E. coli infection up-regulated expression of abcb1 mRNA levels significantly in the kidney, jejunum and ileum (P<0.05), but not significantly in the liver and duodenum (P>0.05). However, the expression level of CYP 3A37 mRNA were observed significantly decreased only in liver and kidney of E. coli infected broilers (P<0.05) compared with healthy birds. Furthermore, the infection reduced absorption of orally administered enrofloxacin, significantly decreased Cmax (0.34 vs 0.98 µg mL−1, P = 0.000) and AUC0-12h (4.37 vs 8.88 µg mL−1 h, P = 0.042) of enrofloxacin, but increased Tmax (8.32 vs 3.28 h, P = 0.040), T1/2a(2.66 vs 1.64 h−1, P = 0.050) and V/F (26.7 vs 5.2 L, P = 0.040). Treatment with verapamil, an inhibitor of P-gp, significantly improved the absorption of enrofloxacin in both healthy and infected broilers. The results suggest that the E. coli infection induces intestine P-gp expression, altering the absorption of orally administered enrofloxacin in broilers. PMID:24498193

Efficacy, Pharmacokinetics, and Metabolism of Tetrahydroquinoline Inhibitors of Plasmodium falciparum Protein Farnesyltransferase▿ †

PubMed Central

Van Voorhis, Wesley C.; Rivas, Kasey L.; Bendale, Pravin; Nallan, Laxman; Hornéy, Carolyn; Barrett, Lynn K.; Bauer, Kevin D.; Smart, Brian P.; Ankala, Sudha; Hucke, Oliver; Verlinde, Christophe L. M. J.; Chakrabarti, Debopam; Strickland, Corey; Yokoyama, Kohei; Buckner, Frederick S.; Hamilton, Andrew D.; Williams, David K.; Lombardo, Louis J.; Floyd, David; Gelb, Michael H.

2007-01-01

New antimalarials are urgently needed. We have shown that tetrahydroquinoline (THQ) protein farnesyltransferase (PFT) inhibitors (PFTIs) are effective against the Plasmodium falciparum PFT and are effective at killing P. falciparum in vitro. Previously described THQ PFTIs had limitations of poor oral bioavailability and rapid clearance from the circulation of rodents. In this paper, we validate both the Caco-2 cell permeability model for predicting THQ intestinal absorption and the in vitro liver microsome model for predicting THQ clearance in vivo. Incremental improvements in efficacy, oral absorption, and clearance rate were monitored by in vitro tests; and these tests were followed up with in vivo absorption, distribution, metabolism, and excretion studies. One compound, PB-93, achieved cure when it was given orally to P. berghei-infected rats every 8 h for a total of 72 h. However, PB-93 was rapidly cleared, and dosing every 12 h failed to cure the rats. Thus, the in vivo results corroborate the in vitro pharmacodynamics and demonstrate that 72 h of continuous high-level exposure to PFTIs is necessary to kill plasmodia. The metabolism of PB-93 was demonstrated by a novel technique that relied on double labeling with a radiolabel and heavy isotopes combined with radiometric liquid chromatography and mass spectrometry. The major liver microsome metabolite of PB-93 has the PFT Zn-binding N-methyl-imidazole removed; this metabolite is inactive in blocking PFT function. By solving the X-ray crystal structure of PB-93 bound to rat PFT, a model of PB-93 bound to malarial PFT was constructed. This model suggests areas of the THQ PFTIs that can be modified to retain efficacy and protect the Zn-binding N-methyl-imidazole from dealkylation. PMID:17606674

Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice

PubMed Central

Corpe, Christopher P.; Tu, Hongbin; Eck, Peter; Wang, Jin; Faulhaber-Walter, Robert; Schnermann, Jurgen; Margolis, Sam; Padayatty, Sebastian; Sun, He; Wang, Yaohui; Nussbaum, Robert L.; Espey, Michael Graham; Levine, Mark

2010-01-01

Levels of the necessary nutrient vitamin C (ascorbate) are tightly regulated by intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Ascorbate levels are controlled in part by regulation of transport through at least 2 sodium-dependent transporters: Slc23a1 and Slc23a2 (also known as Svct1 and Svct2, respectively). Previous work indicates that Slc23a2 is essential for viability in mice, but the roles of Slc23a1 for viability and in adult physiology have not been determined. To investigate the contributions of Slc23a1 to plasma and tissue ascorbate concentrations in vivo, we generated Slc23a1–/– mice. Compared with wild-type mice, Slc23a1–/– mice increased ascorbate fractional excretion up to 18-fold. Hepatic portal ascorbate accumulation was nearly abolished, whereas intestinal absorption was marginally affected. Both heterozygous and knockout pups born to Slc23a1–/– dams exhibited approximately 45% perinatal mortality, and this was associated with lower plasma ascorbate concentrations in dams and pups. Perinatal mortality of Slc23a1–/– pups born to Slc23a1–/– dams was prevented by ascorbate supplementation during pregnancy. Taken together, these data indicate that ascorbate provided by the dam influenced perinatal survival. Although Slc23a1–/– mice lost as much as 70% of their ascorbate body stores in urine daily, we observed an unanticipated compensatory increase in ascorbate synthesis. These findings indicate a key role for Slc23a1 in renal ascorbate absorption and perinatal survival and reveal regulation of vitamin C biosynthesis in mice. PMID:20200446

Combined Effects of Ezetimibe and Phytosterols on Cholesterol Metabolism: A Randomized, Controlled Feeding Study in Humans

PubMed Central

Lin, Xiaobo; Racette, Susan B.; Lefevre, Michael; Ma, Lina; Spearie, Catherine Anderson; Steger-May, Karen; Ostlund, Richard E.

2011-01-01

Background Both ezetimibe and phytosterols inhibit cholesterol absorption. We tested the hypothesis that ezetimibe combined with phytosterols is more effective than ezetimibe alone in altering cholesterol metabolism. Methods and Results Twenty-one mildly hypercholesterolemic subjects completed a randomized, double-blind, placebo-controlled, triple crossover study. Each subject received a phytosterol-controlled diet plus (1) ezetimibe placebo + phytosterol placebo, (2) 10 mg ezetimibe/day + phytosterol placebo, and (3) 10 mg ezetimibe/day + 2.5 g phytosterols/day, for 3 weeks each. All meals were prepared in a metabolic kitchen. Primary outcomes were intestinal cholesterol absorption, fecal cholesterol excretion, and LDL cholesterol levels. The combined treatment resulted in significantly lower intestinal cholesterol absorption (598 mg/day, 95% CI 368 to 828) relative to control (2161 mg/day, 1112 to 3209) and ezetimibe alone (1054 mg/day, 546 to 1561, both P < 0.0001). Fecal cholesterol excretion was significantly greater (P < 0.0001) with combined treatment (962 mg/day, 757 to 1168) relative to control (505 mg/day, 386 to 625) and ezetimibe alone (794 mg/day, 615 to 973). Plasma LDL cholesterol values during control, ezetimibe alone, and ezetimibe + phytosterols averaged 129 (95% CI: 116 to 142), 108 (97 to 119), and 101 (90 to 112) mg/dL (P < 0.0001 relative to control). Conclusion The addition of phytosterols to ezetimibe significantly enhanced the effects of ezetimibe on whole-body cholesterol metabolism and plasma LDL cholesterol. The large cumulative action of combined dietary and pharmacologic treatment on cholesterol metabolism emphasizes the potential importance of dietary phytosterols as adjunctive therapy for the treatment of hypercholesterolemia. PMID:21768544

Cholesterol Absorption and Synthesis in Vegetarians and Omnivores.

PubMed

Lütjohann, Dieter; Meyer, Sven; von Bergmann, Klaus; Stellaard, Frans

2018-03-01

Vegetarian diets are considered health-promoting; however, a plasma cholesterol lowering effect is not always observed. We investigate the link between vegetarian-diet-induced alterations in cholesterol metabolism. We study male and female omnivores, lacto-ovo vegetarians, lacto vegetarians, and vegans. Cholesterol intake, absorption, and fecal sterol excretion are measured as well as plasma concentrations of cholesterol and noncholesterol sterols. These serve as markers for cholesterol absorption, synthesis, and catabolism. The biliary cholesterol secretion rate is estimated. Flux data are related to body weight. Individual vegetarian diet groups are statistically compared to the omnivore group. Lacto vegetarians absorb 44% less dietary cholesterol, synthesized 22% more cholesterol, and show no differences in plasma total and LDL cholesterol. Vegan subjects absorb 90% less dietary cholesterol, synthesized 35% more cholesterol, and have a similar plasma total cholesterol, but a 13% lower plasma LDL cholesterol. No diet-related differences in biliary cholesterol secretion and absorption are observed. Total cholesterol absorption is lower only in vegans. Total cholesterol input is similar under all vegetarian diets. Unaltered biliary cholesterol secretion and higher cholesterol synthesis blunt the lowered dietary cholesterol intake in vegetarians. LDL cholesterol is significantly lower only in vegans. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effect of poorly absorbed solute on intestinal absorption.

PubMed

Menzies, I S; Jenkins, A P; Heduan, E; Catt, S D; Segal, M B; Creamer, B

1990-12-01

To determine the effects of poorly absorbed solute on intestinal absorption, the urinary recovery of ingested lactulose, L-rhamnose, D-xylose, and 3-O-methyl-D-glucose was measured after simultaneous ingestion of various 'loads' of mannitol given in iso-osmolar solution. Mannitol reduced intestinal uptake of the poorly absorbed test sugars, lactulose and L-rhamnose; uptake of D-xylose and 3-O-methyl-D-glucose, which are absorbed by carrier-mediated transport largely from the jejunum, was less affected. The dose-response effect of mannitol on the absorption of L-rhamnose was approximately exponential; doses of 5, 10, and 20 g mannitol reduced the average urinary excretion of L-rhamnose by 34.7%, 51.7%, and 61.2%, respectively. In this respect, an osmotically equivalent load of lactulose, ingested as 'solute', was approximately twice as effective as mannitol in reducing L-rhamnose absorption, probably because lactulose is more poorly absorbed than mannitol (less than 1.0% versus 32-41%). Ingestion of other poorly absorbed solutes such as raffinose, sorbitol, xylitol, magnesium sulphate, and sodium sulphate also significantly depressed the absorption of L-rhamnose; in contrast, more efficiently absorbed solutes, such as sodium chloride, glucose, glycerol, and urea had little effect.

L-carnitine and cancer cachexia. I. L-carnitine distribution and metabolic disorders in cancer cachexia.

PubMed

Szefel, Jarosław; Kruszewski, Wiesław Janusz; Ciesielski, Maciej; Szajewski, Mariusz; Kawecki, Krzysztof; Aleksandrowicz-Wrona, Ewa; Jankun, Jerzy; Lysiak-Szydłowska, Wiesława

2012-07-01

Cancer cachexia (CC), a progressive loss of body mass, is associated with decreased energy production. Abnormally low levels of L-carnitine (LC) in skeletal muscle means that mitochondrial β-oxidation of long-chain fatty acids (LCFA) does not occur efficiently in patients with CC. We assessed the influence of CC on LC distribution and the effects of parenteral lipid emulsions on plasma LC levels and urinary excretion. Fifty patients with CC were randomly assigned to total parenteral nutrition (TPN) with long-chain triglycerides (LCTs), or LCTs plus medium-chain triglycerides (MCTs) as 50/50. Patients were further separated into those with body-mass index (BMI) ≤ 19 kg/m(2) and BMI >19 kg/m(2). Plasma concentrations of total LC (TC) and free LC (FC) and their urinary excretion were measured, along with skeletal muscle LC levels. On average, plasma FC and TC were higher than reference values in all patients. Patients with BMI ≤ 19 kg/m(2) had lower plasma FC and TC than those with BMI >19 kg/m(2). Skeletal muscle FC in the BMI ≤ 19 kg/m(2) group was lower than reference value, but within the normal range in others. LC and FC urinary excretion was higher than reference values. Plasma LC and its urinary excretion were higher in patients administered pure LCTs relative to those given MCTs/LCTs. A decrease in skeletal muscle LC in cancer patients with CC (BMI ≤ 19 kg/m(2)) correlates with an increase in its plasma levels and increased renal excretion. A diet of MCTs/LCTs reduces LC release from muscle to plasma and urine more effectively than LCTs.

Hepatically-metabolized and -excreted artificial oxygen carrier, hemoglobin vesicles, can be safely used under conditions of hepatic impairment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taguchi, Kazuaki; Miyasato, Mayumi; Ujihira, Hayato

2010-11-01

The hemoglobin vesicle (HbV) is an artificial oxygen carrier in which a concentrated Hb solution is encapsulated in lipid vesicles. Our previous studies demonstrated that HbV is metabolized by the mononuclear phagocyte system, and the lipid components are excreted from the liver. It is well-known that many hepatically-metabolized and -excreted drugs show altered pharmaceutics under conditions of liver impairment, which results in adverse effects. The aim of this study was to determine whether the administration of HbV causes toxicity in rats with carbon tetrachloride induced liver cirrhosis. Changes in plasma biochemical parameters, histological staining and the pharmacokinetic distribution of HbVmore » were evaluated after an HbV injection of the above model rats at a putative clinical dose (1400 mgHb/kg). Plasma biochemical parameters were not significantly affected, except for a transient elevation of lipase, lipid components and bilirubin, which recovered within 14 days after an HbV infusion. Negligible morphological changes were observed in the kidney, liver, spleen, lung and heart. Hemosiderin, a marker of iron accumulation in organs, was observed in the liver and spleen up to 14 days after HbV treatment, but no evidence of oxidative stress in the plasma and liver were observed. HbV is mainly distributed in the liver and spleen, and the lipid components are excreted into feces within 7 days. In conclusion, even under conditions of hepatic cirrhosis, HbV and its components exhibit the favorable metabolic and excretion profile at the putative clinical dose. These findings provide further support for the safety and effectiveness of HbV in clinical settings.« less

Pharmacokinetics of intravenous pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor [14C]copanlisib (BAY 80-6946) in a mass balance study in healthy male volunteers.

PubMed

Gerisch, Michael; Schwarz, Thomas; Lang, Dieter; Rohde, Gabriele; Reif, Stefanie; Genvresse, Isabelle; Reschke, Susanne; van der Mey, Dorina; Granvil, Camille

2017-09-01

To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib. A single dose of 12 mg copanlisib containing 2.76 MBq [ 14 C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days. Blood, plasma, urine and feces were collected to monitor total radioactivity, parent compound and metabolites. Copanlisib treatment was well tolerated. Copanlisib was rapidly distributed throughout the body with a volume distribution of 1870 L and an elimination half-life of 52.1-h (range 40.4-67.5-h). Copanlisib was the predominant component in human plasma (84% of total radioactivity AUC) and the morpholinone metabolite M1 was the only circulating metabolite (about 5%). Excretion of drug-derived radioactivity based on all 6 subjects was 86% of the dose within a collection interval of 20-34 days with 64% excreted into feces as major route of elimination and 22% into urine. Unchanged copanlisib was the main component excreted into urine (15% of dose) and feces (30% of dose). Excreted metabolites (41% of dose) of copanlisib resulted from oxidative biotransformation. Copanlisib was eliminated predominantly in the feces compared to urine as well as by hepatic biotransformation, suggesting that the clearance of copanlisib would more likely be affected by hepatic impairment than by renal dysfunction. The dual mode of elimination via unchanged excretion of copanlisib and oxidative metabolism decreases the risk of clinically relevant PK-related drug-drug interactions.

A double-tracer technique to characterize absorption, distribution, metabolism and excretion (ADME) of [14C]-basimglurant and absolute bioavailability after oral administration and concomitant intravenous microdose administration of [13C6]-labeled basimglurant in humans.

PubMed

Guerini, Elena; Schadt, Simone; Greig, Gerard; Haas, Ruth; Husser, Christophe; Zell, Manfred; Funk, Christoph; Hartung, Thomas; Gloge, Andreas; Mallalieu, Navita L

2017-02-01

1. The emerging technique of employing intravenous microdose administration of an isotope tracer concomitantly with an [ 14 C]-labeled oral dose was used to characterize the disposition and absolute bioavailability of a novel metabotropic glutamate 5 (mGlu5) receptor antagonist under clinical development for major depressive disorder (MDD). 2. Six healthy volunteers received a single 1 mg [ 12 C/ 14 C]-basimglurant (2.22 MBq) oral dose and a concomitant i.v. tracer dose of 100 μg of [ 13 C 6 ]-basimglurant. Concentrations of [ 12 C]-basimglurant and the stable isotope [ 13 C 6 ]-basimglurant were determined in plasma by a specific LC/MS-MS method. Total [ 14 C] radioactivity was determined in whole blood, plasma, urine and feces by liquid scintillation counting. Metabolic profiling was conducted in plasma, urine, blood cell pellet and feces samples. 3. The mean absolute bioavailability after oral administration (F) of basimglurant was ∼67% (range 45.7-77.7%). The major route of [ 14 C]-radioactivity excretion, primarily in form of metabolites, was in urine (mean recovery 73.4%), with the remainder excreted in feces (mean recovery 26.5%). The median t max for [ 12 C]-basimglurant after the oral administration was 0.71 h (range 0.58-1.00) and the mean terminal half-life was 77.2 ± 38.5 h. Terminal half-life for the [ 14 C]-basimglurant was 178 h indicating presence of metabolites with a longer terminal half-life. Five metabolites were identified with M1-Glucuronide as major and the others in trace amounts. There was minimal binding of drug to RBCs. IV pharmacokinetics was characterized with a mean ± SD CL of 11.8 ± 7.4 mL/h and a Vss of 677 ± 229 L. 4. The double-tracer technique used in this study allowed to simultaneously characterize the absolute bioavailability and disposition characteristics of the new oral molecular entity in a single study.

Estimating mineral requirements of Nellore beef bulls fed with or without inorganic mineral supplementation and the influence on mineral balance.

PubMed

Zanetti, D; Godoi, L A; Estrada, M M; Engle, T E; Silva, B C; Alhadas, H M; Chizzotti, M L; Prados, L F; Rennó, L N; Valadares Filho, S C

2017-04-01

The objectives of this study were to quantify the mineral balance of Nellore cattle fed with and without Ca, P, and micromineral (MM) supplementation and to estimate the net and dietary mineral requirement for cattle. Nellore cattle ( = 51; 270.4 ± 36.6 kg initial BW and 8 mo age) were assigned to 1 of 3 groups: reference ( = 5), maintenance ( = 4), and performance ( = 42). The reference group was slaughtered prior to the experiment to estimate initial body composition. The maintenance group was used to collect values of animals at low gain and reduced mineral intake. The performance group was assigned to 1 of 6 treatments: sugarcane as the roughage source with a concentrate supplement composed of soybean meal and soybean hulls with and without Ca, P, and MM supplementation; sugarcane as the roughage source with a concentrate supplement composed of soybean meal and ground corn with and without Ca, P, and MM supplementation; and corn silage as the roughage source with a concentrate supplement composed of soybean meal and ground corn with and without Ca, P, and MM supplementation. Orthogonal contrasts were adopted to compare mineral intake, fecal and urinary excretion, and apparent retention among treatments. Maintenance requirements and true retention coefficients were generated with the aid of linear regression between mineral intake and mineral retention. Mineral composition of the body and gain requirements was assessed using nonlinear regression between body mineral content and mineral intake. Mineral intake and fecal and urinary excretion were measured. Intakes of Ca, P, S, Cu, Zn, Mn, Co, and Fe were reduced in the absence of Ca, P, and MM supplementation ( < 0.05). Fecal excretion of Ca, Cu, Zn, Mn, and Co was also reduced in treatments without supplementation ( < 0.01). Overall, excretion and apparent absorption and retention coefficients were reduced when minerals were not supplied ( < 0.05). The use of the true retention coefficient instead of the true absorption coefficient provided a better estimate of mineral requirements. Dietary mineral requirements were lower for P, Cu, and Zn and greater for Fe compared with previously published recommendations. This study provides useful information about mineral requirements and mineral supplementation to obtain adequate dietary mineral supply of Nellore cattle in tropical conditions.

Dermal absorption and urinary elimination of N-methyl-2-pyrrolidone.

PubMed

Bader, Michael; Keener, Stephen A; Wrbitzky, Renate

2005-09-01

The dermal absorption of the solvent N-methyl-2-pyrrolidone (NMP) and its elimination in urine was investigated in an experimental study. Seven volunteers were exposed to 1045 mg of liquid NMP under occlusive conditions for 2 h. Urine was collected before, during and up to 72 h after the exposure and analysed for NMP by GC/MS after liquid-liquid extraction. Additionally, the remaining NMP in the pads was determined to estimate the total dermal uptake. The concentration of NMP in urine increased rapidly after beginning of the exposure up to 1 h after the exposure was completed. A peak concentration of 1,836+/-863 microg/l was observed, the half-life in urine was 3.2 h. About 0.5% of the absorbed dose was excreted metabolically unchanged. An average dermal absorption of 5.5 mg cm(-2) h(-1) was calculated. The results of this study show that the percutaneous absorption of NMP may contribute significantly to the overall uptake of the solvent, e.g. in the workplace. Therefore, a biological monitoring of NMP exposed workers is essential for occupational-medical surveillance.

Blanching improves anthocyanin absorption from highbush blueberry ( Vaccinium corymbosum L.) purée in healthy human volunteers: a pilot study.

PubMed

Del Bo', Cristian; Riso, Patrizia; Brambilla, Ada; Gardana, Claudio; Rizzolo, Anna; Simonetti, Paolo; Bertolo, Gianni; Klimis-Zacas, Dorothy; Porrini, Marisa

2012-09-12

Blueberries ( Vaccinium corymbosum L.) are rich sources of phenolics and anthocyanins (ACNs). We investigated the absorption of ACNs after consumption of one portion (300 g) of minimally processed blueberry purée (P) obtained from blanched (BL) or unblanched (NB) berries. A repeated-measures, crossover design study was conducted on healthy human volunteers. Blood was drawn between baseline and 24 h after BL-P or NB-P consumption, while urine were collected from the day before the experiment up to 48 h. Total plasma ACN content was not significantly different, while phenolics content was higher in BL-P with respect to NB-P. The maximum ACN absorption in plasma was observed after 1.5 h from the intake of the purées and was significantly higher (p ≤ 0.05) after the intake of BL-P. Both products increased the excretion of hippuric acid in urine. In conclusion, blanching had no significant effect on total ACN content and enhanced their absorption from minimally processed purées.

Development of Gastrointestinal Function: Risk Factors for Necrotizing Enterocolitis

PubMed Central

Clark, David A.; Mitchell, Amy L.

2004-01-01

The intestinal tract of the fetus matures rapidly in the third trimester of the pregnancy. The premature infant has decreased intestinal motility, limited digestion, absorption and excretion, and poor intestinal barrier defense. These limitations place the infant at high risk for acute intestinal injury, necrotizing enterocolitis. This article reviews the development of the gastrointestinal tract in the fetus, the barriers to feeding the high risk, premature infant, and the most serious intestinal disease, necrotizing enterocolitis. PMID:23118695

A Review of the Efficacy and Safety of Litramine IQP-G-002AS, an Opuntia ficus-indica Derived Fiber for Weight Management

PubMed Central

Gruenwald, Joerg; Uebelhack, Ralf

2014-01-01

Sedentary lifestyle and caloric overconsumption are the key determinants of the escalating obesity prevalence. Reducing dietary fat absorption may help to induce a negative energy balance and thus help in managing weight problem. Apart from approved drug therapies, weight problems may also be aided with alternative and natural treatments. This paper compiled and reviewed the efficacy and safety of Litramine IQP-G-002AS, an Opuntia ficus-indica (OFI) derived fiber, in reducing dietary fat absorption and promoting weight loss. Evidence reviewed shows that Litramine IQP-G-002AS displays efficacy in promoting fat excretion and weight loss in four randomized, placebo-controlled clinical studies (including an unpublished pilot study). With a daily dosage of 3 g over a seven-day period, Litramine IQP-G-002AS showed an increased faecal fat excretion compared with placebo (15.8% (SD 5.8%) versus 4.6% (SD 3.1%); P < 0.001). In a 12-week study, significant greater weight loss (3.8 kg (SD 1.8 kg) versus 1.4 kg (SD 2.6 kg); P < 0.001) was observed in overweight and obese subjects treated with Litramine IQP-G-002AS as compared to placebo. No relevant gastrointestinal side effects have been reported for Litramine IQP-G-002AS at the dosages studied. PMID:25254061

Oral Fructose Absorption in Obese Children with Non-Alcoholic Fatty Liver Disease

PubMed Central

Sullivan, Jillian S; Le, MyPhuong T; Pan, Zhaoxing; Rivard, Christopher; Love-Osborne, Kathryn; Robbins, Kristen; Johnson, Richard J; Sokol, Ronald J; Sundaram, Shikha S

2014-01-01

Background Fructose intake is associated with NAFLD (Non-Alcoholic Fatty Liver Disease) development. Objective To measure fructose absorption/metabolism in pediatric NAFLD compared to obese and lean controls. Methods Children with histologically proven NAFLD, and obese and lean controls received oral fructose (1 gm/kg ideal body weight). Serum glucose, insulin, uric acid, and fructose, urine uric acid, urine fructose, and breath hydrogen levels were measured at baseline and multiple points until 360 minutes after fructose ingestion. Results Nine NAFLD (89% Hispanic, mean age 14.3 years, mean BMI 35.3 kg/m2), 6 Obese Controls (67% Hispanic, mean age 12.7 years, mean BMI 31.0 kg/m2), and 9 Lean Controls (44% Hispanic, mean age 14.3 years, mean BMI 19.4 kg/m2) were enrolled. Following fructose ingestion, NAFLD vs. Lean Controls had elevated serum glucose, insulin, and uric acid (p<0.05), higher urine uric acid (p=0.001) but lower fructose excretion (p=0.002) and lower breath hydrogen 180-min AUC (p=0.04). NAFLD vs. Obese Controls had similar post-fructose serum glucose, insulin, urine uric acid, and breath hydrogen, but elevated serum uric acid (p<0.05) and lower urine fructose excretion (p=0.02). Conclusions Children with NAFLD absorb and metabolize fructose more effectively than lean subjects, associated with an exacerbated metabolic profile following fructose ingestion. PMID:24961681

Clinical value of dual-isotope fat absorption test system (FATS) using glycerol (/sup 125/I)trioleate and glycerol (/sup 75/Se)triether

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lembcke, B.; Loesler, A.C.; Caspary, W.F.

1986-08-01

In order to delineate the clinical value of a dual-isotope fat absorption test system (FATS) using glycerol (/sup 75/Se)triether as lipid-phase marker and glycerol (/sup 125/I)trioleate as the test lipid, fecal isotope ratios from single stools (and a 72-hr stool homogenate) were compared to quantitative fecal fat excretion. The study included 11 patients without and 24 patients with steatorrhea. With a figure of 0.8% as the upper limit of normal, the test was a reliable indicator of steatorrhea with 87.5% sensitivity and 81.8% specificity; efficiency was 85.7%. Related to a prevalence of steatorrhea of 45.9% as the mean value ofmore » 1269 consecutive 72-hr specimens investigated for steatorrhea during 1978-1982, the positive (negative) predictive value of the FATS is 80.3% (87.2%). With 2% as the upper limit of normal, no false positive results ensued. It is concluded that a two-step interpretation of the FATS (0.8% limit and 2% limit) may be regarded a valid qualitative index for steatorrhea. The FATS isotope ratio using single stools correlated well with FATS ratios in the 72-hr stool homogenates (r = 0.97). FATS therefore allows a convenient estimate of steatorrhea from measuring single stools. As a quantitative measure of fecal fat excretion, the FATS is unreliable.« less

Pharmacokinetics, distribution, metabolism, and excretion of the dual reuptake inhibitor [(14)C]-nefopam in rats.

PubMed

Yu, Jian; Solon, Eric; Shen, Helen; Modi, Nishit B; Mittur, Aravind

2016-11-01

1. This study examined the pharmacokinetics, distribution, metabolism, and excretion of [(14)C] nefopam in rats after a single oral administration. Blood, plasma, and excreta were analyzed for total radioactivity, nefopam, and metabolites. Metabolites were profiled and identified. Radioactivity distribution was determined by quantitative whole-body autoradiography. 2. The pharmacokinetic profiles of total radioactivity and nefopam were similar in male and female rats. Radioactivity partitioned approximately equally between plasma and red blood cells. A majority of the radioactivity was excreted in urine within 24 hours and mass balance was achieved within 7 days. 3. Intact nefopam was a minor component in plasma and excreta. Numerous metabolites were identified in plasma and urine generated by multiple pathways including: hydroxylation/oxidation metabolites (M11, M22a and M22b, M16, M20), some of which were further glucuronidated (M6a to M6c, M7a to M7c, M8a and M8b, M3a to M3d); N-demethylation of nefopam to metabolite M21, which additionally undergoes single or multiple hydroxylations or sulfation (M9, M14, M23), with some of the hydroxylated metabolites further glucuronidated (M2a to M2d). 4. Total radioactivity rapidly distributed with highest concentrations found in the urinary bladder, stomach, liver, kidney medulla, small intestine, uveal tract, and kidney cortex without significant accumulation or persistence. Radioactivity reversibly associated with melanin-containing tissues.

Carbohydrate derived energy and gross energy absorption in preterm infants fed human milk or formula.

PubMed Central

De Curtis, M; Senterre, J; Rigo, J; Putet, G

1986-01-01

Significant production of breath hydrogen has been shown in premature infants, suggesting limited intestinal capacity for digestion of carbohydrate. To evaluate net absorption of carbohydrate 24 three day balance studies were carried out in seven preterm infants fed pasteurised banked human milk and in 17 preterm infants fed a formula containing 75% lactose and 25% glucose polymers. Because carbohydrate reaching the colon may be converted to organic acids by bacterial flora, carbohydrate net absorption was determined by quantitating the faecal excretion of energy derived from carbohydrate. The carbohydrate derived energy content of milk and stools was calculated as the difference between the measured gross energy and the sum of energy related to nitrogen and fat. Faecal loss of carbohydrate derived energy was lower in the group fed formula (1.9 (SD 1.2) kcal/kg/day) than in the group fed human milk (4.0 (SD 1.8) kcal/kg/day). Net absorption of carbohydrate derived energy was 97.0 (SD 1.9)% as opposed to 92.6 (SD 3.9)%, respectively. Within each group there was no significant relation between carbohydrate energy absorption and fat, nitrogen, or gross energy absorption. Thus, although less complete with human milk than with formula, apparent absorption of energy derived from carbohydrate seemed quite satisfactory in these preterm infants. PMID:3639729

Urinary protein excretion profile: A contribution for subclinical renal damage identification among environmental heavy metals exposure in Southeast Brazil

NASA Astrophysics Data System (ADS)

Garlipp, C. R.; Bottini, P. V.; de Capitan, E. M.; Pinho, M. C.; Panzan, A. D. N.; Sakuma, A. M. A.; Paoliello, M. B.

2003-05-01

In Southeast Brazil. Ribeira Valley region has been a major public health concern due to he environmental heavy metals contamination indexes of vegetation, rocks and aquifers, caused by locai mining in the past. Human contamination low levels of heavy rnetals doesn't cause acute intoxication but ni chronic exposure, renal damage may occur with progressive tubuJointerstitial changes evolvil1g to glomemlar 1esiol1, ln this stndy we invesligated the relationship between thc profile of utillan, excreted proteins (glomerular or lubular origin) of arsenic and mercury and blood lead concentration in chiJdren and adults from highly e) qJosed regions of the Ribeira Valley. The subjects were classieed as GROUP 1 (GI; higher environmental risk n=333) and GROUP 2 (G2; lower risk of contamination. n=104). In order to determine the urinary excretion of total protein, albumin (MA, glomerular marker) and alpha i microglobulin (AIM, tubular marker) and the blood lead concentrations. random wine and blood samples were obtaiiied. Plasmatic lead levels were assessed by atomic absorption spectrometty with graphite fumace. Totai protein concentration (PROT) was assessed on a biochemical analyzer ,progallol red method). MA and AIM were determined by nephelometric method. Croup 1 showcd a higher frequency of altered urinary excretion of PROT (GI=3.4%; G2=1.0%), MA (Gl=9.0%; G2=5.1%) and AIM (Gt=7.5%, G2=3.8%), without significant differences between both groups. Elevated arscnic levels were more prevaient among subjects from Group 1 (2.8.8%) and demonstrated a significant corrolation with abiiormal iirinarv excretion of ilbumin and alpha-l-micrglobulin (p=0.019).Leadaand mercury levels showed no difference among the groups and no correlation will MAa and/or M. Oti-c dala suggests that abnormal itrinary protein excretion is relatively frequent in this population independently of the plasmatic or urinaryl heavy metal levels. The early detection of possible renal damage become necessary for effective measures can be taken to prevent clinical nephropathies.

Oxalate and Sucralose Absorption in Idiopathic Calcium Oxalate Stone Formers

PubMed Central

Knight, John; Jiang, Juquan; Wood, Kyle D.; Holmes, Ross P.; Assimos, Dean G.

2011-01-01

Objectives Oxalate has been hypothesized to undergo absorption in the large and small intestine by both paracellular and transepithelial transport. Sucralose is a chlorinated sugar that is absorbed by paracellular mechanisms. This study's objective was to better understand intestinal oxalate transport by correlating oxalate and sucralose absorption in idiopathic calcium oxalate stone formers. Methods Idiopathic calcium oxalate stone formers were recruited to provide urine specimens on both a self-selected diet and following a meal containing 90 mg of 13C2-oxalate and 5 grams of sucralose, and a stool sample for determination of Oxalobacter formigenes colonization. The 24 hour urine collections were fractionated into the first 6 hours and the subsequent 18 hours. Sucralose and oxalate excretion were measured during these periods and used to estimate absorption. Results A total of 38 subjects were evaluated. The majority of both the 13C2-oxalate and sucralose absorption occurred within the 0-6 hour collection. The 13C2-oxalate and sucralose absorptions were significantly correlated at the 0-6 hour, the 6-24 hour, and the total 24 hour time periods (p<0.04). All five oxalate hyperabsorbers(> 15% absorption) also absorbed significantly more sucralose during the 0-6 hour and whole 24 hour time points (p<0.04). Oxalobacter formigenes colonization did not significantly alter oxalate absorption. Conclusion The results suggest that the majority of oxalate is absorbed in the proximal portion of the gastrointestinal tract and that paracelluar transport is involved. Augmented paracellular transport, as evidenced by increased sucralose absorption, may also influence oxalate absorption. PMID:21676449

Excretion of (3H)prednisolone in clinically normal and experimentally infected bovine udders

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geleta, J.N.; Shimoda, W.; Mercer, H.D.

1984-08-01

The excretion rate of (3H)prednisolone from clinically normal and experimentally infected udders of 10 lactating cows was studied. Each quarter of 6 cows was injected with a single dose of (3H)prednisolone mixed with non-radioactive prednisolone equivalent to 10 mg in 10 ml of peanut oil base. Each of the remaining 4 cows was given 40 mg of nonradioactive prednisolone and (3H)prednisolone in 60% ethanol IV. Control and postadministration samples of blood, milk, and urine were examined for radioactivity. The effects of (3H)prednisolone were evaluated in the same cows, first in clinically normal udders, then 2 weeks later in udders experimentallymore » infected with Streptococcus agalactiae. Absorption and elimination of prednisolone were the same before and after induced infection. Within 3 hours after intramammary injection, 95% of the labeled prednisolone was absorbed systemically, less than 5% of this dose was recovered in milk, and 29% was excreted in urine. After IV injection of (3H)prednisolone, less than 0.2% of the total radioactivity was recovered in milk and less than 46% was excreted in urine. Clinical mastitis induced by S agalactiae was moderate. Circulating blood leukocytes and somatic cells in the milk of normal cows remained essentially unchanged. The leukocyte response to induced infection was rapid in blood and milk. Large numbers of leukocytes were noticed in the milk and a severe leukopenia occurred. Prednisolone treatment did not alter the number of somatic cells in milk or reduce the inflammatory response of experimentally infected cows.« less

Blueberry anthocyanins at doses of 0.5 and 1 % lowered plasma cholesterol by increasing fecal excretion of acidic and neutral sterols in hamsters fed a cholesterol-enriched diet.

PubMed

Liang, Yintong; Chen, Jingnan; Zuo, Yuanyuan; Ma, Ka Ying; Jiang, Yue; Huang, Yu; Chen, Zhen-Yu

2013-04-01

The present study investigated the underlying mechanism associated with the hypocholesterolemic activity of blueberry anthocyanins by examining its effect on fecal sterol excretion and gene expression of major receptors, enzymes, and transporters involved in cholesterol metabolism. Hamsters were divided into three groups and fed a 0.1 % cholesterol diet containing 0 % (CTL), 0.5 % (BL), and 1.0 % (BH) blueberry anthocyanins, respectively, for six weeks. Plasma total cholesterol (TC), triacylglycerols (TAG), and non-high-density lipoproteins cholesterol (non-HDL-C) were measured using the enzymatic kits, and the gene expression of transporters, enzymes, and receptors involved in cholesterol absorption and metabolism was quantified using the quantitative PCR. GC analysis was used to quantify hepatic cholesterol and fecal acidic and neutral sterols. Dietary supplementation of 0.5 and 1.0 % blueberry anthocyanins for 6 weeks decreased plasma TC concentration by 6-12 % in a dose-dependent manner. This was accompanied by increasing the excretion of fecal neutral and acidic sterols by 22-29 % and 41-74 %, respectively. Real-time PCR analyses demonstrated that incorporation of blueberry anthocyanins into diet down-regulated the genes of NPC1L1, ACAT-2, MTP, and ABCG 8. In addition, blueberry anthocyanins were also able to down-regulate the gene expression of hepatic HMG-CoA reductase. The cholesterol-lowering activity of blueberry anthocyanins was most likely mediated by enhancing the excretion of sterols accompanied with down-regulation on gene expression of intestinal NPC1L1, ACAT-2, MTP, and ABCG 8.

A method for assessing real time rates of dissolution and absorption of carbohydrate and other food matrices in human subjects.

PubMed

Lentle, R G; Sequeira, I R; Hardacre, A K; Reynolds, G

2016-06-15

We prepared pasta of differing physical dimensions but identical chemical composition that contained two monosaccharide probes (lactulose and mannitol) that are absorbed passively and promptly excreted in urine. We showed that the rates of their liberation from the pasta under simulated gastric and small intestinal conditions largely depended upon the rate of digestion of the starchy matrix. We showed, in 20 female subjects, that excretion of mannitol was slower from the pasta with the larger particle size. Hence, after consumption of either the powdered pasta or the simple solution of probe sugars, the mass of mannitol excreted between 1 and 2½ hours was greater than that excreted between 2½ and 4 hours. However these masses did not differ significantly after consumption of the pasta pellets. These differences were not reflected in the concurrent patterns of variation in either serum glucose or insulin taken over 120 minutes, their levels being similar for pasta pellets and powder with their peak values occurring synchronously during the first hour. Hence feeding test foods impregnated with lactulose and mannitol probes provided a reproducible and practical means of assessing the timing of digestion of the carbohydrate matrix and showed that this was more protracted than suggested by post prandial glucose levels. Further, the transit times calculated on a basis of the ratios of the two marker sugars could identify that the prolongation of digestion of larger particles was not accompanied by retention of digesta in particular segments of the gut.

Nifedipine Increases Iron Content in WKPT-0293 Cl.2 Cells via Up-Regulating Iron Influx Proteins

PubMed Central

Yu, Shuang-Shuang; Jiang, Li-Rong; Ling, Yan; Qian, Zhong-Ming; Zhou, Yu-Fu; Li, Juan; Ke, Ya

2017-01-01

Nifedipine was reported to enhance urinary iron excretion in iron overloaded mice. However, it remains unknown how nifedipine stimulates urinary iron excretion in the kidney. We speculated that nifedipine might inhibit the TfR1/ DMT1 (transferrin receptor 1/divalent metal transporter1)-mediated iron uptake by proximal tubule cells in addition to blocking L-type Ca2+ channels, leading to an increase in iron in lumen-fluid and then urinary iron excretion. To test this hypothesis, we investigated the effects of nifedipine on iron content and expression of TfR1, DMT1 and ferroportin1 (Fpn1) in WKPT-0293 Cl.2 cells of the S1 segment of the proximal tubule in rats, using a graphite furnace atomic absorption spectrophotometer and Western blot analysis, respectively. We demonstrated for the first time that nifedipine significantly enhanced iron content as well as TfR1 and DMT1 expression and had no effect on Fpn1 levels in the cells. We also found that ferric ammonium citrate decreased TfR1 levels, increased Fpn1 expression and had no effect on DMT1 content, while co-treatment with nifedipine and FAC increase TfR1 and DMT1 expression and also had no effect on Fpn1 levels. These findings suggest that the nifedipine-induced increase in cell iron may mainly be due to the corresponding increase in TfR1 and DMT1 expression and also imply that the effects of nifedipine on iron transport in proximal tubule cells can not explain the increase in urinary iron excretion. PMID:28243203

Intestinal Adaptations in Chronic Kidney Disease and the Influence of Gastric Bypass Surgery

PubMed Central

Hatch, Marguerite

2015-01-01

Studies have shown that compensatory adaptations in gastrointestinal oxalate transport can impact the amount of oxalate excreted by the kidney. Hyperoxaluria is a major risk factor in the formation of kidney stones and oxalate is derived from both the diet as well as from liver metabolism of glyoxylate. Although the intestine generally absorbs oxalate from dietary sources, and can contribute as much as 50% of urinary oxalate, enteric oxalate elimination plays a significant role when renal function is compromised. While the mechanistic basis for these changes in the direction of intestinal oxalate movements in chronic renal failure involves an up-regulation of angiotensin II (ANG) receptors in the large intestine, enteric secretion/excretion of oxalate can also occur by mechanisms that are independent of ANG II. Most notably, the commensal bacterium Oxalobacter sp. interacts with the host enterocyte and promotes the movement of oxalate from blood into the lumen resulting in the beneficial effect of significantly lowering urinary oxalate excretion. Changes in the passive permeability of the intestine such as in steatorrhea and following gastric bypass also promote oxalate absorption and hyperoxaluria. In summary, this report highlights the two-way physiological signaling between the gut and the kidney which may help to alleviate the consequences of certain kidney diseases. PMID:24951497

Urinary levels of nickel and chromium associated with dental restoration by nickel–chromium based alloys

PubMed Central

Chen, Bo; Xia, Gang; Cao, Xin-Ming; Wang, Jue; Xu, Bi-Yao; Huang, Pu; Chen, Yue; Jiang, Qing-Wu

2013-01-01

This paper aims to investigate if the dental restoration of nickel–chromium based alloy (Ni–Cr) leads to the enhanced excretions of Ni and Cr in urine. Seven hundred and ninety-five patients in a dental hospital had single or multiple Ni–Cr alloy restoration recently and 198 controls were recruited to collect information on dental restoration by questionnaire and clinical examination. Urinary concentrations of Ni and Cr from each subject were measure by graphite furnace atomic absorption spectrometry. Compared to the control group, the urinary level of Ni was significantly higher in the patient group of <1 month of the restoration duration, among which higher Ni excretions were found in those with either a higher number of teeth replaced by dental alloys or a higher index of metal crown not covered with the porcelain. Urinary levels of Cr were significantly higher in the three patient groups of <1, 1 to <3 and 3 to <6 months, especially in those with a higher metal crown exposure index. Linear curve estimations showed better relationships between urinary Ni and Cr in patients within 6-month groups. Our data suggested significant increased excretions of urinary Ni and Cr after dental restoration. Potential short- and long-term effects of Ni–Cr alloy restoration need to be investigated. PMID:23579466

The effects of changing ration ingredients on acid-base status, renal function, and macromineral metabolism.

PubMed

Delaquis, A M; Block, E

1995-09-01

Ten Holstein and 2 Ayrshire cows were used in a switchback design to compare diets based on alfalfa haylage and corn silage. Both diets had a similar cation-anion difference and contained 1% NaHCO3. Dietary treatment did not affect DMI, DM digestibility, milk production, or milk composition. Intake, absorption, and urinary excretion of N were significantly increased by the ration based on haylage, but the overall balance remained unaffected. Cows consuming haylage absorbed and excreted significantly more water than did cows consuming corn silage and consequently had significantly larger urine volumes. Blood volume was increased by the ration based on haylage. Intakes of Mg, K, Cl, and S differed between diets, but only K balance was increased by the diet based on haylage. The fractional excretion of K, Cl, and S in urine was increased by the diet based on haylage, demonstrating that the kidneys responded to the increased intakes by diminishing the reabsorption or by increasing the secretion of these minerals. Acid-base parameters for blood, urine, and milk were unaffected by dietary treatment. A diet based on alfalfa haylage, compared with a diet based on corn silage with similar cation-anion difference, resulted in different water and mineral metabolism but did not affect the acid-base status of cows in early lactation.

Carbohydrate absorption from one serving of fruit juice in young children: age and carbohydrate composition effects.

PubMed

Nobigrot, T; Chasalow, F I; Lifshitz, F

1997-04-01

To test the hypotheses that: the efficiency of carbohydrate absorption in childhood increases with age, and decreased carbohydrate absorption occurs more frequently with juices containing more fructose than glucose and/or sorbitol than with juices which contain equal amounts of fructose and glucose and are sorbitol-free. One hundred and four healthy children were recruited from the Ambulatory Center at Maimonides Children's Center. They were assigned to one of three age groups: approximately 1, 3 and 5 years of age. Each child received one age-specific dose (by randomization) of one of four juices: a) pear juice which contains fructose in excess to glucose and a large amount of sorbitol; b) apple juice which is similar to pear juice in its fructose to glucose ratio but contains four times less sorbitol than pear juice; c) white grape juice or d) purple grape juice both of which contain equal amounts of fructose and glucose and are sorbitol-free. Breath hydrogen excretion (BH2) was utilized as the index of carbohydrate absorption. It was measured in fasting children and at 30-minute intervals for 3 hours after drinking the single serving of juice. Multiple breath hydrogen related parameters were quantified and results were expressed as: BH2 peak, area under the curve, and degree of carbohydrate malabsorption. After the test, parents completed a questionnaire and recorded signs and symptoms of intestinal malabsorption for 24 hours. Pear juice related BH2 levels were significantly higher among children 1 and 3 years of age as compared to the levels achieved after the other juices. Apple juice related BH2 levels were significantly higher only among the youngest age group of children. There was no significant difference in carbohydrate absorption among the 5 year old children regardless of the juice consumed. Incomplete carbohydrate absorption (BH2 peak above 20 ppm) occurred more frequently after pear juice consumption (84%) than after apple juice (41%) or grape juice (white 20%, purple 24%) [p < 0.05]. Further outcome measures of BH2 excretion did not elicit differences beyond those detected by the above-mentioned parameters. Parents reported diarrhea in six children after pear juice, two after apple juice and two after purple grape juice and these children had the highest BH2 levels in their respective groups. No other symptoms were reported. The data show that the efficiency of carbohydrate absorption of one age-specific serving of juice increases with advancing age of children. Decreased carbohydrate absorption occurs more often after ingestion of juices that contain more sorbitol, a nonabsorbable sugar and higher concentrations of fructose over glucose than after ingestion of juices which lack sorbitol and contain equal amounts of fructose and glucose.

Studies of the prevalence and significance of radiolabeled bile acid malabsorption in a group of patients with idiopathic chronic diarrhea

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schiller, L.R.; Hogan, R.B.; Morawski, S.G.

1987-01-01

We studied radiolabeled fecal bile acid excretion in 11 normal subjects and 17 patients with idiopathic chronic diarrhea for three major purposes: to establish normal values for this test in the presence of increased stool volumes (induced in normal subjects by ingestion of poorly absorbable solutions); to test for bile acid malabsorption in the patients and to correlate this with an independent test of ileal function, the Schilling test; and to compare the results of the bile acid excretion test with the subsequent effect of a bile acid binding agent (cholestyramine) on stool weight. In normal subjects fecal excretion ofmore » the radiolabel was increased with increasing stool volumes. As a group, patients with idiopathic chronic diarrhea excreted radiolabeled bile acid more rapidly than normal subjects with induced diarrhea (t1/2 56 +/- 8 vs. 236 +/- 60 h, respectively, p less than 0.005). There was a statistically significant positive correlation between t1/2 of radiolabeled bile acid and Schilling test results in these patients. Although 14 of 17 patients absorbed labeled taurocholic acid less well than any of the normal subjects with comparable volumes of induced diarrhea, cholestyramine had no statistically significant effect on stool weight in the patient group, and in none of the patients was stool weight reduced to within the normal range. In summary, most patients with idiopathic chronic diarrhea have bile acid malabsorption (as measured by fecal excretion of labeled bile acid), but they do not respond to cholestyramine therapy with a significant reduction in stool weight. Although the significance of these findings was not clearly established, the most likely interpretation is that bile acid malabsorption is a manifestation of an underlying intestinal motility or absorptive defect rather than the primary cause of diarrhea.« less

Pharmacokinetics, Metabolism, Distribution and Permeability of Nanomedicine.

PubMed

Ravindran, Selvan; Suthar, Jitendra Kumar; Rokade, Rutuja; Deshpande, Pooja; Singh, Pooja; Pratinidhi, Ashutosh; Khambadkhar, Rajeshree; Utekar, Srushti

2018-01-01

Medical application of nanotechnology is termed as Nanomedicine and is widely used in healthcare industries. Nanotechnology has helped Physicians, Scientists and Technologists to understand the changes in cellular levels to develop nanomedicines and address the challenges faced by the healthcare sectors. Nanoparticles with less than 1nm in size have been used as drug delivery and gene delivery systems to accelerate the drug action in humans. Size of nanomaterials is akin to that of biomolecules and expected to have better interactions. Hence, its utility for various biomedical applications is explored. Pharmacokinetics, metabolism, permeability, distribution and elimination studies of nanoparticles are essential to understand its potency, toxicity threshold and confirm its safe use in humans. Reports were available for toxicity studies on nanoparticles, but work on metabolism, pharmacokinetics, distribution and permeability of nanomedicine is limited. Hence, the main focus of this review article is about metabolism, pharmacokinetics, permeability and biodistribution of nanomaterials used in nanomedicine. Nanomedicine is increasingly becoming important in the treatment of diseases and diagnosis. Size of the particle plays an important role. As the particle size decreases its effect to cure the disease increases. Pharmacokinetics, bioavailability, half-life, metabolism, biodistribution and permeability of nanomedicine were found to be better than that of microsized drugs. In vitro and In vivo ADME (Absorption, Distribution, Metabolism and Excretion) studies are mandatory for pharmaceutical organic drugs. Similarly, nanomaterials should be subjected to both in vitro and in vivo ADME studies. Thus, nanomedicine can assist in the development of safe personalized medicine in humans. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Toward antituberculosis drugs: in silico screening of synthetic compounds against Mycobacterium tuberculosisl,d-transpeptidase 2.

PubMed

Billones, Junie B; Carrillo, Maria Constancia O; Organo, Voltaire G; Macalino, Stephani Joy Y; Sy, Jamie Bernadette A; Emnacen, Inno A; Clavio, Nina Abigail B; Concepcion, Gisela P

2016-01-01

Mycobacterium tuberculosis (Mtb) the main causative agent of tuberculosis, is the main reason why this disease continues to be a global public health threat. It is therefore imperative to find a novel antitubercular drug target that is unique to the structural machinery or is essential to the growth and survival of the bacterium. One such target is the enzyme l,d-transpeptidase 2, also known as LdtMt2, a protein primarily responsible for the catalysis of 3→3 cross-linkages that make up the mycolyl-arabinogalactan-peptidoglycan complex of Mtb. In this study, structure-based pharmacophore screening, molecular docking, and in silico toxicity evaluations were employed in screening compounds from a database of synthetic compounds. Out of the 4.5 million database compounds, 18 structures were identified as high-scoring, high-binding hits with very satisfactory absorption, distribution, metabolism, excretion, and toxicity properties. Two out of the 18 compounds were further subjected to in vitro bioactivity assays, with one exhibiting a good inhibitory activity against the Mtb H37Ra strain.

Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

PubMed Central

Williams, Charles H.; Hong, Charles C.

2011-01-01

In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET) properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design. PMID:21731440

Pharmacophore-based virtual screening of catechol-o-methyltransferase (COMT) inhibitors to combat Alzheimer's disease.

PubMed

Patel, Chirag N; Georrge, John J; Modi, Krunal M; Narechania, Moksha B; Patel, Daxesh P; Gonzalez, Frank J; Pandya, Himanshu A

2017-12-27

Alzheimer's disease (AD) is one of the most significant neurodegenerative disorders and its symptoms mostly appear in aged people. Catechol-o-methyltransferase (COMT) is one of the known target enzymes responsible for AD. With the use of 23 known inhibitors of COMT, a query has been generated and validated by screening against the database of 1500 decoys to obtain the GH score and enrichment value. The crucial features of the known inhibitors were evaluated by the online ZINC Pharmer to identify new leads from a ZINC database. Five hundred hits were retrieved from ZINC Pharmer and by ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering by using FAF-Drug-3 and 36 molecules were considered for molecular docking. From the COMT inhibitors, opicapone, fenoldopam, and quercetin were selected, while ZINC63625100_413 ZINC39411941_412, ZINC63234426_254, ZINC63637968_451, and ZINC64019452_303 were chosen for the molecular dynamics simulation analysis having high binding affinity and structural recognition. This study identified the potential COMT inhibitors through pharmacophore-based inhibitor screening leading to a more complete understanding of molecular-level interactions.

Identification of novel indole based heterocycles as selective estrogen receptor modulator.

PubMed

Singla, Ramit; Prakash, Kunal; Bihari Gupta, Kunj; Upadhyay, Shishir; Dhiman, Monisha; Jaitak, Vikas

2018-04-24

In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-α competitor assay kit by utilizing estrogen receptor-α (ER-α) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells). Cell imaging experiment suggested that both the compounds successfully cross cellular biomembrane and accumulate in nuclear, cytoplasmic and plasma membrane region. Semiquantitative RT-PCR and Western blotting experiments further supported that both compounds reduced the expression of mRNA and receptor protein of ER-α, thereby preventing downstream transactivation and signaling pathway in T47D cells line. Current findings imply that 5c and 6d represent novel ER-α antagonists and may be used in the development of chemotherapy for the management of BC. Copyright © 2018 Elsevier Inc. All rights reserved.

Biogeochemical spatio-temporal transformation of copper in Aspergillus niger colonies grown on malachite with different inorganic nitrogen sources.

PubMed

Fomina, Marina; Bowen, Andrew D; Charnock, John M; Podgorsky, Valentin S; Gadd, Geoffrey M

2017-03-01

This work elucidates spatio-temporal aspects of the biogeochemical transformation of copper mobilized from malachite (Cu 2 (CO 3 )(OH) 2 ) and bioaccumulated within Aspergillus niger colonies when grown on different inorganic nitrogen sources. It was shown that the use of either ammonium or nitrate determined how copper was distributed within the colony and its microenvironment and the copper oxidation state and succession of copper coordinating ligands within the biomass. Nitrate-grown colonies yielded ∼1.7× more biomass, bioaccumulated ∼7× less copper, excreted ∼1.9× more oxalate and produced ∼1.75× less water-soluble copper in the medium in contrast to ammonium-grown colonies. Microfocus X-ray absorption spectroscopy revealed that as the mycelium matured, bioaccumulated copper was transformed from less stable and more toxic Cu(I) into less toxic Cu(II) which was coordinated predominantly by phosphate/malate ligands. With time, a shift to oxalate coordination of bioaccumulated copper occurred in the central older region of ammonium-grown colonies. © 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.

A review of nanoelectrospray ionization applications for drug metabolism and pharmacokinetics.

PubMed

Wickremsinhe, Enaksha R; Singh, Gurkeerat; Ackermann, Bradley L; Gillespie, Todd A; Chaudhary, Ajai K

2006-12-01

Although traditionally reserved for proteomic analysis, nanoESI has found increased use for small molecule applications related to drug metabolism/pharmacokinetics (DMPK). NanoESI, which refers to ESI performed at flow rates in the range of 200 to 1000 nL/min using smaller diameter emitters (10 to 100 microm id), produces smaller droplets than conventional ESI resulting in more efficient ionization. Benefits include greater sensitivity, enhanced dynamic range, and a reduced competition for ionization. These advantages may now be harnessed largely due to the introduction of a commercial system for automated nanoESI infusion. This development in turn has allowed ADME (absorption, distribution, metabolism, and excretion) scientists to consider novel approaches to mass spectrometric analysis without direct LC interfacing. While it is freely acknowledged that nanoESI infusion is not likely to supplant LC-MS as the primary analytical platform for ADME, nanoESI infusion has been successfully applied to both quantitative (bioanalysis) and qualitative (metabolite identification) applications. This review summarizes published applications of this technology and offers a perspective on where it fits best into the DMPK laboratory.

Bioengineered humanized livers as better three-dimensional drug testing model system.

PubMed

Vishwakarma, Sandeep Kumar; Bardia, Avinash; Lakkireddy, Chandrakala; Nagarapu, Raju; Habeeb, Md Aejaz; Khan, Aleem Ahmed

2018-01-27

To develop appropriate humanized three-dimensional ex-vivo model system for drug testing. Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses. The bioengineered humanized livers showed cellular and molecular characteristics of human livers. The bioengineered liver showed three-dimensional natural architecture with intact vasculature and extra-cellular matrix. Human hepatic cells were engrafted similar to the human liver. Drug metabolism studies provided a suitable platform alternative to available ex-vivo and in vivo models for identifying cellular and molecular dynamics of pharmacological drugs. The present study paves a way towards the development of suitable humanized preclinical model systems for pharmacological testing. This approach may reduce the cost and time duration of preclinical drug testing and further overcomes on the anatomical and physiological variations in xenogeneic systems.

Gaussian processes: a method for automatic QSAR modeling of ADME properties.

PubMed

Obrezanova, Olga; Csanyi, Gabor; Gola, Joelle M R; Segall, Matthew D

2007-01-01

In this article, we discuss the application of the Gaussian Process method for the prediction of absorption, distribution, metabolism, and excretion (ADME) properties. On the basis of a Bayesian probabilistic approach, the method is widely used in the field of machine learning but has rarely been applied in quantitative structure-activity relationship and ADME modeling. The method is suitable for modeling nonlinear relationships, does not require subjective determination of the model parameters, works for a large number of descriptors, and is inherently resistant to overtraining. The performance of Gaussian Processes compares well with and often exceeds that of artificial neural networks. Due to these features, the Gaussian Processes technique is eminently suitable for automatic model generation-one of the demands of modern drug discovery. Here, we describe the basic concept of the method in the context of regression problems and illustrate its application to the modeling of several ADME properties: blood-brain barrier, hERG inhibition, and aqueous solubility at pH 7.4. We also compare Gaussian Processes with other modeling techniques.

Emerging aspects of nanotoxicology in health and disease: From agriculture and food sector to cancer therapeutics.

PubMed

Piperigkou, Zoi; Karamanou, Konstantina; Engin, Ayse Basak; Gialeli, Chrysostomi; Docea, Anca Oana; Vynios, Demitrios H; Pavão, Mauro S G; Golokhvast, Kirill S; Shtilman, Mikhail I; Argiris, Athanassios; Shishatskaya, Ekaterina; Tsatsakis, Aristidis M

2016-05-01

Nanotechnology is an evolving scientific field that has allowed the manufacturing of materials with novel physicochemical and biological properties, offering a wide spectrum of potential applications. Properties of nanoparticles that contribute to their usefulness include their markedly increased surface area in relation to mass, surface reactivity and insolubility, ability to agglomerate or change size in different media and enhanced endurance over conventional-scale substance. Here, we review nanoparticle classification and their emerging applications in several fields; from active food packaging to drug delivery and cancer research. Nanotechnology has exciting therapeutic applications, including novel drug delivery for the treatment of cancer. Additionally, we discuss that exposure to nanostructures incorporated to polymer composites, may result in potential human health risks. Therefore, the knowledge of processes, including absorption, distribution, metabolism and excretion, as well as careful toxicological assessment is critical in order to determine the effects of nanomaterials in humans and other biological systems. Expanding the knowledge of nanoparticle toxicity will facilitate designing of safer nanocomposites and their application in a beneficial manner. Copyright © 2016 Elsevier Ltd. All rights reserved.

Omics Approaches To Probe Microbiota and Drug Metabolism Interactions.

PubMed

Nichols, Robert G; Hume, Nicole E; Smith, Philip B; Peters, Jeffrey M; Patterson, Andrew D

2016-12-19

The drug metabolism field has long recognized the beneficial and sometimes deleterious influence of microbiota in the absorption, distribution, metabolism, and excretion of drugs. Early pioneering work with the sulfanilamide precursor prontosil pointed toward the necessity not only to better understand the metabolic capabilities of the microbiota but also, importantly, to identify the specific microbiota involved in the generation and metabolism of drugs. However, technological limitations important for cataloging the microbiota community as well as for understanding and/or predicting their metabolic capabilities hindered progress. Current advances including mass spectrometry-based metabolite profiling as well as culture-independent sequence-based identification and functional analysis of microbiota have begun to shed light on microbial metabolism. In this review, case studies will be presented to highlight key aspects (e.g., microbiota identification, metabolic function and prediction, metabolite identification, and profiling) that have helped to clarify how the microbiota might impact or be impacted by drug metabolism. Lastly, a perspective of the future of this field is presented that takes into account what important knowledge is lacking and how to tackle these problems.

Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors.

PubMed

Tashima, Toshihiko; Murata, Hiroaki; Kodama, Hidehiko

2014-07-15

Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038μM; HDAC2, 0.0082μM; HDAC3, 0.015μM; HDAC8, 0.0060μM; HDAC4, 0.058μM; HDAC9, 0.0052μM; HDAC6, 0.058μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process. Copyright © 2014 Elsevier Ltd. All rights reserved.

American Association of Pharmaceutical Scientists National Biotechnology Conference Short Course: Translational Challenges in Developing Antibody-Drug Conjugates: May 24, 2012, San Diego, CA.

PubMed

Thudium, Karen; Bilic, Sanela; Leipold, Douglas; Mallet, William; Kaur, Surinder; Meibohm, Bernd; Erickson, Hans; Tibbitts, Jay; Zhao, Hong; Gupta, Manish

2013-01-01

The American Association of Pharmaceutical Scientists (AAPS) National Biotechnology Conference Short Course "Translational Challenges in Developing Antibody-Drug Conjugates (ADCs)," held May 24, 2012 in San Diego, CA, was organized by members of the Pharmacokinetics, Pharmacodynamics and Drug Metabolism section of AAPS. Representatives from the pharmaceutical industry, regulatory authorities, and academia in the US and Europe attended this short course to discuss the translational challenges in ADC development and the importance of characterizing these molecules early in development to achieve therapeutic utility in patients. Other areas of discussion included selection of target antigens; characterization of absorption, distribution, metabolism, and excretion; assay development and hot topics like regulatory perspectives and the role of pharmacometrics in ADC development. MUC16-targeted ADCs were discussed to illustrate challenges in preclinical development; experiences with trastuzumab emtansine (T-DM1; Genentech) and the recently approved brentuximab vedotin (Adcetris; Seattle Genetics) were presented in depth to demonstrate considerations in clinical development. The views expressed in this report are those of the participants and do not necessarily represent those of their affiliations.

SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules

PubMed Central

Daina, Antoine; Michielin, Olivier; Zoete, Vincent

2017-01-01

To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours. PMID:28256516

Olive oil phenolics are dose-dependently absorbed in humans.

PubMed

Visioli, F; Galli, C; Bornet, F; Mattei, A; Patelli, R; Galli, G; Caruso, D

2000-02-25

Olive oil phenolic constituents have been shown, in vitro, to be endowed with potent biological activities including, but not limited to, an antioxidant action. To date, there is no information on the absorption and disposition of such compounds in humans. We report that olive oil phenolics, namely tyrosol and hydroxytyrosol, are dose-dependently absorbed in humans after ingestion and that they are excreted in the urine as glucuronide conjugates. Furthermore, an increase in the dose of phenolics administered increased the proportion of conjugation with glucuronide.

Tissue distribution, metabolism and excretion of 3, 3′-dichloro-4′-sulfooxy-biphenyl in the rat

PubMed Central

Grimm, Fabian A.; He, Xianran; Teesch, Lynn M.; Lehmler, Hans-Joachim; Robertson, Larry W.; Duffel, Michael W.

2015-01-01

Polychlorinated biphenyls (PCBs) with lower numbers of chlorine atoms exhibit a greater susceptibility to metabolism than their higher-chlorinated counterparts. Following initial hydroxylation of these lower chlorinated PCBs, metabolic sulfation to form PCB sulfates is increasingly recognized as an important component of their toxicology. Since procedures for the quantitative analysis of PCB sulfates in tissue samples have not been previously available, we have now developed an efficient, LC-ESI-MS/MS based, protocol for the quantitative analysis of 4-PCB 11 sulfate in biological samples. This procedure was used to determine the distribution of 4-PCB 11 sulfate in liver, kidney, lung, and brain, as well as its excretion profile, following its intravenous administration to male Sprague-Dawley rats. Following initial uptake of 4-PCB 11 sulfate, its concentration in these tissues and serum declined within the first hour following injection. Although biliary secretion was detected, analysis of 24 hour collections of urine and feces revealed recovery of less than 4% of the administered 4-PCB 11 sulfate. High-resolution LC-MS analysis of bile, urine, and feces showed metabolic products derived from 4-PCB 11 sulfate. Thus, 4-PCB 11 sulfate at this dose was not directly excreted in the urine, but was, instead, re-distributed to tissues and/or subjected to further metabolism. PMID:26046945

Application of a liquid chromatography-tandem mass spectrometry method to the pharmacokinetics, tissue distribution and excretion studies of Dactylicapnos scandens in rats.

PubMed

Guo, Changchuan; Jiang, Yan; Li, Li; Hong, Lan; Wang, Yuqing; Shen, Qian; Lou, Yan; Hu, Haihong; Zhou, Hui; Yu, Lushan; Jiang, Huidi; Zeng, Su

2013-02-23

The herbal ingredients of isocorydine and protopine were isolated from Dactylicapnos scandens. This study was aimed at developing a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method to quantify isocorydine and protopine in rat plasma and tissues for pharmacokinetic, tissue distribution and excretion studies. Biological samples were processed with ethyl acetate extraction, and corydaline was chosen as the internal standard (IS). The analytes were separated by a C(18) column and detected with a triple quadrupole mass spectrometer using positive ion ESI in the multiple reaction monitoring (MRM) mode. The MS/MS ion transitions monitored were m/z 342.0→278.9 for isocorydine, 354.1→188.0 for protopine and 370.0→192.0 for IS, respectively. Excellent linearity was observed over the concentration range between 10 and 3000 ng/mL for isocorydine and 10-300 ng/mL for protopine. The lower limit of quantification (LLOQ) was 10 ng/mL for both isocorydine and protopine. This novel method was rapid, accurate, high sensitive and high selective. It was successfully applied to the pharmacokinetic, tissue distribution and excretion studies of D. scandens. These preclinical data of D. scandens would be useful for the clinical reference. Copyright © 2012 Elsevier B.V. All rights reserved.

The distribution of lithium and its effects on the distribution and excretion of other ions in the rat

PubMed Central

Birch, N. J.; Jenner, F. A.

1973-01-01

1. In rats, lithium (ca 1 mEquiv/kg body weight) decreased brain sodium and magnesium, bone sodium and calcium and increased muscle calcium, plasma magnesium, urinary calcium and urine volume. 2. Lithium was particularly concentrated in bone. PMID:4730833

The effect of variable calcium and very low calcium diets on human calcium metabolism. Ph.D. Thesis. Final Report

NASA Technical Reports Server (NTRS)

Chu, J.

1971-01-01

The effects of a very low calcium diet, with variable high and low protein intake, on the dynamics of calcium metabolism and the mechanism of calciuretics, are examined. The experiment, using male subjects, was designed to study the role of intestinal calcium absorption on urinary calcium excretion, and the rate of production of endogeneously secreted calcium in the gastrointestinal tract. The study showed an average of 70% fractional absorption rate during very low calcium intake, and that a decrease in renal tubular reabsorption of calcium is responsible for calciuretic effects of high protein intake. The study also indicates that there is a tendency to develop osteoporosis after long periods of low calcium intake, especially with a concurrent high protein intake.

[Prevention of osteoporosis by foods and dietary supplements. Chocolate malt drink MILO: nutrition in children and calcium absorption].

PubMed

Fukushima, Yoichi; Kumagai, Akiko

2006-10-01

Calcium is not sufficiently consumed by Japanese at any age groups. Childhood is an important period, when they should earn bone minerals to reach higher peak bone mass for reducing the risk of osteoporosis in their later life. Children require higher calcium consumption per body weight than adults, and also establish their dietary pattern in this period. MILO has attracted widespread popularity as a good-taste chocolate-flavored malt drink with balanced nutrients for children. We developed FOSHU MILO with fructooligosaccharides (FOS) aiming at improving absorption of calcium, which is originally rich in the products. Using the calcium stable isotope (44)Ca, we found that the urinary excretion in the subject fed the products with FOS was higher than that of control product without FOS, suggesting that the FOSHU MILO is effective in promoting calcium absorption from the intestines. MILO could contribute to bone health by increasing consumption of calcium and/or improving the calcium bioavailability.

Human absorption and retention of polonium-210 from caribou meat.

PubMed

Thomas, P A; Fisenne, I; Chorney, D; Baweja, A S; Tracy, B L

2001-01-01

The gastrointestinal (GI) absorption factors and the biological retention times for polonium were determined for a group of 14 volunteers--seven men and seven women--from Saskatoon, Saskatchewan, Canada. Each volunteer consumed 2.0 kg of caribou meat containing known amounts of naturally occurring 210Po. Urine and faecal samples were collected for up to 65 days after meat consumption and analysed for 210Po. The average GI absorption factor for the 14 volunteers was 56 +/- 4% (range = 31-71%), not significantly different from the ICRP value of 50%. About 3% of absorbed polonium underwent prompt excretion by the urinary pathway. The remainder was retained by the body with a half-time >100 days, compared to the ICRP value of 50 days. The effect of these findings increases the dose estimate for ingestion of 210Po in food by a factor of 1.5 to 3.5. Thus, background doses to people consuming caribou and reindeer may be higher than previously thought.

40 CFR 716.3 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., distribution, metabolism, and excretion; cumulative, additive, and synergistic effects; and acute, subchronic... imports a chemical substance, including a chemical substance as a part of a mixture or article, into the...

Log-normal distribution of the trace element data results from a mixture of stocahstic input and deterministic internal dynamics.

PubMed

Usuda, Kan; Kono, Koichi; Dote, Tomotaro; Shimizu, Hiroyasu; Tominaga, Mika; Koizumi, Chisato; Nakase, Emiko; Toshina, Yumi; Iwai, Junko; Kawasaki, Takashi; Akashi, Mitsuya

2002-04-01

In previous article, we showed a log-normal distribution of boron and lithium in human urine. This type of distribution is common in both biological and nonbiological applications. It can be observed when the effects of many independent variables are combined, each of which having any underlying distribution. Although elemental excretion depends on many variables, the one-compartment open model following a first-order process can be used to explain the elimination of elements. The rate of excretion is proportional to the amount present of any given element; that is, the same percentage of an existing element is eliminated per unit time, and the element concentration is represented by a deterministic negative power function of time in the elimination time-course. Sampling is of a stochastic nature, so the dataset of time variables in the elimination phase when the sample was obtained is expected to show Normal distribution. The time variable appears as an exponent of the power function, so a concentration histogram is that of an exponential transformation of Normally distributed time. This is the reason why the element concentration shows a log-normal distribution. The distribution is determined not by the element concentration itself, but by the time variable that defines the pharmacokinetic equation.

Distribution, metabolism and excretion of a synthetic androgen 7alpha-methyl-19-nortestosterone, a potential male-contraceptive.

PubMed

Prasad, Pramod Vishwanath; Arumugam, Ramamani; Willman, Mark; Ge, Ren-Shan; Sitruk-Ware, Regine; Kumar, Narender

2009-01-01

A synthetic androgen 7alpha-Methyl-19-nortestosterone (MENT) has a potential for therapeutic use in 'androgen replacement therapy' for hypogonadal men or as a hormonal male-contraceptive in normal men. Its tissue distribution, excretion and metabolic enzyme(s) have not been reported. Therefore, the present study tested the distribution and excretion of MENT in Sprague-Dawley rats castrated 24h prior to the injection of tritium-labeled MENT ((3)H-MENT). Rats were euthanized at different time intervals after dosing, and the amount of radioactivity in various tissues/organs was measured following combustion in a Packard oxidizer. The radioactivity (% injected dose) was highest in the duodenal contents in the first 30min of injection. Specific uptake of the steroid was observed in target tissues such as ventral prostate and seminal vesicles at 6h, while in other tissues radioactivity equilibrated with blood. Liver and duodenum maintained high radioactivity throughout, as these organs were actively involved in the metabolism and excretion of most drugs. The excretion of (3)H-MENT was investigated after subcutaneous injection of (3)H-MENT into male rats housed in metabolic cages. Urine and feces were collected at different time intervals (up to 72h) following injection. Results showed that the radioactivity was excreted via feces and urine in equal amounts by 30h. Aiming to identify enzyme(s) involved in the MENT metabolism, we performed in vitro metabolism of (3)H-MENT using rat and human liver microsomes, cytosol and recombinant cytochrome P(450) (CYP) isozymes. The metabolites were separated by thin-layer chromatography (TLC). Three putative metabolites (in accordance with the report of Agarwal and Monder [Agarwal AK, Monder C. In vitro metabolism of 7alpha-methyl-19-nortestosterone by rat liver, prostate, and epididymis. Endocrinology 1988;123:2187-93]), [i] 3-hydroxylated MENT by both rat and human liver cytosol; [ii] 16alpha-hydroxylated MENT (a polar metabolite) by both rat and human hepatic microsomes; and [iii] 7alpha-methyl-19-norandrostenedione (a non-polar metabolite) by human hepatic microsomes, were obtained. By employing chemical inhibitors and specific anti-CYP antibodies, (3)H-MENT was found to be metabolized specifically by rat CYP 2C11 and 3-hydroxysteroid dehydrogenase (3-HSD) enzymes whereas in humans it was accomplished by CYP 3A4, 17beta-hydroxysteroid dehydrogenase (17beta-HSD) and 3-HSD enzymes.

The Effect of Coenzyme A on the Metabolic Oxidation of LabeledFatty Acids: Rate Studies, Instrumentation, and Liver Fractionation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tolbert, B.M.; Hughes, Ann M.; Kirk, Martha R.

The effect of pantothenic acid deficiency on the rate of C{sup 14}O{sub 2} excretion and on distribution of radioactivity in liver fractions has been studied in rats given sodium acetate-2-C{sup 14} and sodium heptanoate-7-C{sup 14} The rate of excretion of breath C{sub 14}O has been measured by use of a method in which a sensitive ionization chamber and electrometer directly and continuously record carbon-14 excretion. The labeled fatty acids are more rapidly metabolized to C{sup 14}O{sub 2} in PAD rats than in normal rats. CoA depresses the C{sup 14}O excretion 2 in both normal and PAD rats in experiments withmore » either labeled acid. There are differences in the oxidation of these two fatty acids, and the differences are consistent with postulated metabolic schemes. CoA increases radioactivity deposited in the fat of the liver, but does not appreciably change the radioactivity incorporated in the protein and nonsaponifiable lipid fractions.« less

Radiolabeling, whole-body single photon emission computed tomography/computed tomography imaging, and pharmacokinetics of carbon nanohorns in mice

PubMed Central

Zhang, Minfang; Jasim, Dhifaf A; Ménard-Moyon, Cécilia; Nunes, Antonio; Iijima, Sumio; Bianco, Alberto; Yudasaka, Masako; Kostarelos, Kostas

2016-01-01

In this work, we report that the biodistribution and excretion of carbon nanohorns (CNHs) in mice are dependent on their size and functionalization. Small-sized CNHs (30–50 nm; S-CNHs) and large-sized CNHs (80–100 nm; L-CNHs) were chemically functionalized and radiolabeled with [111In]-diethylenetriaminepentaacetic acid and intravenously injected into mice. Their tissue distribution profiles at different time points were determined by single photon emission computed tomography/computed tomography. The results showed that the S-CNHs circulated longer in blood, while the L-CNHs accumulated faster in major organs like the liver and spleen. Small amounts of S-CNHs- and L-CNHs were excreted in urine within the first few hours postinjection, followed by excretion of smaller quantities within the next 48 hours in both urine and feces. The kinetics of excretion for S-CNHs were more rapid than for L-CNHs. Both S-CNH and L-CNH material accumulated mainly in the liver and spleen; however, S-CNH accumulation in the spleen was more prominent than in the liver. PMID:27524892

Identification of Inhibitors against Metastasis Protein “Survivin:” In silico Discovery Using Virtual Screening and Molecular Docking Studies

PubMed Central

Mishra, Swechha; Singh, Sangeeta

2017-01-01

Background: In experimental therapy of cancer, survivin is considered to be one of the well-established targets. Studies have found that it is overexpression in most of the human tumors, but it is rarely found in normal tissues. It is having varied structural and functional role. It controls cell division and cellular stress response and also regulates metastasis and migration of cancerous cells. It has also been recognized as a biomarker which makes it unconventional drug target. In spite of being one of the centrally active components in metastasis and invasion, their clinical use is minimal. To increase the therapeutic efficiency of cancer and its various stages, it is important to survey novel reagents targeting the pathways and mechanism involving survivin. Objective: The aim of this study was to identify novel survivin inhibitor candidates using in silico screening. Materials and Methods: In this course of work, virtual screening on a dataset of natural compounds retrieved from ZINC and other libraries were performed. Comparative analysis of the protein was done by studying the binding affinity of inhibitors that are already available. The best interacting complex was set for molecular dynamics simulation for 25 ns to validate the stability of system. These molecules were checked for their toxicity and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties using OSIRIS and pre-ADMET tools. Results: We discovered ten such candidates with better binding efficiency with survivin in comparison to marketed chemical against the same. Furthermore, these inhibitor candidates did not induce cell toxicity. Binding affinity of reference molecules was varied from −6.8 to −8.5 kcal/mol while that of top scoring compound ZINC00689728 is −9.3 kcal/mol binding energy. Good placement and strong bond formation of selected molecule was observed during course of work. It is also having permissible ADMET property. Conclusion: Considering all the parameters, the screened molecule can be considered as a potential lead compound for designing new drug against survivin. Further investigation and testing will be required to make it to the final stage. SUMMARY Survivin is one of the important protein of metastasis. Inhibiting survivin might led to the increased therapeutic efficiency of cancer. In this work we are screening library of natural compounds in view of finding some potent inhibitor against survivin. Abbreviations used: MD: Molecular dynamics, LogS: Aqueous solubility, Acceptor HB: Hydrogen bond acceptor, Donor HB: Donor hydrogen bond donor, ADMET: Absorption, distribution, metabolism, excretion, and toxicity, RCSB: Research Collaboratory for Structural Bioinformatics, OPLS: Optimized potentials for liquid simulations, RMSD: Root-mean-square deviation. PMID:29491627

Segmental transport of Ca²⁺ and Mg²⁺ along the gastrointestinal tract.

PubMed

Lameris, Anke L; Nevalainen, Pasi I; Reijnen, Daphne; Simons, Ellen; Eygensteyn, Jelle; Monnens, Leo; Bindels, René J M; Hoenderop, Joost G J

2015-02-01

Calcium (Ca(2+)) and magnesium (Mg(2+)) ions are involved in many vital physiological functions. Since dietary intake is the only source of minerals for the body, intestinal absorption is essential for normal homeostatic levels. The aim of this study was to characterize the absorption of Ca(2+) as well as Mg(2+) along the gastrointestinal tract at a molecular and functional level. In both humans and mice the Ca(2+) channel transient receptor potential vanilloid subtype 6 (TRPV6) is expressed in the proximal intestinal segments, whereas Mg(2+) channel transient receptor potential melastatin subtype 6 (TRPM6) is expressed in the distal parts of the intestine. A method was established to measure the rate of Mg(2+) absorption from the intestine in a time-dependent manner by use of (25)Mg(2+). In addition, local absorption of Ca(2+) and Mg(2+) in different segments of the intestine of mice was determined by using surgically implanted intestinal cannulas. By these methods, it was demonstrated that intestinal absorption of Mg(2+) is regulated by dietary needs in a vitamin D-independent manner. Also, it was shown that at low luminal concentrations, favoring transcellular absorption, Ca(2+) transport mainly takes place in the proximal segments of the intestine, whereas Mg(2+) absorption predominantly occurs in the distal part of the gastrointestinal tract. Vitamin D treatment of mice increased serum Mg(2+) levels and 24-h urinary Mg(2+) excretion, but not intestinal absorption of (25)Mg(2+). Segmental cannulation of the intestine and time-dependent absorption studies using (25)Mg(2+) provide new ways to study intestinal Mg(2+) absorption. Copyright © 2015 the American Physiological Society.

Children's Menu Diversity: Influence on Fluoride Absorption and Excretion.

PubMed

Cavalli, Andreany M; Flório, Flávia M

2018-01-01

The aim of this study is to determine the influence of children's menu diversity on the absorption and excretion of fluoride. The experimental, longitudinal, quantitative study was carried out in a city without fluoridation in water supply. A total of 16 adult volunteers (>63.9 kg) participated in the study who, after a 12-hour fast, ingested two types of children's meals, whose quantity and diversity were determined after weighing the meals best consumed by children at a kindergarten in Campinas, Sao Paulo: Simple child meal (SCM; n = 8) and hearty child meal (HCM; n = 8). The fluoride gel residual after professional application (12,300 ppm, 30.75 mg F, pH = 4.65) was simulated 15 minutes after feeding. Saliva samples (in time intervals of 0, 15, 30, and 45 minutes and 1, 2, 3, 4, 6, and 12 hours after ingestion of the fluorine solution) and urine of the volunteers were analyzed at 24 hours. Fluoride concentrations were determined using a selective ion electrode. Data were analyzed by analysis of variance for repeated measurements (PROC MIXED)/Tukey-Kramer. The concentrations of fluoride in saliva at 0 and 15 minutes and after 6 hours were the same between groups (p > 0.05). From 30 minutes to 4 hours after ingestion, the SCM group showed a higher concentration of fluoride in the saliva, which has a higher absorption (p < 0.05). The fluoride concentration in the urine did not differ between groups at both collection times (p > 0.05), and for both, the fluoride concentration in the urine increased in the final measurement (p < 0.05). The children's menu diversity influenced the absorption of fluoride so that the topical application of fluoride should be performed in infants fed preferably after the fuller diet and following the established guidelines to ensure the safety of the procedure. Knowledge of the influence of the children's menu diversity on fluoride metabolism after professional application is important so that the actions of fluoride therapy may be planned in a safer manner and be based on the reality of the universe of children.

Canagliflozin Lowers Postprandial Glucose and Insulin by Delaying Intestinal Glucose Absorption in Addition to Increasing Urinary Glucose Excretion

PubMed Central

Polidori, David; Sha, Sue; Mudaliar, Sunder; Ciaraldi, Theodore P.; Ghosh, Atalanta; Vaccaro, Nicole; Farrell, Kristin; Rothenberg, Paul; Henry, Robert R.

2013-01-01

OBJECTIVE Canagliflozin, a sodium glucose cotransporter (SGLT) 2 inhibitor, is also a low-potency SGLT1 inhibitor. This study tested the hypothesis that intestinal canagliflozin levels postdose are sufficiently high to transiently inhibit intestinal SGLT1, thereby delaying intestinal glucose absorption. RESEARCH DESIGN AND METHODS This two-period, crossover study evaluated effects of canagliflozin on intestinal glucose absorption in 20 healthy subjects using a dual-tracer method. Placebo or canagliflozin 300 mg was given 20 min before a 600-kcal mixed-meal tolerance test. Plasma glucose, 3H-glucose, 14C-glucose, and insulin were measured frequently for 6 h to calculate rates of appearance of oral glucose (RaO) in plasma, endogenous glucose production, and glucose disposal. RESULTS Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0–2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0–6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003). A modest (∼10%) reduction in acetaminophen absorption was observed over the first 2 h, but this difference was not sufficient to explain the reduction in RaO. Total glucose disposal over 0 to 6 h was similar across groups. CONCLUSIONS Canagliflozin reduces postprandial plasma glucose and insulin by increasing UGE (via renal SGLT2 inhibition) and delaying RaO, likely due to intestinal SGLT1 inhibition. PMID:23412078

Distribution of transuranic elements in bone.

PubMed

Durbin, P W

1992-01-01

The transport, retention, and excretion of transuranic elements from the body have been widely studied for many years. A summary of the results is given with an emphasis on the distribution of these elements in bone. Implications of these studies for understanding the relationships between lead in blood and lead in bone are presented. The expected distribution of lead at various bone sites is also considered.

Disposition and metabolism of a novel prostanoid antiglaucoma medication, tafluprost, following ocular administration to rats.

PubMed

Fukano, Y; Kawazu, K

2009-08-01

The disposition and metabolism of tafluprost, an ester prodrug of the 15,15-difluoro-prostaglandin F(2alpha) antiglaucoma agent, have been studied in rats after ocular administration. Radioactivity was absorbed very rapidly into the eye and systemic circulation after a single ocular dose of 0.005% [(3)H]tafluprost ophthalmic solution, with maximum levels in plasma and most eye tissues occurring within 15 min. The absorption ratio of radioactivity was approximately 75%, suggesting the high availability of ocular administration of tafluprost. Approximately 10% of the dose was present in cornea at this time, and radioactivity concentrations in this tissue exceeded those in aqueous humor and iris/ciliary body throughout the 24-h study period. After repeated daily ocular doses, radioactivity levels remained greatest in cornea, followed by iris/ciliary body that replaced aqueous humor as the eye tissue containing the second highest radioactivity concentration. In female rats, radioactivity was excreted equally between urine and feces after a single ocular dose, whereas in male rats more was excreted in feces, reflecting the greater biliary excretion in males rats (50% dose) compared with females rats (33% dose). Tafluprost was extensively metabolized in the rat, such that intact prodrug was not detected in plasma, tissues, or excreta by radio-high-performance liquid chromatography. On the other hand, the active moiety, tafluprost acid, was the only noteworthy radioactive component in cornea, aqueous humor, and iris/ciliary body for at least 8 h after the ocular dose, and it was also a major plasma metabolite in early time points. The gender differences in conjugation reactions resulted in the differences in the excretion.

SN2-Palmitate Reduces Fatty Acid Excretion in Chinese Formula-fed Infants.

PubMed

Bar-Yoseph, Fabiana; Lifshitz, Yael; Cohen, Tzafra; Malard, Patrice; Xu, Chungdi

2016-02-01

Palmitic acid (PA) comprises 17% to 25% of human milk fatty acids, of which 70% to 75% are esterified to the SN2 position of the triglyceride (SN2-palmitate). In vegetable oils, which are commonly used in infant formulas, palmitate is primarily esterified to other positions, resulting in reduced calcium and fat absorption and hard stools. The aim of this study was to elucidate the effects of SN2-palmitate on nutrient excretion. In total, 171 Chinese infants were included (within 14 days of birth) in this multicenter study. Formula-fed infants were randomly assigned to receive either SN2-palmitate formula (INFAT, n = 57) or control formula (n = 57). The formulas (Biostime, China) differed only in their SN2 PA proportions. Stool was collected at 6 postnatal weeks. The stool dry weight and fat content of the SN2-palmitate group were lower compared with the control group (dry weight 4.25 g vs 7.28 g, P < 0.05; fat 0.8 g vs 1.2 g, P < 0.05). The lipid component was also significantly lower for the SN2-palmitate group (0.79 g vs 1.19 g, P < 0.05). PA, representing ∼50% of the saponified fatty acids, was significantly lower in the SN2-palmitate group compared with the control group (0.3 g vs 0.7 g, P < 0.01). Breast-fed infants had a significantly lower stool dry weight, fat content, and saponified fat excretion compared with formula-fed infants (P < 0.01). Similar to breast milk, the SN2-palmitate infant formula primarily reduced calcium-saponified fat excretion. The results of this study further emphasize the nutritional importance of SN2-palmitate structured fat for infants.

The Hypercalciurias CAUSES, PARATHYROID FUNCTIONS, AND DIAGNOSTIC CRITERIA

PubMed Central

Pak, Charles Y. C.; Ohata, Masahiro; Lawrence, E. Clint; Snyder, W.

1974-01-01

The causes for the hypercalciuria and diagnostic criteria for the various forms of hypercalciuria were sought in 56 patients with hypercalcemia or nephrolithiasis (Ca stones), by a careful assessment of parathyroid function and calcium metabolism. A study protocol for the evaluation of hypercalciuria, based on a constant liquid synthetic diet, was developed. In 26 cases of primary hyperparathyroidism, characteristic features were: hypercalcemia, high urinary cyclic AMP (cAMP, 8.58±3.63 SD μmol/g creatinine; normal, 4.02±0.70 μmol/g creatinine), high immunoreactive serum parathyroid hormone (PTH), hypercalciuria, the urinary Ca exceeding absorbed Ca from intestinal tract (CaA), high fasting urinary Ca (0.2 mg/mg creatinine or greater), and low bone density by 125I photon absorption. The results suggest that hypercalciuria is partly secondary to an excessive skeletal resorption (resorptive hypercalciuria). The 22 cases with renal stones had normocalcemia, hypercalciuria, intestinal hyperabsorption of calcium, normal or low serum PTH and urinary cAMP, normal fasting urinary Ca, and normal bone density. Since their CaA exceeded urinary Ca, the hypercalciuria probably resulted from an intestinal hyperabsorption of Ca (absorptive hypercalciuria). The primacy of intestinal Ca hyperabsorption was confirmed by responses to Ca load and deprivation under a metabolic dietary regimen. During a Ca load of 1,700 mg/day, there was an exaggerated increase in the renal excretion of Ca and a suppression of cAMP excretion. The urinary Ca of 453±154 SD mg/day was significantly higher than the control group's 211±42 mg/day. The urinary cAMP of 2.26±0.56 μmol/g creatinine was significantly lower than in the control group. In contrast, when the intestinal absorption of calcium was limited by cellulose phosphate, the hypercalciuria was corrected and the suppressed renal excretion of cAMP returned towards normal. Two cases with renal stones had normocalcemia, hypercalciuria, and high urinary cAMP or serum PTH. Since CaA was less than urinary Ca, the hypercalciuria may have been secondary to an impaired renal tubular reabsorption of Ca (renal hypercalciuria). Six cases with renal stones had normal values of serum Ca, urinary Ca, urinary cAMP, and serum PTH (normocalciuric nephrolithiasis). Their CaA exceeded urinary Ca, and fasting urinary Ca and bone density were normal. The results support the proposed mechanisms for the hypercalciuria and provide reliable diagnostic criteria for the various forms of hypercalciuria. PMID:4367891

Evaluation of Antiatherogenic Properties of Ezetimibe Using 3H-Labeled Low-Density-Lipoprotein Cholesterol and 99mTc-cAbVCAM1-5 SPECT in ApoE-/- Mice Fed the Paigen Diet.

PubMed

Dumas, Laurent S; Briand, François; Clerc, Romain; Brousseau, Emmanuel; Montemagno, Christopher; Ahmadi, Mitra; Bacot, Sandrine; Soubies, Audrey; Perret, Pascale; Riou, Laurent M; Devoogdt, Nick; Lahoutte, Tony; Barone-Rochette, Gilles; Fagret, Daniel; Ghezzi, Catherine; Sulpice, Thierry; Broisat, Alexis

2017-07-01

The addition of ezetimibe, an intestinal cholesterol absorption inhibitor, to statin therapy has recently shown clinical benefits in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial by reducing low-density-lipoprotein (LDL) cholesterol levels more than statin therapy alone. Here, we investigated the mechanisms by which inhibition of intestinal cholesterol absorption might contribute to the clinically observed reduction in cardiovascular events by evaluating its effect on inflammatory plaque development in apolipoprotein E -/- mice. Methods: Apolipoprotein E -/- mice were fed the Paigen diet (1.25% cholesterol, 0.5% cholic acid, and 15% fat) without or with ezetimibe (7 mg/kg/d) for 6 wk. In a first set of mice ( n = 15), we intravenously injected 3 H-cholesteryl oleate-labeled human LDL to test whether ezetimibe promotes LDL-derived cholesterol fecal excretion. In a second set ( n = 20), we used the imaging agent 99m Tc-cAbVCAM1-5 to evaluate expression of an inflammatory marker, vascular cell adhesion molecule 1 (VCAM-1), in atherosclerotic plaques. In a third set ( n = 21), we compared VCAM-1 expression with 99m Tc-cAbVCAM1-5 uptake in various tissues. Results: Mice treated with ezetimibe showed a 173% higher LDL-cholesteryl ester plasma disappearance rate ( P < 0.001 vs. control) after 3 H-cholesteryl oleate-labeled LDL injection. At 96 h after injection, the hepatic fraction of 3 H-tracer was 61% lower in mice treated with ezetimibe ( P < 0.001). Meanwhile, LDL-derived 3 H-cholesterol excretion in the feces was 107% higher ( P < 0.001). The antiatherogenic effect of ezetimibe monitored by 99m Tc-cAbVCAM1-5 SPECT showed a 49% reduction in aortic tracer uptake (percentage injected dose per cubic centimeter, 0.95 ± 0.04 vs. 1.87 ± 0.11; P < 0.01). In addition to hypercholesterolemia, the proinflammatory Paigen diet significantly increased VCAM-1 expression with respect to the control group in various tissues, including the aorta, and this expression correlated strongly with 99m Tc-cAbVCAM1-5 uptake ( r = 0.75; P < 0.05). Conclusion: Inhibition of intestinal cholesterol absorption with ezetimibe promotes antiatherosclerotic effects through increased LDL cholesterol catabolism and LDL-derived cholesterol fecal excretion and reduces inflamed atherosclerotic plaques. These mechanisms may contribute to the benefits of adding ezetimibe to a statin therapy. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Intestinal adaptations in chronic kidney disease and the influence of gastric bypass surgery.

PubMed

Hatch, Marguerite

2014-09-01

Studies have shown that compensatory adaptations in gastrointestinal oxalate transport can impact the amount of oxalate excreted by the kidney. Hyperoxaluria is a major risk factor in the formation of kidney stones, and oxalate is derived from both the diet and the liver metabolism of glyoxylate. Although the intestine generally absorbs oxalate from dietary sources and can contribute as much as 50% of urinary oxalate, enteric oxalate elimination plays a significant role when renal function is compromised. While the mechanistic basis for these changes in the direction of intestinal oxalate movements in chronic renal failure involves an upregulation of angiotensin II receptors in the large intestine, enteric secretion/excretion of oxalate can also occur by mechanisms that are independent of angiotensin II. Most notably, the commensal bacterium Oxalobacter sp. interacts with the host enterocyte and promotes the movement of oxalate from the blood into the lumen, resulting in the beneficial effect of significantly lowering urinary oxalate excretion. Changes in the passive permeability of the intestine, such as in steatorrhoea and following gastric bypass, also promote oxalate absorption and hyperoxaluria. In summary, this report highlights the two-way physiological signalling between the gut and the kidney, which may help to alleviate the consequences of certain kidney diseases. © 2014 The Author. Experimental Physiology © 2014 The Physiological Society.

Calcium and vitamin D intake and biochemical tests in short-stature children and adolescents.

PubMed

Bueno, A L; Czepielewski, M A; Raimundo, F V

2010-11-01

Growth is highly dependent on the absorption of nutrients. Inadequate calcium and vitamin D intake may compromise bone mineralization and growth. There is a great deal of concern regarding calcium and vitamin D intake, as well as biochemical changes in children and adolescents, which led us to investigate calcium and vitamin D levels during growth. Fifty-eight children and adolescents with short stature (z-score <3 s.d.) were evaluated from September 2005 to February 2007. Blood biochemical analyses and 24-h urine tests were performed and were used to evaluate calcium, phosphorus, creatinine, sodium, alkaline phosphatase, parathyroid hormone (PTH) and 25(OH)D levels. Dietary inquiries, repeated three times, were used to estimate the actual intake of these substances. A reduced calcium (608.6 mg/day) and vitamin D (72.5 IU/day) intake was observed. Calcium excretion in 24-h urine (56 mg/24 h) and calcium excretion by weight (2.0 mg/24 h/kg) showed scores that were below normal. A negative correlation between PTH and both dietary vitamin D (r=-0.46; P<0.01) and calcium intake (r =-0.41; P<0.001) was observed. The low calcium and vitamin D intake observed in short-stature children and adolescents was associated with biochemical results, and suggested that PTH and calcium excretion may be useful screening tests for evaluating dietary calcium and vitamin D.

A stochastic whole-body physiologically based pharmacokinetic model to assess the impact of inter-individual variability on tissue dosimetry over the human lifespan.

PubMed

Beaudouin, Rémy; Micallef, Sandrine; Brochot, Céline

2010-06-01

Physiologically based pharmacokinetic (PBPK) models have proven to be successful in integrating and evaluating the influence of age- or gender-dependent changes with respect to the pharmacokinetics of xenobiotics throughout entire lifetimes. Nevertheless, for an effective application of toxicokinetic modelling to chemical risk assessment, a PBPK model has to be detailed enough to include all the multiple tissues that could be targeted by the various xenobiotics present in the environment. For this reason, we developed a PBPK model based on a detailed compartmentalization of the human body and parameterized with new relationships describing the time evolution of physiological and anatomical parameters. To take into account the impact of human variability on the predicted toxicokinetics, we defined probability distributions for key parameters related to the xenobiotics absorption, distribution, metabolism and excretion. The model predictability was evaluated by a direct comparison between computational predictions and experimental data for the internal concentrations of two chemicals (1,3-butadiene and 2,3,7,8-tetrachlorodibenzo-p-dioxin). A good agreement between predictions and observed data was achieved for different scenarios of exposure (e.g., acute or chronic exposure and different populations). Our results support that the general stochastic PBPK model can be a valuable computational support in the area of chemical risk analysis. (c)2010 Elsevier Inc. All rights reserved.

Correlation between structure, retention, property, and activity of biologically relevant 1,7-bis(aminoalkyl)diazachrysene derivatives.

PubMed

Šegan, Sandra; Trifković, Jelena; Verbić, Tatjana; Opsenica, Dejan; Zlatović, Mario; Burnett, James; Šolaja, Bogdan; Milojković-Opsenica, Dušanka

2013-01-01

The physicochemical properties, retention parameters (R(M)(0)), partition coefficients (logP(OW)), and pK(a) values for a series of thirteen 1,7-bis(aminoalkyl) diazachrysene (1,7-DAAC) derivatives were determined in order to reveal the characteristics responsible for their biological behavior. The investigated compounds inhibit three unrelated pathogens (the Botulinum neurotoxin serotype A light chain (BoNT/A LC), Plasmodium falciparum malaria, and Ebola filovirus) via three different mechanisms of action. To determine the most influential factors governing the retention and activities of the investigated diazachrysenes, R(M)(0), logP(OW), and biological activity values were correlated with 2D and 3D molecular descriptors, using a partial least squares regression. The resulting quantitative structure-retention (property) relationships indicate the importance of descriptors related to the hydrophobicity of the molecules (e.g., predicted partition coefficients and hydrophobic surface area). Quantitative structure-activity relationship models for describing biological activity against the BoNT/A LC and malarial strains also include overall compound polarity, electron density distribution, and proton donor/acceptor potential. Furthermore, models for Ebola filovirus inhibition are presented qualitatively to provide insights into parameters that may contribute to the compounds' antiviral activities. Overall, the models form the basis for selecting structural features that significantly affect the compound's absorption, distribution, metabolism, excretion, and toxicity profiles. Copyright © 2012 Elsevier B.V. All rights reserved.

Effect of dietary phytate on zinc homeostasis in young and elderly Korean women.

PubMed

Kim, Jihye; Paik, Hee Young; Joung, Hyojee; Woodhouse, Leslie R; Li, Shanji; King, Janet C

2007-02-01

Previous studies suggest that consumption of predominantly plant-based diets with high phytate content contribute to zinc deficiency by inhibiting zinc absorption. Age of the individual may also affect the ability to maintain zinc homeostasis. This study was designed to determine the effect of dietary phytate on zinc homeostasis and to evaluate the effect of age on the capacity to maintain the zinc homeostasis with changes in dietary phytate in young and elderly Korean women. Seven healthy young women (22-24 yr) and 10 healthy elderly women (66-75 yr) were studied consecutively for 3 months in 2 metabolic periods (MP) in two different metabolic units. During MP1 the women consumed a high phytate (HP) diet (P:Zn molar ratio = 23) for 9 days. After a 10 d wash-out period at home eating their usual diets, a lower phytate diet (LP) (P:Zn molar ratio = 10) was fed in MP2 for 9 d. Phytase was added to selected foods in the high phytate diet to reduce the phytate content of the meals in the LP period. The zinc content of both diets was about 6.5 mg/d. Stable isotopes of Zn ((70)Zn) were administered intravenously on d 5 of MP 1 and 2 for measuring endogenous fecal zinc excretion. Plasma samples were also collected on d 5 for measuring plasma zinc concentrations by Inductively Coupled Plasma-Atomic Emission Spectrometry (ICP-AES). 24 hr urine samples were collected for 5 d and complete fecal samples were collected for 9 d after isotope administration. Fractional zinc absorption (FZA) was calculated from mass balance corrected for endogenous fecal zinc (EFZ) excretion and EFZ was determined by using an isotopic dilution technique. Isotopic ratios for FZA and EFZ were measured by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Statistical analyses were done using ANOVA. Both the young and elderly women were in negative zinc balance during the HP period. This was due to a significant decrease in FZA and total absorbed zinc (TAZ) with a HP diet (43 vs 22% in young women, 34 vs 20% in elderly women, p < 0.001). EFZ excretion did not differ in the young and elderly women during the LP and HP periods. Dietary phytate did not alter plasma zinc concentrations or and urinary zinc excretion in either group. Adjustments in zinc homeostasis with an increase in dietary phytate did not differ between young and elderly women in this study.

[Effects of nandrolone decanoate on bone mineral content and intestinal absorption of calcium].

PubMed

Nuti, R; Righi, G A; Turchetti, V; Vattimo, A

1984-01-28

To evaluate the effects of a long-term treatment with nandrolone decanoate on metabolism of the skeleton, a double-blind randomized study was carried out in women with joint diseases without metabolic bone derangement. Ten patients were treated with 50 mg of nandrolone decanoate every three weeks for two years; in six subjects a treatment with placebo was performed. As it concerns plasma calcium and phosphate, serum alkaline phosphatase, urinary excretion of calcium, phosphate, hydroxyproline and cAMP, as parathyroid index, it was not observed significant differences in the two examined groups. While in placebo group at the end of the study the intestinal radiocalcium remained unchanged and bone mineral content showed a slight decrease, on the contrary nandrolone decanoate treatment promoted a significant improvement in intestinal calcium absorption and an increase in bone mineral content.

The Tissue Distribution and Urinary Excretion Study of Gallic Acid and Protocatechuic Acid after Oral Administration of Polygonum Capitatum Extract in Rats.

PubMed

Ma, Feng-Wei; Deng, Qing-Fang; Zhou, Xin; Gong, Xiao-Jian; Zhao, Yang; Chen, Hua-Guo; Zhao, Chao

2016-03-24

In the present study, we investigated the tissue distribution and urinary excretion of gallic acid (GA) and protocatechuic acid (PCA) after rat oral administration of aqueous extract of Polygonum capitatum (P. capitatum, named Herba Polygoni Capitati in China). An UHPLC-MS/MS analytical method was developed and adopted for quantification of GA and PCA in different tissue homogenate and urine samples. Interestingly, we found that GA and PCA showed a relatively targeted distribution in kidney tissue after dosing 60 mg/kg P. capitatum extract (equivalent to 12 mg/kg of GA and 0.9 mg/kg of PCA). The concentrations of GA and PCA in the kidney tissue reached 1218.62 ng/g and 43.98 ng/g, respectively, at one hour after oral administration. The results helped explain the empirical use of P. capitatum for kidney diseases in folk medicine. Further studies on urinary excretion of P. capitatum extract indicated that GA and PCA followed a concentrated elimination over a 4-h period. The predominant metabolites were putatively identified to be 4-methylgallic acid (4-OMeGA) and 4-methylprotocatechuic acid (4-OMePCA) by analyzing their precursor ions and characteristic fragment ions using tandem mass spectrometry. However, the amount of unchanged GA and PCA that survived the metabolism were about 14.60% and 15.72% of the total intake, respectively, which is reported for the first time in this study.

Distribution and chemical forms of gadolinium in the brain: a review.

PubMed

Kanda, Tomonori; Nakai, Yudai; Hagiwara, Akifumi; Oba, Hiroshi; Toyoda, Keiko; Furui, Shigeru

2017-11-01

In the 3 years since residual gadolinium-based contrast agent (GBCA) in the brain was first reported, much has been learned about its accumulation, including the pathway of GBCA entry into the brain, the brain distribution of GBCA and its excretion. Here we review recent progress in understanding the routes of gadolinium deposition in brain structures.

Dual-isotope method for determination of human zinc absorption: the use of a test meal of turkey meat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Flanagan, P.R.; Cluett, J.; Chamberlain, M.J.

The percentage of /sup 65/Zn taken up (absorbed) from extrinsically labeled turkey meat was calculated from the amounts of /sup 65/Zn and a nonabsorbed /sup 51/Cr marker present in the body or in a single stool specimen after 1-2 d. /sup 51/CrCl/sub 3/ proved to be a suitable marker for unabsorbed /sup 65/Zn and so the early determination of /sup 65/Zn absorption was possible. With stool counting, /sup 65/Zn absorption data from first stool samples after 1-2 d were accurate as judged by correlation with the amount of /sup 65/Zn in the body 7-10 d later (retention); results from subsequentmore » stools gave lower absorption values due to the early excretion of some absorbed /sup 65/Zn. The dual-isotope method gave reproducible results when four successive tests of zinc absorption were carried out in a group of six subjects. The average (mean +/- SD) /sup 65/Zn absorption from turkey meals containing 31 mumol (2 mg) and 46 mumol (3 mg) of zinc was 39 +/- 8% and 29 +/- 6%, respectively, measured by stool counting; /sup 65/Zn absorption and retention correlated well in both studies. A series of different beverages was given in place of water with the turkey meal. Orange juice significantly reduced /sup 65/Zn absorption and milk also showed this tendency, but tea, whiskey, wine or beer had no significant effect on the absorption of /sup 65/Zn from the turkey meal. In groups of subjects the mean ratio of /sup 65/Zn absorption from extrinsically labeled turkey meat on two occasions (1.06) was not significantly different from that of the absorption of extrinsic to intrinsic /sup 65/Zn labels (1.16). The dual-isotope technique with either stool or body counting is suitable for the rapid determination of /sup 65/Zn absorption from extrinsically labeled turkey within 2 d.« less

Intestinal bile acid malabsorption in cystic fibrosis.

PubMed

O'Brien, S; Mulcahy, H; Fenlon, H; O'Broin, A; Casey, M; Burke, A; FitzGerald, M X; Hegarty, J E

1993-08-01

This study aimed at examining the mechanisms participating in excessive faecal bile acid loss in cystic fibrosis. The study was designed to define the relation between faecal fat and faecal bile acid loss in patients with and without cystic fibrosis related liver disease; to assess terminal ileal bile acid absorption by a seven day whole body retention of selenium labelled homotaurocholic acid (SeHCAT); and to determine if small intestinal bacterial overgrowth contributes to faecal bile acid loss. The study population comprised 40 patients (27 men; median age 18 years) with cystic fibrosis (n = 8) and without (n = 32) liver disease and eight control subjects. Faecal bile acid excretion was significantly higher in cystic fibrosis patients without liver disease compared with control subjects (mean (SEM) 21.5 (2.4) and 7.3 (1.2) micromoles/kg/24 hours respectively; p < 0.01) and patients with liver disease (7.9 (1.3) micromoles/kg/24 hours; p < 0.01). No correlation was found between faecal fat (g fat/24 hours) and faecal bile acid (micromoles 24 hours) excretion. Eight (33%) of cystic fibrosis patients had seven day SeHCAT retention < 10% (normal retention > 20%). SeHCAT retention in cystic fibrosis patients with liver disease was comparable with control subjects (30.0 (SEM) 8.3% v 36.8 (5.9)%; p = NS) while SeHCAT retention in cystic fibrosis patients who did not have liver disease was significantly reduced (19.9 (3.8); p < 0.05). Although evidence of small bowel bacterial overgrowth was present in 40% of patients no relation was found between breath hydrogen excretion, faecal fat, and faecal bile acid loss. The results are consistent with the presence of an abnormality in terminal ideal function in patients with cystic fibrosis who do not have liver disease and that a defect in the ileal absorption of bile acids may be a contributory factor to excessive faecal bile acid loss. Faecal bile acid loss in cystic fibrosis is unrelated to the presence of intraluminal fat or intestinal bacterial overgrowth.

Intestinal bile acid malabsorption in cystic fibrosis.

PubMed Central

O'Brien, S; Mulcahy, H; Fenlon, H; O'Broin, A; Casey, M; Burke, A; FitzGerald, M X; Hegarty, J E

1993-01-01

This study aimed at examining the mechanisms participating in excessive faecal bile acid loss in cystic fibrosis. The study was designed to define the relation between faecal fat and faecal bile acid loss in patients with and without cystic fibrosis related liver disease; to assess terminal ileal bile acid absorption by a seven day whole body retention of selenium labelled homotaurocholic acid (SeHCAT); and to determine if small intestinal bacterial overgrowth contributes to faecal bile acid loss. The study population comprised 40 patients (27 men; median age 18 years) with cystic fibrosis (n = 8) and without (n = 32) liver disease and eight control subjects. Faecal bile acid excretion was significantly higher in cystic fibrosis patients without liver disease compared with control subjects (mean (SEM) 21.5 (2.4) and 7.3 (1.2) micromoles/kg/24 hours respectively; p < 0.01) and patients with liver disease (7.9 (1.3) micromoles/kg/24 hours; p < 0.01). No correlation was found between faecal fat (g fat/24 hours) and faecal bile acid (micromoles 24 hours) excretion. Eight (33%) of cystic fibrosis patients had seven day SeHCAT retention < 10% (normal retention > 20%). SeHCAT retention in cystic fibrosis patients with liver disease was comparable with control subjects (30.0 (SEM) 8.3% v 36.8 (5.9)%; p = NS) while SeHCAT retention in cystic fibrosis patients who did not have liver disease was significantly reduced (19.9 (3.8); p < 0.05). Although evidence of small bowel bacterial overgrowth was present in 40% of patients no relation was found between breath hydrogen excretion, faecal fat, and faecal bile acid loss. The results are consistent with the presence of an abnormality in terminal ideal function in patients with cystic fibrosis who do not have liver disease and that a defect in the ileal absorption of bile acids may be a contributory factor to excessive faecal bile acid loss. Faecal bile acid loss in cystic fibrosis is unrelated to the presence of intraluminal fat or intestinal bacterial overgrowth. PMID:8174969

Biotransformation and toxicokinetics of the insect repellent IR3535® in male and female human subjects after dermal exposure.

PubMed

Broschard, Thomas H; Bohlmann, Anja M; Konietzny, Stefan; Schauer, Ute M D; Dekant, Wolfgang

2013-04-26

The absorption and excretion of the insect repellent IR3535(®) was studied in human subjects (five males and five females) after dermal application of approx. 3g of a formulation containing 20% IR3535(®), i.e. the amounts of IR3535(®) applied were between 1.94 and 3.4 mmol/person (418-731 mg/person). Blood and urinary concentrations of IR3535(®) and its only metabolite, IR3535(®)-free acid, were determined over time. In plasma, concentrations of the parent compound IR3535(®) were at or below the limit of quantification (0.037 μmol/L). IR3535(®)-free acid peaked in plasma samples 2-6h after dermal application. Cmax mean values were 5.7 μmol/L in males, 3.0 μmol/L in females and 4.2 μmol/L in all volunteers. Mean AUC values were 41.6, 24.5 and 33.9 μmolL(-1)h in males, females and all subjects, respectively. In urine samples from all human subjects, both IR3535(®) and IR3535(®)-free acid were detectable, however, only very small amounts of IR3535(®) were found. Concentrations of IR3535(®)-free acid were several thousand-fold higher than the parent compound and peaked at the first two sampling points (4h and 8h after dermal application). Overall, IR3535(®) and IR3535(®)-free acid excreted with urine over 48 h representing 13.3 ± 3.05% of the dose applied. Since IR3535(®) is rapidly and extensively metabolized, and IR3535(®)-free acid has a low molecular weight and high water solubility, it is expected that urinary excretion of IR3535(®)-free acid and IR3535(®) represents the total extent of absorption of IR3535(®) in humans. Based on the results of this study, the skin penetration rate of IR3535(®) is 13.3% in humans after dermal application. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Sound absorption by suspensions of nonspherical particles: Measurements compared with predictions using various particle sizing techniques

NASA Astrophysics Data System (ADS)

Richards, Simon D.; Leighton, Timothy G.; Brown, Niven R.

2003-10-01

Knowledge of the particle size distribution is required in order to predict ultrasonic absorption in polydisperse particulate suspensions. This paper shows that the method used to measure the particle size distribution can lead to important differences in the predicted absorption. A reverberation technique developed for measuring ultrasonic absorption by suspended particles is used to measure the absorption in suspensions of nonspherical particles. Two types of particulates are studied: (i) kaolin (china clay) particles which are platelike in form; and (ii) calcium carbonate particles which are more granular. Results are compared to theoretical predictions of visco-inertial absorption by suspensions of spherical particles. The particle size distributions, which are required for these predictions, are measured by laser diffraction, gravitational sedimentation and centrifugal sedimentation, all of which assume spherical particles. For a given sample, each sizing technique yields a different size distribution, leading to differences in the predicted absorption. The particle size distributions obtained by gravitational and centrifugal sedimentation are reinterpreted to yield a representative size distribution of oblate spheroids, and predictions for absorption by these spheroids are compared with the measurements. Good agreement between theory and measurement for the flat kaolin particles is obtained, demonstrating that these particles can be adequately represented by oblate spheroids.

Chloride accumulation vs chloride excretion: Phytoextraction potential of three halophytic grass species growing in a salinized landfill.

PubMed

McSorley, Kaitlin A; Rutter, Allison; Cumming, Robert; Zeeb, Barbara A

2016-12-01

Phragmites australis, Puccinnellia nuttalliana (salt accumulators), and Spartina pectinata (salt excretor) were investigated based on their relative abilities to phytoextract chloride from a cement kiln dust landfill in Bath, ON. Salt tolerance mechanisms were found to affect phytoextraction performance. On the basis of accumulation alone, P. australis had the greatest phytoextraction efficiency compared to the other two species due to its high biomass (despite having the lowest shoot ion concentrations). Conversely, when weekly salt excretion on the leaf surfaces of S. pectinata was accounted for over an eight week period from July to August 2014, removal of Cl - increased by 160% surpassing the extraction ability of P. australis by nearly 60%. Energy dispersive spectroscopy analysis of the excreted salt particles on S. pectinata indicates that they were composed of the plant macronutrient, potassium and micronutrient, chloride. Wind re-distribution of these nutrients may actually have beneficial effects on the environment, as they are required by both plants and animals for various metabolic functions. This is the first study to demonstrate salt excretion for the remediation of an industrially salinized landfill in Canada. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparison of plutonium systemic distribution in rats and dogs with published data in humans.

PubMed

Melo, Dunstana R; Weber, Waylon; Doyle-Eisele, Melanie; Guilmette, Raymond A

2014-11-01

This manuscript compares the behavior of monomeric (239)Pu(4+)-citrate injected intravenously in rats and dogs with a comparison of available humans' data. The experimental design for these two studies consisted of eight groups sacrificed at predetermined time-points post exposure. All organs and tissues as well as daily urinary and fecal excretion were analyzed. Liver and skeleton were the organs with the highest (239)Pu uptake in both species; 76% in dogs and 70% in rats at 24 hours (h) post IV administration. By the end of the study (28 days, d), the activity in skeleton and liver was 85% in dogs and 65% in rats. The urinary excretion function seems to be similar for rats, dogs and humans but the daily fecal to urinary excretion ratio differs between species. A rapid clearance from the liver of rats was observed compared to dogs. Skeleton-to-liver ratios are variable between species. Urinary and fecal excretion patterns for dogs are consistent with human data, indicating that dogs seem to represent better the (239)Pu behavior in humans. The data confirm that the better animal model to evaluate the efficacy of (239)Pu chelating compounds is the canine model.

Making bread with sourdough improves mineral bioavailability from reconstituted whole wheat flour in rats.

PubMed

Lopez, Hubert W; Duclos, Virgile; Coudray, Charles; Krespine, Virginie; Feillet-Coudray, Christine; Messager, Arnaud; Demigné, Christian; Rémésy, Christian

2003-06-01

We compared the effects of different kinds of bread fermentation on mineral bioavailability. Wistar rats were fed one of the following experimental diets for 21 d: control, reconstituted whole wheat flour (white flour plus bran), yeast bread, and sourdough bread. The apparent mineral absorption and intestinal fermentation were measured in each animal. Phytate contents in yeast and sourdough bread were lower than in reconstituted whole wheat flour (-52% and -71%, respectively). Total cecal pool of short-chain fatty acids, in particular the butyrate pool, was significantly increased by the ingestion of unrefined products. Calcium homeostasis was not modified by these nutritional conditions, whereas magnesium absorption was significantly greater in rats fed the control and sourdough diets than in those consuming whole wheat flour and yeast bread. Magnesium kidney excretion was slightly stimulated by sourdough bread. Compared with the control diet, iron balance was significantly reduced by reconstituted whole wheat flour diet. Yeast bread making counteracted the deleterious effects of whole wheat on iron absorption, whereas sourdough bread making enhanced iron absorption. Further, liver and plasma iron and transferrin saturation levels were lower in rats adapted to the flour diet than in other groups. Zinc absorption was strongly depressed in the presence of unprocessed reconstituted whole wheat flour in the diet, but yeast fermentation afforded a zinc assimilation comparable to the control diet, whereas the sourdough bread led to maximal zinc absorption. Copper absorption increased significantly when rats were fed the sourdough bread, whereas unprocessed whole flour depressed copper absorption (-41% versus control diet). Mineral bioavailability from reconstituted whole wheat flour can be improved by bread making. Although yeast fermentation minimizes the unfavorable effects of phytic acid, sourdough bread is a better source of available minerals, especially magnesium, iron, and zinc.

HCO3− secretion and CaCO3 precipitation play major roles in intestinal water absorption in marine teleost fish in vivo

PubMed Central

Cooper, Christopher A.; Wilson, Rod W.

2010-01-01

The intestine of marine teleosts must effectively absorb fluid from ingested seawater to avoid dehydration. This fluid transport has been almost exclusively characterized as driven by NaCl absorption. However, an additional feature of the osmoregulatory role of the intestine is substantial net HCO3− secretion. This is suggested to drive additional fluid absorption directly (via Cl−/HCO3− exchange) and indirectly by precipitating ingested Ca2+ as CaCO3, thus creating the osmotic gradient for additional fluid absorption. The present study tested this hypothesis by perfusing the intestine of the European flounder in vivo with varying [Ca2+]: 10 (control), 40, and 90 mM. Fractional fluid absorption increased from 47% (control) to 73% (90 mM Ca2+), where almost all secreted HCO3− was excreted as CaCO3. This additional fluid absorption could not be explained by NaCl cotransport. Instead, a significant positive relationship between Na+-independent fluid absorption and total HCO3− secretion was consistent with the predicted roles for anion exchange and CaCO3 precipitation. Further analysis suggested that Na+-independent fluid absorption could be accounted for by net Cl− and H+ absorption (from Cl−/HCO3− exchange and CO2 hydration, respectively). There was no evidence to suggest that CaCO3 alone was responsible for driving fluid absorption. However, by preventing the accumulation of luminal Ca2+ it played a vital role by dynamically maintaining a favorable osmotic gradient all along the intestine, which permits substantially higher rates of solute-linked fluid absorption. To overcome the resulting hyperosmotic and highly acidic absorbate, it is proposed that plasma HCO3− buffers the absorbed H+ (from HCO3− production), and consequently reduces the osmolarity of the absorbed fluid entering the body. PMID:20130226

Quantitative determination of five metabolites of aspirin by UHPLC-MS/MS coupled with enzymatic reaction and its application to evaluate the effects of aspirin dosage on the metabolic profile.

PubMed

Li, Jian-Ping; Guo, Jian-Ming; Shang, Er-Xin; Zhu, Zhen-Hua; Liu, Yang; Zhao, Bu-Chang; Zhao, Jing; Tang, Zhi-Shu; Duan, Jin-Ao

2017-05-10

Acetylsalicylic acid (Aspirin, ASA) is a famous drug for cardiovascular diseases in recent years. Effects of ASA dosage on the metabolic profile have not been fully understood. The purpose of our study is to establish a rapid and reliable method to quantify ASA metabolites in biological matrices, especially for glucuronide metabolites whose standards are not commercially available. Then we applied this method to evaluate the effects of ASA dosage on the metabolic and excretion profile of ASA metabolites in rat urine. Salicylic acid (SA), gentisic acid (GA) and salicyluric acid (SUA) were determined directly by UHPLC-MS/MS, while salicyl phenolic glucuronide (SAPG) and salicyluric acid phenolic glucuronide (SUAPG) were quantified indirectly by measuring the released SA and SUA from SAPG and SUAPG after β-glucuronidase digestion. SUA and SUAPG were the major metabolites of ASA in rat urine 24h after ASA administration, which accounted for 50% (SUA) and 26% (SUAPG). When ASA dosage was increased, the contributions dropped to 32% and 18%, respectively. The excretion of other three metabolites (GA, SA and SAPG) however showed remarkable increases by 16%, 6% and 4%, respectively. In addition, SUA and SUAPG were mainly excreted in the time period of 12-24h, while GA was excreted in the earlier time periods (0-4h and 4-8h). SA was mainly excreted in the time period of 0-4h and 12-24h. And the excretion of SAPG was equally distributed in the four time periods. We went further to show that the excretion of five metabolites in rat urine was delayed when ASA dosage was increased. In conclusion, we have developed a rapid and sensitive method to determine the five ASA metabolites (SA, GA, SUA, SAPG and SUAPG) in rat urine. We showed that ASA dosage could significantly influence the metabolic and excretion profile of ASA metabolites in rat urine. Copyright © 2016 Elsevier B.V. All rights reserved.

Accumulation, organ distribution, and excretion kinetics of ²⁴¹Am in Mayak Production Association workers.

PubMed

Suslova, Klara G; Sokolova, Alexandra B; Efimov, Alexander V; Miller, Scott C

2013-03-01

Americium-241 (²⁴¹Am) is the second most significant radiation hazard after ²³⁹Pu at some of the Mayak Production Association facilities. This study summarizes current data on the accumulation, distribution, and excretion of americium compared with plutonium in different organs from former Mayak PA workers. Americium and plutonium were measured in autopsy and bioassay samples and correlated with the presence or absence of chronic disease and with biological transportability of the aerosols encountered at different workplaces. The relative accumulation of ²⁴¹Am was found to be increasing in the workers over time. This is likely from ²⁴¹Pu that increases with time in reprocessed fuel and from the increased concentrations of ²⁴¹Am and ²⁴¹Pu in inhaled alpha-active aerosols. While differences were observed in lung retention with exposures to different industrial compounds with different transportabilities (i.e., dioxide and nitrates), there were no significant differences in lung retention between americium and plutonium within each transportability group. In the non-pulmonary organs, the highest ratios of ²⁴¹Am/²⁴¹Am + SPu were observed in the skeleton. The relative ratios of americium in the skeleton versus liver were significantly greater than for plutonium. The relative amounts of americium and plutonium found in the skeleton compared with the liver were even greater in workers with documented chronic liver diseases. Excretion rates of ²⁴¹Am in ‘‘healthy’’ workers were estimated using bioassay and autopsy data. The data suggest that impaired liver function leads to reduced hepatic ²⁴¹Am retention, leading to increased ²⁴¹Am excretion.

Emission estimation and multimedia fate modeling of seven steroids at the river basin scale in China.

PubMed

Zhang, Qian Qian; Zhao, Jian-Liang; Ying, Guang-Guo; Liu, You-Sheng; Pan, Chang-Gui

2014-07-15

Steroids are excreted from humans and animals and discharged with wastewaters into the environment, resulting in potential adverse effects on organisms. Based on the excretion rates from different groups of humans and animals, the emissions of seven steroids (estrone (E1), 17β-estradiol (E2), estriol (E3), testosterone (T), androsterone (A), progesterone (P), and cortisol (C)) were comprehensively estimated in 58 river basins of whole China, and their multimedia fate was simulated by using a level III fugacity multimedia model. The results showed that higher emission densities for the steroids were found in the river basins of east China than in west China. This distribution was found to be generally similar to the distribution of Gross Domestic Product (GDP) across China. E3, A, and P displayed higher emission densities than the other steroids in most of the river basins. The total excretion of steroids by humans and animals in China was estimated to be 3069 t/yr. The excretion of steroids from animals was two times larger than that from humans. After various treatments, the total emission of steroids was reduced to 2486 t/yr, of which more than 80% was discharged into the water compartment. The predicted concentrations in water were within an order of magnitude of the measured concentrations available in the literature. Owing to wastewater irrigation, more steroid mass loadings in agricultural soil were found in the basins of Haihe River and Huaihe River in comparison with the other river basins. To the best of our knowledge, this is the first report on the emissions and multimedia fate of seven steroids in the river basins of China.

Age-Related Shifts in the Density and Distribution of Genetic Marker Water Quality Indicators in Cow and Calf Feces (Journal)

EPA Science Inventory

Calves (≤ 226 kg body mass) make up about 16% of the current bovine population in the United States and can excrete high levels of human pathogens. We describe the density and distribution of genetic markers from 11 PCR- and real-time quantitative PCR-based assays including CF...

Excretion and toxicity evaluation of 131I-Sennoside A as a necrosis-avid agent.

PubMed

Yin, Zhiqi; Sun, Lidan; Jin, Qiaomei; Song, Shaoli; Feng, Yuanbo; Liao, Hong; Ni, Yicheng; Zhang, Jian; Liu, Wei

2017-11-01

1. Sennoside A (SA) is a newly identified necrosis-avid agent that shows capability for imaging diagnosis and tumor necrosis targeted radiotherapy. As a water-soluble compound, 131 I-Sennoside A ( 131 I-SA) might be excreted predominately through the kidneys with the possibility of nephrotoxicity. 2. To further verify excretion pathway and examine nephrotoxicity of 131 I-SA, excretion and nephrotoxicity were appraised. The pharmacokinetics, hepatotoxicity and hematotoxicity of 131 I-SA were also evaluated to accelerate its possible clinical translation. All these studies were conducted in mice with ethanol-induced muscular necrosis following a single intravenous administration of 131I-SA at 18.5 MBq/kg or 370 MBq/kg. 3. Excretion data revealed that 131 I-SA was predominately (73.5% of the injected dose (% ID)) excreted via the kidneys with 69.5% ID detected in urine within 72 h post injection. Biodistribution study indicated that 131 I-SA exhibited initial high distribution in the kidneys but subsequently a fast renal clearance, which was further confirmed by the results of autoradiography and single-photon emission computed tomography-computed tomography (SPECT-CT) imaging. The maximum necrotic to normal muscle ratio reached to 7.9-fold at 48 h post injection, which further verified the necrosis avidity of 131 I-SA. Pharmacokinetic parameters showed that 131 I-SA had fast blood clearance with an elimination half-life of 6.7 h. Various functional indexes were no significant difference (p > 0.05) between before administration and 1 d, 8 d, 16 d after administration. Histopathology showed no signs of tissue damage. 4. These data suggest 131 I-SA is a safe and promising necrosis-avid agent applicable in imaging diagnosis and tumor necrosis targeted radiotherapy.

Recommendation to Exclude Bile-Duct-Cannulated Rats with Hyperbilirubinemia for Proper Conduct of Biliary Drug Excretion Studies.

PubMed

Kato, Koji; Hasegawa, Yoshitaka; Iwata, Katsuya; Ichikawa, Takuya; Yahara, Tohru; Tsuji, Satoshi; Sugiura, Masayuki; Yamaguchi, Jun-Ichi

2016-08-01

Hyperbilirubinemia (HB) is sometimes encountered following bile-duct cannulation in rats. It possibly originates from the reduced functioning of multidrug resistance-associated protein 2 (Mrp2) and subsequent adaptive alterations in the expression of Mrp3 and the organic anion transporting polypeptides (Oatps). Our aim was to clarify the importance of excluding bile-duct-cannulated (BDC) rats with HB for proper conduct of drug excretion studies. We detected HB [serum total bilirubin concentration (TBIL) ≥0.20 mg/dl] in 16% of all BDC rats prepared. The serum activities of aspartate aminotransferase, alanine aminotransferase, leucine aminopeptidase, and alkaline phosphatase were within the respective normal ranges in the BDC rats with mild HB (TBIL, 0.20-0.79 mg/dl), indicating the absence of hepatic failure. In the pharmacokinetics of pravastatin, an Oatps/Mrp2 probe drug in the BDC rats, the apparent volume of distribution and the clearance were smaller in the mild HB group as compared with the normal group, suggesting the reduction of apparent hepatic uptake and hepatobiliary elimination. The biliary excretion (percentage of dose) was significantly reduced by 54%, suggesting that the biliary efflux activity via Mrp2 was reduced to a greater extent relative to metabolic activity in hepatocytes. The serum γ-glutamyltransferase (GGT) activity correlated with TBIL and inversely correlated with biliary excretion of pravastatin, a finding which could serve as a clue to uncover the regulatory system involving cooperation between GGT and Mrp2. In conclusion, BDC rats with HB, however mild, should be excluded from drug excretion studies to avoid the risk of underestimation of the biliary excretion of drugs. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Differences in the Fecal Concentrations and Genetic Diversities of Campylobacter jejuni Populations among Individual Cows in Two Dairy Herds

PubMed Central

Ross, Colleen M.; Pleydell, Eve J.; Muirhead, Richard W.

2012-01-01

Dairy cows have been identified as common carriers of Campylobacter jejuni, which causes many of the human gastroenteritis cases reported worldwide. To design on-farm management practices that control the human infection sourced from dairy cows, the first step is to acquire an understanding of the excretion patterns of the cow reservoir. We monitored the same 35 cows from two dairy farms for C. jejuni excretion fortnightly for up to 12 months. The objective was to examine the concentration of C. jejuni and assess the genetic relationship of the C. jejuni populations excreted by individual cows. Significant differences (P < 0.01) in C. jejuni fecal concentration were observed among the 35 cows, with median concentrations that varied by up to 3.6 log10 · g−1 feces. A total of 36 different genotypes were identified from the 514 positive samples by using enterobacterial repetitive intergenic consensus (ERIC)-PCR. Although 22 of these genotypes were excreted by more than one cow, the analysis of frequencies and distribution of the genotypes by model-based statistics revealed a high degree of individuality in the C. jejuni population in each cow. The observed variation in the frequency of excretion of a genotype among cows and the analysis by multilocus sequence typing (MLST) of these genotypes suggest that excretion of C. jejuni in high numbers is due to a successful adaptation of a particular genotype to a particular cow's gut environment, but that animal-related factors render some individual cows resistant to colonization by particular genotypes. The reasons for differences in C. jejuni colonization of animals warrant further investigation. PMID:22904055

Reduced Hepatic Uptake and Intestinal Excretion of Organic Cations in Mice with a Targeted Disruption of the Organic Cation Transporter 1 (Oct1 [Slc22a1]) Gene

PubMed Central

Jonker, Johan W.; Wagenaar, Els; Mol, Carla A. A. M.; Buitelaar, Marije; Koepsell, Hermann; Smit, Johan W.; Schinkel, Alfred H.

2001-01-01

The polyspecific organic cation transporter 1 (OCT1 [SLC22A1]) mediates facilitated transport of small (hydrophilic) organic cations. OCT1 is localized at the basolateral membrane of epithelial cells in the liver, kidney, and intestine and could therefore be involved in the elimination of endogenous amines and xenobiotics via these organs. To investigate the pharmacologic and physiologic role of this transport protein, we generated Oct1 knockout (Oct1−/−) mice. Oct1−/− mice appeared to be viable, healthy, and fertile and displayed no obvious phenotypic abnormalities. The role of Oct1 in the pharmacology of substrate drugs was studied by comparing the distribution and excretion of the model substrate tetraethylammonium (TEA) after intravenous administration to wild-type and Oct1−/− mice. In Oct1−/− mice, accumulation of TEA in liver was four to sixfold lower than in wild-type mice, whereas direct intestinal excretion of TEA was reduced about twofold. Excretion of TEA into urine over 1 h was 53% of the dose in wild-type mice, compared to 80% in knockout mice, probably because in Oct1−/− mice less TEA accumulates in the liver and thus more is available for rapid excretion by the kidney. In addition, we found that absence of Oct1 leads to decreased liver accumulation of the anticancer drug metaiodobenzylguanidine and the neurotoxin 1-methyl-4-phenylpyridium. In conclusion, our data show that Oct1 plays an important role in the uptake of organic cations into the liver and in their direct excretion into the lumen of the small intestine. PMID:11463829

SeHCAT absorption: a simple test of ileal dysfunction.

PubMed

Fagan, E A; Chadwick, V S; Baird, I M

1983-01-01

A new selenium-labelled synthetic bile salt SeHCAT (taurine conjugate of 23-[75Se]-25-homocholic acid) was assessed as a test of ileal dysfunction in 20 patients with inflammatory bowel disease (IBD). Whole body retention of SeHCAT was compared with tests of vitamin B12 absorption (Schilling test and whole body retention) and the cholylglycine-1-14C breath test and faecal isotope excretion. Clear differentiation, with no overlap was obtained between 10 normal subjects and patients with ileal disease/resection in the SeHCAT 7-day retention results. The Schilling test was more sensitive; enabling discrimination between patients with limited and extensive ileal disease/resection. An unexpected rise in SeHCAT retention was observed in patients with colonic IBD. The 7-day SeHCAT retention is a safe, simple screening test for ileal dysfunction and has practical advantages compared with the Schilling test.

Intestinal "bioavailability" of solutes and water: we know how but not why.

PubMed Central

Charney, A. N.

1996-01-01

Only minimal quantities of ingested and normally secreted solutes and water are excreted in the stool. This near 100% bioavailability means that the diet and kidneys are relatively more important determinants of solute, water and acid-base balance than the intestine. Intestinal bioavailability is based on excess transport capacity under normal conditions and the ability to adapt to altered or abnormal conditions. Indeed, the regulatory system of the intestine is as complex, segmented and multi factorial as in the kidney. Alterations in the rate and intestinal site of absorption reflect this regulation, and the diagnosis and treatment of various clinical abnormalities depend on the integrity of intestinal absorptive processes. However, the basis for this regulation an bioavailability are uncertain. Perhaps they had survival value for mammals, a phylogenic class that faced the twin threats of intestinal pathogens and shortages of solutes and water. PMID:9273987

Morphogenesis and maturation of the embryonic and postnatal intestine.

PubMed

Chin, Alana M; Hill, David R; Aurora, Megan; Spence, Jason R

2017-06-01

The intestine is a vital organ responsible for nutrient absorption, bile and waste excretion, and a major site of host immunity. In order to keep up with daily demands, the intestine has evolved a mechanism to expand the absorptive surface area by undergoing a morphogenetic process to generate finger-like units called villi. These villi house specialized cell types critical for both absorbing nutrients from food, and for protecting the host from commensal and pathogenic microbes present in the adult gut. In this review, we will discuss mechanisms that coordinate intestinal development, growth, and maturation of the small intestine, starting from the formation of the early gut tube, through villus morphogenesis and into early postnatal life when the intestine must adapt to the acquisition of nutrients through food intake, and to interactions with microbes. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

The pharmacokinetics and disposition of MK-0524, a Prosglandin D2 Receptor 1 antagonist, in rats, dogs and monkeys.

PubMed

Chang, S W; Reddy, V; Pereira, T; Dean, B J; Xia, Y-Q; Seto, C; Franklin, R B; Karanam, B V

2007-05-01

MK-0524 is a potent, selective and orally active Prosglandin D(2) Receptor 1 (DP(1)) antagonist currently under clinical development for the treatment of niacin-induced flushing. Experiments to study the pharmacokinetics, metabolism and excretion of MK-0524 were conducted in rats, dogs and monkeys. MK-0524 displayed linear kinetics and rapid absorption following an oral dose. Following intravenous (i.v.) administration of MK-0524 to rats and dogs (1 and 5 mg/kg), the mean Cl(p) was approximately 2 and approximately 6 ml/min/kg, the T(1/2) was approximately 7 and approximately 13 h and the Vd(ss) was approximately 1 and approximately 5 L/kg, respectively. In monkeys dosed i.v. at 3 mg/kg, the corresponding values were 8 ml/min/kg, 3 h and 1 L/kg, respectively. Following oral dosing of MK-0524 to rats (5, 25 and 100 mg/kg), dogs (5 mg/kg) and monkeys (3 mg/kg), the absorption was rapid with the mean C(max) occurring between 1 and 4 h. Absolute oral bioavailability values in rats, dogs and monkeys were 50, 70 and 8%, respectively. The major circulating metabolite was the acyl glucuronide of MK-0524 (M2), with ratios of glucuronide to the parent aglycone being highest in the monkey followed by dog and rat. In bile duct-cannulated rats and dogs, MK-0524 was eliminated primarily via acyl glucuronidation followed by biliary excretion of the acyl glucuronide, M2, the major drug-related entity in bile.

An open-label, single-dose, phase 1 study of the absorption, metabolism and excretion of quizartinib, a highly selective and potent FLT3 tyrosine kinase inhibitor, in healthy male subjects, for the treatment of acute myeloid leukemia.

PubMed

Sanga, Madhu; James, Joyce; Marini, Joseph; Gammon, Guy; Hale, Christine; Li, Jianke

2017-10-01

1. Quizartinib absorption, metabolism and excretion were characterized in six healthy men receiving a single oral dose of 60 mg (≈100 μCi) of [ 14 C]-quizartinib. Blood, plasma, urine and faeces were collected ≤336 h postdose. 2. Four hours postdose, maximum mean ± SD blood radioactivity concentrations were 296 ± 67.4 ng equivalents/g. A mean ± SD of 1.64 ± 0.482% and 76.3 ± 6.23% of the dose was recovered in urine and faeces, respectively, within 336 h postdose. 3. Radio-detector high-performance liquid chromatography (radio-HPLC) and liquid chromatography-mass spectrometry (LC-MS) showed two main radioactive peaks in plasma, unchanged quizartinib and mono-oxidative metabolite, AC886. Five additional metabolites in plasma were identified by LC-MS, but low levels prevented radio-HPLC detection. Although unchanged quizartinib was the main radioactive component in faeces (mean, 4.0% of administered dose), 15 metabolites representing a mean of 1.0-3.5% of administered dose were found. Quizartinib was predominantly metabolized by phase I biotransformations (oxidation, reduction, dealkylation, deamination, hydrolysis and combinations thereof). 4. This study indicated that quizartinib was rapidly and orally bioavailable, extensively metabolized, with AC886 as the major circulating metabolite, and predominantly eliminated in faeces. Quizartinib was well tolerated in the subjects.

Comparison of breath testing with fructose and high fructose corn syrups in health and IBS

PubMed Central

Skoog, S. M.; Bharucha, A. E.; Zinsmeister, A. R.

2008-01-01

Although incomplete fructose absorption has been implicated to cause gastrointestinal symptoms, foods containing high fructose corn syrup (HFCS) contain glucose. Glucose increases fructose absorption in healthy subjects. Our hypothesis was that fructose intolerance is less prevalent after HFCS consumption compared to fructose alone in healthy subjects and irritable bowel syndrome (IBS). Breath hydrogen levels and gastrointestinal symptoms were assessed after 40 g of fructose (12% solution) prepared either in water or as HFCS, administered in double-blind randomized order on 2 days in 20 healthy subjects and 30 patients with IBS. Gastrointestinal symptoms were recorded on 100-mm Visual Analogue Scales. Breath hydrogen excretion was more frequently abnormal (P < 0.01) after fructose (68%) than HFCS (26%) in controls and patients. Fructose intolerance (i.e. abnormal breath test and symptoms) was more prevalent after fructose than HFCS in healthy subjects (25% vs 0%, P = 0.002) and patients (40% vs 7%, P = 0.062). Scores for several symptoms (e.g. bloating r = 0.35) were correlated (P ≤ 0.01) to peak breath hydrogen excretion after fructose but not HFCS; in the fructose group, this association did not differ between healthy subjects and patients. Symptoms were not significantly different after fructose compared to HFCS. Fructose intolerance is more prevalent with fructose alone than with HFCS in health and in IBS. The prevalence of fructose intolerance is not significantly different between health and IBS. Current methods for identifying fructose intolerance should be modified to more closely reproduce fructose ingestion in daily life. PMID:18221251

Comparison of breath testing with fructose and high fructose corn syrups in health and IBS.

PubMed

Skoog, S M; Bharucha, A E; Zinsmeister, A R

2008-05-01

Although incomplete fructose absorption has been implicated to cause gastrointestinal symptoms, foods containing high fructose corn syrup (HFCS) contain glucose. Glucose increases fructose absorption in healthy subjects. Our hypothesis was that fructose intolerance is less prevalent after HFCS consumption compared to fructose alone in healthy subjects and irritable bowel syndrome (IBS). Breath hydrogen levels and gastrointestinal symptoms were assessed after 40 g of fructose (12% solution) prepared either in water or as HFCS, administered in double-blind randomized order on 2 days in 20 healthy subjects and 30 patients with IBS. Gastrointestinal symptoms were recorded on 100-mm Visual Analogue Scales. Breath hydrogen excretion was more frequently abnormal (P < 0.01) after fructose (68%) than HFCS (26%) in controls and patients. Fructose intolerance (i.e. abnormal breath test and symptoms) was more prevalent after fructose than HFCS in healthy subjects (25% vs. 0%, P = 0.002) and patients (40% vs. 7%, P = 0.062). Scores for several symptoms (e.g. bloating r = 0.35) were correlated (P < or = 0.01) to peak breath hydrogen excretion after fructose but not HFCS; in the fructose group, this association did not differ between healthy subjects and patients. Symptoms were not significantly different after fructose compared to HFCS. Fructose intolerance is more prevalent with fructose alone than with HFCS in health and in IBS. The prevalence of fructose intolerance is not significantly different between health and IBS. Current methods for identifying fructose intolerance should be modified to more closely reproduce fructose ingestion in daily life.

Pharmacokinetic modeling of 4,4'-methylenedianiline released from reused polyurethane dialyzer potting materials.

PubMed

Do Luu, H M; Hutter, J C

2000-01-01

4, 4'-Methylenedianiline (MDA) is a hydrolysis degradation product that can be released from polyurethanes commonly used in medical device applications. MDA is mutagenic and carcinogenic in animals. In humans, it is hepatotoxic, a known contact and respiratory allergen, and a suspected carcinogen. A physiologically based pharmacokinetic (PBPK) model was developed to estimate the absorption, distribution, metabolism, and excretion of MDA in patients exposed to MDA leached from the potting materials of hemodialyzers. A worst-case reuse situation and a single use case were investigated. The PBPK model included five tissue compartments: liver, kidney, gastrointestinal tract, slowly perfused tissues, and richly perfused tissues. Physiological and chemical parameters of a healthy individual used in the model were obtained from the literature. The model was calibrated using previously published kinetic studies of IV administered doses of (14) C-MDA to rats. The model was validated using independent data published for MDA-exposed workers. The PBPK results indicated that dialysis patients who are exposed to MDA released from dialyzers (new or reused) could accumulate low levels of MDA and metabolites (total MDA) over time. Copyright 2000 John Wiley & Sons, Inc.

Discovery of a Hepatitis C Virus NS5B Replicase Palm Site Allosteric Inhibitor (BMS-929075) Advanced to Phase 1 Clinical Studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yeung, Kap-Sun; Beno, Brett R.; Parcella, Kyle

The hepatitis C virus (HCV) NS5B replicase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Inspired by the overlay of bound structures of three structurally distinct NS5B palm site allosteric inhibitors, the high-throughput screening hit anthranilic acid 4, the known benzofuran analogue 5, and the benzothiadiazine derivative 6, an optimization process utilizing the simple benzofuran template 7 as a starting point for a fragment growing approach was pursued. A delicate balance of molecular properties achieved via disciplined lipophilicity changes was essential to achieve both high affinity binding and a stringentmore » targeted absorption, distribution, metabolism, and excretion profile. These efforts led to the discovery of BMS-929075 (37), which maintained ligand efficiency relative to early leads, demonstrated efficacy in a triple combination regimen in HCV replicon cells, and exhibited consistently high oral bioavailability and pharmacokinetic parameters across preclinical animal species. The human PK properties from the Phase I clinical studies of 37 were better than anticipated and suggest promising potential for QD administration.« less

Computational optimization of AG18051 inhibitor for amyloid-beta binding alcohol dehydrogenase enzyme

NASA Astrophysics Data System (ADS)

Marques, Alexandra T.; Antunes, Agostinho; Fernandes, Pedro A.; Ramos, Maria J.

Amyloid-beta (Abeta) binding alcohol dehydrogenase (ABAD) is a multifunctional enzyme involved in maintaining the homeostasis. The enzyme can also mediate some diseases, including genetic diseases, Alzheimer's disease, and possibly some prostate cancers. Potent inhibitors of ABAD might facilitate a better clarification of the functions of the enzyme under normal and pathogenic conditions and might also be used for therapeutic intervention in disease conditions mediated by the enzyme. The AG18051 is the only presently available inhibitor of ABAD. It binds in the active-site cavity of the enzyme and reacts with the NAD+ cofactor to form a covalent adduct. In this work, we use computational methods to perform a rational optimization of the AG18051 inhibitor, through the introduction of chemical substitutions directed to improve the affinity of the inhibitor to the enzyme. The molecular mechanics-Poisson-Boltzmann surface area methodology was used to predict the relative free binding energy of the different modified inhibitor-NAD-enzyme complexes. We show that it is possible to increase significantly the affinity of the inhibitor to the enzyme with small modifications, without changing the overall structure and ADME (absorption, distribution, metabolism, and excretion) properties of the original inhibitor.

Development and validation of a physiology-based model for the prediction of pharmacokinetics/toxicokinetics in rabbits

PubMed Central

Hermes, Helen E.; Teutonico, Donato; Preuss, Thomas G.; Schneckener, Sebastian

2018-01-01

The environmental fates of pharmaceuticals and the effects of crop protection products on non-target species are subjects that are undergoing intense review. Since measuring the concentrations and effects of xenobiotics on all affected species under all conceivable scenarios is not feasible, standard laboratory animals such as rabbits are tested, and the observed adverse effects are translated to focal species for environmental risk assessments. In that respect, mathematical modelling is becoming increasingly important for evaluating the consequences of pesticides in untested scenarios. In particular, physiologically based pharmacokinetic/toxicokinetic (PBPK/TK) modelling is a well-established methodology used to predict tissue concentrations based on the absorption, distribution, metabolism and excretion of drugs and toxicants. In the present work, a rabbit PBPK/TK model is developed and evaluated with data available from the literature. The model predictions include scenarios of both intravenous (i.v.) and oral (p.o.) administration of small and large compounds. The presented rabbit PBPK/TK model predicts the pharmacokinetics (Cmax, AUC) of the tested compounds with an average 1.7-fold error. This result indicates a good predictive capacity of the model, which enables its use for risk assessment modelling and simulations. PMID:29561908

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

PubMed Central

Baquedano, Ylenia; Alcolea, Verónica; Toro, Miguel Ángel; Gutiérrez, Killian Jesús; Nguewa, Paul; Font, María; Moreno, Esther; Espuelas, Socorro; Jiménez-Ruiz, Antonio; Palop, Juan Antonio; Plano, Daniel

2016-01-01

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 μM and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3′-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design. PMID:27067328

Drug interactions evaluation: An integrated part of risk assessment of therapeutics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Lei; Reynolds, Kellie S.; Zhao, Ping

2010-03-01

Pharmacokinetic drug interactions can lead to serious adverse events or decreased drug efficacy. The evaluation of a new molecular entity's (NME's) drug-drug interaction potential is an integral part of risk assessment during drug development and regulatory review. Alteration of activities of enzymes or transporters involved in the absorption, distribution, metabolism, or excretion of a new molecular entity by concomitant drugs may alter drug exposure, which can impact response (safety or efficacy). The recent Food and Drug Administration (FDA) draft drug interaction guidance ( (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072101.pdf)) highlights the methodologies and criteria that may be used to guide drug interaction evaluation by industrymore » and regulatory agencies and to construct informative labeling for health practitioner and patients. In addition, the Food and Drug Administration established a 'Drug Development and Drug Interactions' website to provide up-to-date information regarding evaluation of drug interactions ( (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm080499.htm)). This review summarizes key elements in the FDA drug interaction guidance and new scientific developments that can guide the evaluation of drug-drug interactions during the drug development process.« less

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

PubMed Central

Makarov, Vadim; Neres, João; Hartkoorn, Ruben C.; Ryabova, Olga B.; Kazakova, Elena; Šarkan, Michal; Huszár, Stanislav; Piton, Jérémie; Kolly, Gaëlle S.; Vocat, Anthony; Conroy, Trent M.; Mikušová, Katarína

2015-01-01

8-Nitro-benzothiazinones (BTZs), such as BTZ043 and PBTZ169, inhibit decaprenylphosphoryl-β-d-ribose 2′-oxidase (DprE1) and display nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. To date, substitution of the 8-nitro group has led to extensive loss of antimycobacterial activity. Here, we report the synthesis and characterization of the pyrrole-benzothiazinones PyrBTZ01 and PyrBTZ02, non-nitro-benzothiazinones that retain significant antimycobacterial activity, with MICs of 0.16 μg/ml against M. tuberculosis. These compounds inhibit DprE1 with 50% inhibitory concentration (IC50) values of <8 μM and present favorable in vitro absorption-distribution-metabolism-excretion/toxicity (ADME/T) and in vivo pharmacokinetic profiles. The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency. PMID:25987616

Precision-cut intestinal slices: alternative model for drug transport, metabolism, and toxicology research.

PubMed

Li, Ming; de Graaf, Inge A M; Groothuis, Geny M M

2016-01-01

The absorption, distribution, metabolism, excretion and toxicity (ADME-tox) processes of drugs are of importance and require preclinical investigation intestine in addition to the liver. Various models have been developed for prediction of ADME-tox in the intestine. In this review, precision-cut intestinal slices (PCIS) are discussed and highlighted as model for ADME-tox studies. This review provides an overview of the applications and an update of the most recent research on PCIS as an ex vivo model to study the transport, metabolism and toxicology of drugs and other xenobiotics. The unique features of PCIS and the differences with other models as well as the translational aspects are also discussed. PCIS are a simple, fast, and reliable ex vivo model for drug ADME-tox research. Therefore, PCIS are expected to become an indispensable link in the in vitro-ex vivo-in vivo extrapolation, and a bridge in translation of animal data to the human situation. In the future, this model may be helpful to study the effects of interorgan interactions, intestinal bacteria, excipients and drug formulations on the ADME-tox properties of drugs. The optimization of culture medium and the development of a (cryo)preservation technique require more research.

Review on Prescription Compatibility of Shaoyao Gancao Decoction and Reflection on Pharmacokinetic Compatibility Mechanism of Traditional Chinese Medicine Prescription Based on In Vivo Drug Interaction of Main Efficacious Components

PubMed Central

Bi, Xiaolin; Gong, Meirong; Di, Liuqing

2014-01-01

Shaoyao Gancao Decoction (SGD) derived from Zhang Zhongjing's “Typhoid Theory” is composed of peony and licorice, having the efficacy of nourishing liver, relaxing spasm, and relieving pain. Modern compatibility studies of SGD on chemistry, pharmacology, and pharmacokinetics all demonstrate the reasonable compatibility of peony and licorice. However, the present research on pharmacokinetics is only descriptive and limited to the influence on in vivo dynamic process of certain ingredients; correspondingly, there is lack of studies on the essence of these efficacious substances' in vivo changes; that is, whether it is because there exists in vivo drug interaction in absorption, distribution, metabolism, and excretion (ADME) of active ingredients that leads to the improvement of bioavailability. We herein take SGD as an example and suggest that it is necessary to study in vivo drug interaction of main efficacious components mediated by metabolic enzymes, transport proteins, or plasma protein binding in the course of ADME, which is helpful to illustrate the principle of pharmacokinetic compatibility from the essence leading to the changes of effective substances in vivo. PMID:25147573

Polychlorinated biphenyl congener patterns in fish near the Hanford Site (Washington State, USA).

PubMed

Rodenburg, Lisa A; Delistraty, Damon; Meng, Qingyu

2015-03-03

It is well-known that absorption, distribution, metabolism, and excretion (ADME) processes in fish can alter polychlorinated biphenyl (PCB) congener patterns in fish, but these patterns have never been investigated using an advanced source-apportionment tool. In this work, PCB congener patterns in freshwater fish were examined with positive matrix factorization (PMF). PCB congeners were quantified via EPA Method 1668 in fillet and carcass of six species in four study areas in the Columbia River near the Hanford Site. Six factors were resolved with PMF2 software. Depletion and enhancement of PCB congeners in factors, relative to Aroclor 1254, suggested biotransformation (via cytochrome P450) and bioaccumulation in fish, respectively. Notable differences were observed among species and across study locations. For example, sturgeon and whitefish exhibited congener patterns consistent with Aroclor weathering, suggesting potential PCB metabolism in these species. In terms of location, average concentration of total PCBs for all species combined was significantly higher (P < 0.05) at Hanford 100 and 300 areas, relative to upriver and downriver study sites. Furthermore, a distinct PCB signature in sturgeon and whitefish, collected at Hanford study areas, suggests that Hanford is a unique PCB source.

[Interaction between CYP450 enzymes and metabolism of traditional Chinese medicine as well as enzyme activity assay].

PubMed

Lu, Tu-lin; Su, Lian-lin; Ji, De; Gu, Wei; Mao, Chun-qin

2015-09-01

Drugs are exogenous compounds for human bodies, and will be metabolized by many enzymes after administration. CYP450 enzyme, as a major metabolic enzyme, is an important phase I drug metabolizing enzyme. In human bodies, about 75% of drug metabolism is conducted by CYP450 enzymes, and CYP450 enzymes is the key factor for drug interactions between traditional Chinese medicine( TCM) -TCM, TCM-medicine and other drug combination. In order to make clear the interaction between metabolic enzymes and TCM metabolism, we generally chose the enzymatic activity as an evaluation index. That is to say, the enhancement or reduction of CYP450 enzyme activity was used to infer the inducing or inhibitory effect of active ingredients and extracts of traditional Chinese medicine on enzymes. At present, the common method for measuring metabolic enzyme activity is Cocktail probe drugs, and it is the key to select the suitable probe substrates. This is of great significance for study drug's absorption, distribution, metabolism and excretion (ADME) process in organisms. The study focuses on the interaction between TCMs, active ingredients, herbal extracts, cocktail probe substrates as well as CYP450 enzymes, in order to guide future studies.

Insecticide ADME for support of early-phase discovery: combining classical and modern techniques.

PubMed

David, Michael D

2017-04-01

The two factors that determine an insecticide's potency are its binding to a target site (intrinsic activity) and the ability of its active form to reach the target site (bioavailability). Bioavailability is dictated by the compound's stability and transport kinetics, which are determined by both physical and biochemical characteristics. At BASF Global Insecticide Research, we characterize bioavailability in early research with an ADME (Absorption, Distribution, Metabolism and Excretion) approach, combining classical and modern techniques. For biochemical assessment of metabolism, we purify native insect enzymes using classical techniques, and recombinantly express individual insect enzymes that are known to be relevant in insecticide metabolism and resistance. For analytical characterization of an experimental insecticide and its metabolites, we conduct classical radiotracer translocation studies when a radiolabel is available. In discovery, where typically no radiolabel has been synthesized, we utilize modern high-resolution mass spectrometry to probe complex systems for the test compounds and its metabolites. By using these combined approaches, we can rapidly compare the ADME properties of sets of new experimental insecticides and aid in the design of structures with an improved potential to advance in the research pipeline. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Addressing the inter-individual variation in response to consumption of plant food bioactives: Towards a better understanding of their role in healthy aging and cardiometabolic risk reduction.

PubMed

Manach, Claudine; Milenkovic, Dragan; Van de Wiele, Tom; Rodriguez-Mateos, Ana; de Roos, Baukje; Garcia-Conesa, Maria Teresa; Landberg, Rikard; Gibney, Eileen R; Heinonen, Marina; Tomás-Barberán, Francisco; Morand, Christine

2017-06-01

Bioactive compounds in plant-based foods have health properties that contribute to the prevention of age-related chronic diseases, particularly cardiometabolic disorders. Conclusive proof and understanding of these benefits in humans is essential in order to provide effective dietary recommendations but, so far, the evidence obtained from human intervention trials is limited and contradictory. This is partly due to differences between individuals in the absorption, distribution, metabolism and excretion of bioactive compounds, as well as to heterogeneity in their biological response regarding cardiometabolic health outcomes. Identifying the main factors underlying inter-individual differences, as well as developing new and innovative methodologies to account for such variability constitute an overarching goal to ultimately optimize the beneficial health effects of plant food bioactives for each and every one of us. In this respect, this position paper from the COST Action FA1403-POSITIVe examines the main factors likely to affect the individual responses to consumption of plant food bioactives and presents perspectives for assessment and consideration of inter-individual variability. © 2016 The Authors. Molecular Nutrition & Food Research published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Single Nucleotide Polymorphisms in Cellular Drug Transporters Are Associated with Intolerance to Antiretroviral Therapy in Brazilian HIV-1 Positive Individuals.

PubMed

Arruda, Mônica Barcellos; Campagnari, Francine; de Almeida, Tailah Bernardo; Couto-Fernandez, José Carlos; Tanuri, Amilcar; Cardoso, Cynthia Chester

2016-01-01

Adverse reactions are the main cause of treatment discontinuation among HIV+ individuals. Genes related to drug absorption, distribution, metabolism and excretion (ADME) influence drug bioavailability and treatment response. We have investigated the association between single nucleotide polymorphisms (SNPs) in 29 ADME genes and intolerance to therapy in a case-control study including 764 individuals. Results showed that 15 SNPs were associated with intolerance to nucleoside and 11 to non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs), and 8 to protease inhibitors (PIs) containing regimens under alpha = 0.05. After Bonferroni adjustment, two associations remained statistically significant. SNP rs2712816, at SLCO2B1 was associated to intolerance to NRTIs (ORGA/AA = 2.37; p = 0.0001), while rs4148396, at ABCC2, conferred risk of intolerance to PIs containing regimens (ORCT/TT = 2.64; p = 0.00009). Accordingly, haplotypes carrying rs2712816A and rs4148396T alleles were also associated to risk of intolerance to NRTIs and PIs, respectively. Our data reinforce the role of drug transporters in response to HIV therapy and may contribute to a future development of personalized therapies.

Maximizing the success of bile duct cannulation studies in rats: recommendations for best practice.

PubMed

Burden, Natalie; Kendrick, John; Knight, Lindsay; McGregor, Victoria; Murphy, Helen; Punler, Malcolm; van Wijk, Hans

2017-10-01

Bile duct cannulation (BDC) studies are usually carried out in the rat to support the absorption, distribution, metabolism and excretion profiling of novel agrochemicals and pharmaceuticals. The different aspects of these studies (e.g. surgical preparation, dosing and collection of bile) can be intricate and/or technically complex. The animals are often kept singly housed for the duration of the studies following surgical implantation of the cannulas. The generation of insufficient data to meet the study objectives, for example due to failure in cannula patency, can result in the need to repeat these studies. A working group of contract research organizations that routinely carry out BDC studies was brought together by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) to share their experiences, and to establish the key factors necessary to ensure routinely high success rates. Through these discussions the group has identified opportunities for best practice across various aspects of the studies. The aim of these recommendations is to support all staff involved in conducting BDC studies to maximize the amount of useful data generated using the fewest animals possible, while ensuring the highest possible standards of animal welfare.

The Effects of Obesity on Drug Metabolism in Children.

PubMed

Oeser, Steffen G; Rougee, Luc R A; Collier, Abby C

2015-01-01

Obesity in children is a significant clinical concern. There are many anecdotes and case studies regarding specific reactions of obese children to medications including therapeutic failure, adverse drug reactions and/or requirements for higher weight-adjusted dosing. There isis, however, a lack of basic and clinical data dissecting the mechanisms of these effects on pharmaceutical efficacy and safety. At present it is unknown how much of the difference in drug disposition in obese children can be attributed to obesity, to maturation or to an interaction between the two. Since a major determinant of drug disposition is hepatic metabolism, here we review how obesity alters hepatic drug disposition in children. Basic as well as clinical data summarizing the current knowledge of biochemical, physiological and clinical effects of pediatric obesity on drug disposition are considered. We conclude that there is a dire need for increased research into the direct effects of obesity on absorption, distribution, metabolism and excretion, as well as changes to pharmacokinetic parameters such as bioavailability and clearance. Increased effort in this area may elucidate the effects of obesity on clinical drug disposition with sufficient detail to provide better dosing guidelines where needed for children.

TOXICOKINETICS OF CHIRAL POLYCHLORINATED BIPHENYLS ACROSS DIFFERENT SPECIES—A REVIEW

PubMed Central

Kania-Korwel, Izabela; Lehmler, Hans-Joachim

2015-01-01

Nineteen PCBs (chiral or C-PCBs) exist as two stable rotational isomers (atropisomers) that are non-superimposable mirror images of each other. C-PCBs are released into the environment as racemic (i.e., equal) mixtures of both atropisomers and undergo atropisomeric enrichment due to biological, but not abiotic processes. In particular toxicokinetic studies provide important, initial insights into atropselective processes involved in the disposition (i.e., absorption, distribution, biotransformation and excretion) of C-PCBs. The toxicokinetic of C-PCBs is highly congener and species dependent. In particular at lower trophic levels, abiotic processes play a predominant role in C-PCB toxicokinetics. Biotransformation plays an important role in the elimination of C-PCBs in mammals. The elimination of C-PCB follows the approximate order mammals > birds > amphibians > fish, mostly due to a corresponding decrease in metabolic capacity. A few studies have shown differences in the toxicokinetics of C-PCB atropisomers; however, more work in needed to understand the toxicokinetics of C-PCBs and the underlying biological processes. Such studies will not only contribute to our understanding of the fate of C-PCBs in aquatic and terrestrial food webs, but also facilitate our understanding of human exposures to C-PCBs. PMID:25824003

Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson's disease model.

PubMed

Ham, Sangwoo; Lee, Yun-Il; Jo, Minkyung; Kim, Hyojung; Kang, Hojin; Jo, Areum; Lee, Gum Hwa; Mo, Yun Jeong; Park, Sang Chul; Lee, Yun Song; Shin, Joo-Ho; Lee, Yunjong

2017-04-03

Dysfunctional parkin due to mutations or post-translational modifications contributes to dopaminergic neurodegeneration in Parkinson's disease (PD). Overexpression of parkin provides protection against cellular stresses and prevents dopamine cell loss in several PD animal models. Here we performed an unbiased high-throughput luciferase screening to identify chemicals that can increase parkin expression. Among promising parkin inducers, hydrocortisone possessed the most favorable profiles including parkin induction ability, cell protection ability, and physicochemical property of absorption, distribution, metabolism, and excretion (ADME) without inducing endoplasmic reticulum stress. We found that hydrocortisone-induced parkin expression was accountable for cell protection against oxidative stress. Hydrocortisone-activated parkin expression was mediated by CREB pathway since gRNA to CREB abolished hydrocortisone's ability to induce parkin. Finally, hydrocortisone treatment in mice increased brain parkin levels and prevented 6-hydroxy dopamine induced dopamine cell loss when assessed at 4 days after the toxin's injection. Our results showed that hydrocortisone could stimulate parkin expression via CREB pathway and the induced parkin expression was accountable for its neuroprotective effect. Since glucocorticoid is a physiological hormone, maintaining optimal levels of glucocorticoid might be a potential therapeutic or preventive strategy for Parkinson's disease.

Exploring different strategies for imbalanced ADME data problem: case study on Caco-2 permeability modeling.

PubMed

Pham-The, Hai; Casañola-Martin, Gerardo; Garrigues, Teresa; Bermejo, Marival; González-Álvarez, Isabel; Nguyen-Hai, Nam; Cabrera-Pérez, Miguel Ángel; Le-Thi-Thu, Huong

2016-02-01

In many absorption, distribution, metabolism, and excretion (ADME) modeling problems, imbalanced data could negatively affect classification performance of machine learning algorithms. Solutions for handling imbalanced dataset have been proposed, but their application for ADME modeling tasks is underexplored. In this paper, various strategies including cost-sensitive learning and resampling methods were studied to tackle the moderate imbalance problem of a large Caco-2 cell permeability database. Simple physicochemical molecular descriptors were utilized for data modeling. Support vector machine classifiers were constructed and compared using multiple comparison tests. Results showed that the models developed on the basis of resampling strategies displayed better performance than the cost-sensitive classification models, especially in the case of oversampling data where misclassification rates for minority class have values of 0.11 and 0.14 for training and test set, respectively. A consensus model with enhanced applicability domain was subsequently constructed and showed improved performance. This model was used to predict a set of randomly selected high-permeability reference drugs according to the biopharmaceutics classification system. Overall, this study provides a comparison of numerous rebalancing strategies and displays the effectiveness of oversampling methods to deal with imbalanced permeability data problems.

Molecular docking studies of anti-cancerous candidates in Hippophae rhamnoides and Hippophae salicifolia

PubMed Central

Usha, Talambedu; Middha, Sushil Kumar; Goyal, Arvind Kumar; Karthik, Mahesh; Manoj, DA; Faizan, Syed; Goyal, Peyush; Prashanth, HP; Pande, Veena

2014-01-01

Abstract Actinorhizal plants contain numerous antioxidants that may play a crucial role in preventing the formation of tumors. H-Ras p21, a member of the Ras-GTPase family, is a promising target to treat various kinds of cancers. An in silico docking study was carried out to identify the inhibitory potential of compounds of these plants against H-Ras by using Discovery Studio 3.5 and by using Autodock 4.2. Docking studies revealed that four compounds, isorhamnetin-7-rhamnoside, quercetin-3-glucoside-7-rhamnoside (present in H. rhamnoides), zeaxanthin, and translutein (present in H. salicifolia) significantly bind with binding energies −17.1534, −14.7936, −10.2105 and −17.2217 Kcal/mol, respectively, even though they slightly deviate from Lipinski's rule. Absorption, distribution, metabolism, excretion and toxicity (ADME/tox) analyses of these compounds and their stereoisomers showed that they were less toxic and non-mutagenic. Amongst them, isorhamntein-7-rhamnoside showed hepatotoxicity. Hence, these compounds can be further investigated in vivo to optimize their formulation and concentration and to develop potential chemical entities for the prevention and treatment of cancers. PMID:25332713

In silico identification of potential inhibitors targeting Streptococcus mutans sortase A

PubMed Central

Luo, Hao; Liang, Dan-Feng; Bao, Min-Yue; Sun, Rong; Li, Yuan-Yuan; Li, Jian-Zong; Wang, Xin; Lu, Kai-Min; Bao, Jin-Ku

2017-01-01

Dental caries is one of the most common chronic diseases and is caused by acid fermentation of bacteria adhered to the teeth. Streptococcus mutans (S. mutans) utilizes sortase A (SrtA) to anchor surface proteins to the cell wall and forms a biofilm to facilitate its adhesion to the tooth surface. Some plant natural products, especially several flavonoids, are effective inhibitors of SrtA. However, given the limited number of inhibitors and the development of drug resistance, the discovery of new inhibitors is urgent. Here, the high-throughput virtual screening approach was performed to identify new potential inhibitors of S. mutans SrtA. Two libraries were used for screening, and nine compounds that had the lowest scores were chosen for further molecular dynamics simulation, binding free energy analysis and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties analysis. The results revealed that several similar compounds composed of benzofuran, thiadiazole and pyrrole, which exhibited good affinities and appropriate pharmacokinetic parameters, were potential inhibitors to impede the catalysis of SrtA. In addition, the carbonyl of these compounds can have a key role in the inhibition mechanism. These findings can provide a new strategy for microbial infection disease therapy. PMID:28358034

Probiotic actions on diseases: implications for therapeutic treatments.

PubMed

Chiu, Yi-Heng; Lin, Shiao-Lin; Tsai, Jaw-Ji; Lin, Meei-Yn

2014-04-01

The ecology of gut microflora, which colonizes all body surfaces, has long coevolved with its hosts in a complicated fashion. Health benefits conferred by gut microflora include defense against invading pathogens, improvement of nutritional bioavailability, and development of the regional and systemic immune systems. The past decade has witnessed growing interest in the fact that the gut microflora affects the host's energy homeostasis by means of various mechanisms, including supplying nourishment from indigestible compounds, producing small biomolecules responsible for lipid profiles, and participating in the absorption, distribution, metabolism and excretion of nutrition. Much in vitro and in vivo research has indicated that aberrant gut microflora plays an important role in the pathogenesis of a wide spectrum of diseases. This is accomplished by a shift in focus, from laying an emphasis on pharmacotherapy to placing more effort on gut microflora normalization. The objectives of this review include illustrating trends in the clinical application of probiotics on diseases, as well as discussing current methodology limitations on probiotic selection. Furthermore, it is expected to shed light on the nature of probiotics, with the aim of giving greater insight into the implications for clinical use of probiotics in the treatment of diseases.

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents.

PubMed

Baquedano, Ylenia; Alcolea, Verónica; Toro, Miguel Ángel; Gutiérrez, Killian Jesús; Nguewa, Paul; Font, María; Moreno, Esther; Espuelas, Socorro; Jiménez-Ruiz, Antonio; Palop, Juan Antonio; Plano, Daniel; Sanmartín, Carmen

2016-06-01

A series of new selenocyanates and diselenides bearing interesting bioactive scaffolds (quinoline, quinoxaline, acridine, chromene, furane, isosazole, etc.) was synthesized, and their in vitro leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells were determined. Interestingly, most tested compounds were active in the low micromolar range and led us to identify four lead compounds (1h, 2d, 2e, and 2f) with 50% effective dose (ED50) values ranging from 0.45 to 1.27 μM and selectivity indexes of >25 for all of them, much higher than those observed for the reference drugs. These active derivatives were evaluated against infected macrophages, and in order to gain preliminary knowledge about their possible mechanism of action, the inhibition of trypanothione reductase (TryR) was measured. Among these novel structures, compounds 1h (3,5-dimethyl-4-isoxazolyl selenocyanate) and 2d [3,3'-(diselenodiyldimethanediyl)bis(2-bromothiophene)] exhibited good association between TryR inhibitory activity and antileishmanial potency, pointing to 1h, for its excellent theoretical ADME (absorption, distribution, metabolism, and excretion) properties, as the most promising lead molecule for leishmancidal drug design. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

A structured approach to Exposure Based Waiving of human health endpoints under REACH developed in the OSIRIS project.

PubMed

Marquart, Hans; Meijster, Tim; Van de Bovenkamp, Marja; Ter Burg, Wouter; Spaan, Suzanne; Van Engelen, Jacqueline

2012-03-01

Exposure Based Waiving (EBW) is one of the options in REACH when there is insufficient hazard data on a specific endpoint. Rules for adaptation of test requirements are specified and a general option for EBW is given via Appendix XI of REACH, allowing waiving of repeated dose toxicity studies, reproductive toxicity studies and carcinogenicity studies under a number of conditions if exposure is very low. A decision tree is described that was developed in the European project OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-Test and Test Information) to help decide in what cases EBW can be justified. The decision tree uses specific criteria as well as more general questions. For the latter, guidance on interpretation and resulting conclusions is provided. Criteria and guidance are partly based on an expert elicitation process. Among the specific criteria a number of proposed Thresholds of Toxicological Concern are used. The decision tree, expanded with specific parts on absorption, distribution, metabolism and excretion that are not described in this paper, is implemented in the OSIRIS webtool on integrated testing strategies. Copyright © 2011 Elsevier Inc. All rights reserved.

Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug-Drug Interactions.

PubMed

de Kanter, Ruben; Sidharta, Patricia N; Delahaye, Stéphane; Gnerre, Carmela; Segrestaa, Jerome; Buchmann, Stephan; Kohl, Christopher; Treiber, Alexander

2016-03-01

Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577. A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro. The model predicted the observed pharmacokinetics of macitentan and its active metabolite ACT-132577 after single and multiple dosing. It performed well in recovering the observed effect of the CYP3A4 inhibitors ketoconazole and cyclosporine, and the CYP3A4 inducer rifampicin, as well as in predicting interactions with S-warfarin and sildenafil. The model was robust enough to allow prospective predictions of macitentan-drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs. Among these were the HIV drugs ritonavir and saquinavir, which were included because HIV infection is a known risk factor for the development of PAH. This example of the application of PBPK modeling to predict drug-drug interactions was used to support the labeling of macitentan (Opsumit).

Bioequivalence studies of drugs prescribed mainly for women.

PubMed

McGilveray, Iain J

2011-01-01

The basic components of pharmacokinetics are absorption, distribution, metabolism, and excretion. During pregnancy there may be changes in one or many of these components. Early drug studies did not include a representative proportion of women, however, researchers as well as regulators agree that studies on the sex differences in the disposition of drugs are important, but at what stage in the clinical trial process? Except for drugs used only in women, such as those for estrogen-dependent breast cancer, caution prevails and the differences are usually studied at phase 3. Studies in pregnant women are much rarer but some do get done, e.g., with antivirals and antimalarials, where the positive risk-benefit of these agents is the likelihood that fetal transfer of these drugs might help protect the fetus. Women are being included in pharmacokinetic studies for new drug applications in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), U.S. Food and Drug Administration (FDA), and Health Canada (HC) guidances. A new look at bioequivalence studies, to compare results in men and women, would help determine if interactions of formulation and gender are a problem.

PRECLINICAL PHARMACOKINETIC ANALYSIS OF (E)-METHYL-4-ARYL-4-OXABUT-2-ENOATE, A NOVEL SER/THR PROTEIN KINASE B INIBITOR, IN RATS.

PubMed

Zhai, Qian-Qian; Pang, Jing; Li, Guo-Qing; Li, Cong-Ran; Wang, Yu-Cheng; Yu, Li-Yan; Li, Jian; YOUm, Xue-Fu

2017-01-01

(E)-Methyl-4-aryl-4-oxabut-2-enoate, designated YH-8, is a novel Serflhr protein kinase B (PknB) inhibitor, which is designed for the treatment of tuberculosis. The aim of this study was to investigate the pharmacokinetics, bioavailability, tissue distribution and excretion characteristics of YH-8 in rats and study its plasma protein binding in vitro. The pharmacokinetic properties were examined after intravenously injected YH-8 at 10 and 20 mg/kg and oral administrated YH-8 at 50, 100 and 200 mg/kg to rats. The concentrations of YH-8 in plasma were determined with LC-MS/MS, with a liquid-liquid extraction. The tissue distribution and urinary, fecal and -biliary excretion patterns of YH-8 were investigated following a single oral dosing of 100 mg/kg. The plasma protein binding rates of YH-8 were determined using ultra-filtration method. After intra- venous and oral administration, YH-8 showed dose-independent pharmacokinetic characteristics, with T(1/2) of approximately 5.5 h and 7.1 h, respectively. The oral absolute bioavailability of YH-8 was relatively low (about 12%). YH-8 was widely distributed in various tissues and showed substantial deposition in intestine, stomach, liver, lung and kidney. The drug was mainly eliminated via fecal excretion and its binding rate with plasma protein was concentration-dependent. In conclusion, this study as first provided the full pharmacokinetic characteristics of YH-8, which would be helpful for its further development and clinical application.

Bioavailability of chlorogenic acids following acute ingestion of coffee by humans with an ileostomy.

PubMed

Stalmach, Angélique; Steiling, Heike; Williamson, Gary; Crozier, Alan

2010-09-01

The intestinal absorption and metabolism of 385 micromol chlorogenic acids following a single intake of 200 mL of instant coffee by human volunteers with an ileostomy was investigated. HPLC-MS(3) analysis of 0-24h post-ingestion ileal effluent revealed the presence of 274+/-28 micromol of chlorogenic acids and their metabolites accounting for 71+/-7% of intake. Of the compounds recovered, 78% comprised parent compounds initially present in the coffee, and 22% were metabolites including free and sulfated caffeic and ferulic acids. Over a 24h period after ingestion of the coffee, excretion of chlorogenic acid metabolites in urine accounted for 8+/-1% of intake, the main compounds being ferulic acid-4-O-sulfate, caffeic acid-3-O-sulfate, isoferulic acid-3-O-glucuronide and dihydrocaffeic acid-3-O-sulfate. In contrast, after drinking a similar coffee, urinary excretion by humans with an intact colon corresponded to 29+/-4% of chlorogenic acid intake. This difference was due to the excretion of higher levels of dihydroferulic acid and feruloylglycine together with sulfate and glucuronide conjugates of dihydrocaffeic and dihydroferulic acids. This highlights the importance of colonic metabolism. Comparison of the data obtained in the current study with that of Stalmach et al. facilitated elucidation of the pathways involved in post-ingestion metabolism of chlorogenic acids and also helped distinguish between compounds absorbed in the small and the large intestine. Copyright © 2010 Elsevier Inc. All rights reserved.

Tunable, biodegradable gold nanoparticles as contrast agents for computed tomography and photoacoustic imaging

PubMed Central

Cheheltani, Rabee; Ezzibdeh, Rami M.; Chhour, Peter; Pulaparthi, Kumidini; Kim, Johoon; Jurcova, Martina; Hsu, Jessica C.; Blundell, Cassidy; Litt, Harold I.; Ferrari, Victor A.; Allcock, Harry R.; Sehgal, Chandra M.; Cormode, David P.

2016-01-01

Gold nanoparticles (AuNP) have been proposed for many applications in medicine. Although large AuNP (>5.5 nm) are desirable for their longer blood circulation and accumulation in diseased tissues, small AuNP (<5.5 nm) are required for excretion via the kidneys. We present a novel platform where small, excretable AuNP are encapsulated into biodegradable poly di(carboxylatophenoxy)phosphazene (PCPP) nanospheres. These larger nanoparticles (Au-PCPP) can perform their function as contrast agents, then subsequently break down into harmless byproducts and release the AuNP for swift excretion. Homogeneous Au-PCPP were synthesized using a microfluidic device. The size of the Au-PCPP can be controlled by the amount of polyethylene glycol-polylysine (PEG-PLL) block co-polymer in the formulation. Synthesis of Au-PCPP nanoparticles and encapsulation of AuNP in PCPP were evaluated using transmission electron microscopy and their biocompatibility and biodegradability confirmed in vitro. The Au-PCPP nanoparticles were found to produce strong computed tomography contrast. The UV-Vis absorption peak of Au-PCPP can be tuned into the near infrared region via inclusion of varying amounts of AuNP and controlling the nanoparticle size. In vitro and in vivo experiments demonstrated the potential of Au-PCPP as contrast agents for photoacoustic imaging. Therefore, Au-PCPP nanoparticles have high potency as contrast agents for two imaging modalities, as well as being biocompatible and biodegradable, and thus represent a platform with potential for translation into the clinic. PMID:27322961

Biotransformation and mass balance of tipranavir, a nonpeptidic protease inhibitor, when co-administered with ritonavir in Sprague-Dawley rats.

PubMed

Macha, Sreeraj; Chen, Linzhi; Norris, Stephen H; Philip, Elsy; Mao, Yanping; Silverstein, Helga; Struble, Craig; Beers, Wendy

2007-09-01

In this study, tipranavir (TPV) biotransformation and disposition when co-administered with ritonavir (RTV) were characterized in Sprague-Dawley rats. Rats were administered a single intravenous (5 mg kg(-1)) or oral (10 mg kg(-1)) dose of [(14)C]TPV with co-administration of RTV (10 mg kg(-1)). Blood, urine, faeces and bile samples were collected at specified time-points over a period of 168 h. Absorption of TPV-related radioactivity ranged from 53.2-59.6%. Faecal excretion was on average 86.7% and 82.4% (intravenous) and 75.0% and 82.0% (oral) of dosed radioactivity in males and females, respectively. Urinary excretion was on average 4.06% and 6.73% (intravenous) and 9.71% and 8.28% (oral) of dosed radioactivity in males and females, respectively. In bile-duct-cannulated rats, 39.8% of the dose was recovered in bile. After oral administration, unchanged TPV accounted for the majority of the radioactivity in plasma (85.7-96.3%), faeces (71.8-80.1%) and urine (33.3-62.3%). The most abundant metabolite in faeces was an oxidation metabolite R-2 (5.9-7.4% of faecal radioactivity, 4.4-6.1% of dose). In urine, no single metabolite was found to be significant, and comprised <1% of dose. TPV when co-administered with RTV to rats was mainly excreted in feces via bile and the parent compound was the major component in plasma and faeces.

An acute study on the relative gastro-intestinal absorption of a novel form of calcium ascorbate.

PubMed

Bush, M J; Verlangieri, A J

1987-07-01

Several functions of L-ascorbic acid (vitamin C) have been suggested in addition to its role in the prevention of scurvy. Consequently, a controversy has arisen over the daily intake of the vitamin which will afford maximum benefits. Rapid cellular uptake and delayed renal excretion of ascorbic acid would be conducive to providing optimum cellular concentration for biochemical activity. ESTER-C (patent pending), a complex consisting of L-ascorbic acid and Ca++, has been recently developed by Inter-Cal Corporation (421 Miller Road, Prescott, AZ 86301). It has been proposed that the structure of ESTER-C may render it more readily absorbed and less rapidly excreted than the acid or salt form of the vitamin. To test this hypothesis, ESTER-C and L-ascorbic acid were administered to two groups of rats. Blood was sampled at 20, 40, 80, 160 and 240 minutes and plasma analyzed for ascorbic acid. As urine appeared in collection cups, it was tested qualitatively for the presence of ascorbic acid. The plasma concentration of ascorbic acid was higher in ESTER-C treated rats at 20, 40 and 80 minutes than in rats given L-ascorbic acid. Ascorbic acid was detected in the urine of animals administered ESTER-C later than in those treated with L-ascorbic acid. These results support the hypothesis that ESTER-C is absorbed more readily and excreted less rapidly than L-ascorbic acid.

Pharmacokinetics and metabolism of radiolabelled SNI-2011, a novel muscarinic receptor agonist, in healthy volunteers. Comprehensive understanding of absorption, metabolism and excretion using radiolabelled SNI-2011.

PubMed

Washio, Takuo; Kohsaka, Kazuhiro; Arisawa, Hirohiko; Masunaga, Hiroaki; Nagatsuka, Shin-ichiro; Satoh, Yoshiaki

2003-01-01

The pharmacokinetics and metabolism of SNI-2011 ((+/-)-cis-2-methylspiro[1,3-oxathiolane-5,3'-quinuclidine]monohydrochloride hemihydrate, cevimeline, CAS 153504-70-2), a novel muscarinic acetylcholine receptor agonist developed for the treatment of Sjögen's syndrome, were investigated in six healthy volunteers after a single oral administration of 14C-SNI-2011. After administration, plasma concentrations of the radioactivity and SNI-2011 reached to Cmax at approximately 2 h, and then decreased with t 1/2 of 9 and 4 h, respectively. Cmax and AUC0-infinity of the radioactivity in plasma were 2.2 and 5.0 times higher than those of SNI-2011, respectively. The main excretion route of the radioactivity was urine, and 97.3% of the dose excreted in urine within 168 h, indicating that 14C-SNI-2011 was completely absorbed. The mean recoveries of the metabolites in urine at 24 h after administration were 16.0% for SNI-2011, 35.8% for SNI-2011 trans-sulfoxide (SNI-t-SO), 8.7% for SNI-2011 cis-sulfoxide, 4.1% for SNI-2011 N-oxide, furthermore, two unknown metabolites, UK-1 and UK-2, were detected 14.6% and 7.7%, respectively. LC/MS analysis and hydrolysis studies revealed that UK-1 and UK-2 were glucuronic acid conjugates of SNI-2011 and SNI-t-SO, respectively.

Efficacy of chewed vs. crushed lanthanum on phosphorus binding in healthy volunteers.

PubMed

How, P P; Mason, D L; Arruda, J A; Lau, A H

2010-05-01

For effective dietary phosphorous (P) binding, patients are recommended to chew lanthanum tablets completely before swallowing, with or immediately after meals. However, some patients are unable to chew the tablets. It is not known if crushing the tablets prior to taking them with food is as efficacious as chewing them. This study was conducted to compare the efficacy of chewed vs. crushed lanthanum on P binding. 12 healthy subjects were randomized and crossed-over to receive: (A) a standardized meal containing 1 g (32 mmol) of elemental P; (B) a single 1 g oral dose of lanthanum, chewed and taken with the standardized meal; (C) a single 1 g oral dose of lanthanum, crushed into a fine powder using a pestle and mortar, mixed with applesauce, and taken with the standardized meal. Blood and urine samples were collected from baseline to 8 hours after meal completion. The changes in serum P, urinary P excretion and fractional excretion of P (FePi) were compared among treatment arms using ANOVA. Co-administration of lanthanum with meal resulted in a smaller increase in serum P, compared with meal alone (p < 0.05). The smaller increase in serum P was similar for both chewed and crushed lanthanum. The amount of P excreted and FePi were also lower when chewed or crushed lanthanum was administered with meal, compared with meal alone (p = n.s. and p < 0.05, respectively). Both chewed and crushed lanthanum are effective in lowering P absorption after a dietary P load.

The kidney in hyperuricemia and gout.

PubMed

Mount, David B

2013-03-01

Gout is a painful inflammatory arthritis associated with hyperuricemia, with a prevalence of almost 10 million in the USA. Reduced renal excretion of urate is the underlying hyperuricemic mechanism in the vast majority of gout patients; most of the genes that affect serum urate level (SUA) encode urate transporters or associated regulatory proteins. Acquired influences can also modulate SUA and renal urate excretion, sometimes precipitating acute gout. Coincidentally, the prevalence of renal comorbidities in gout - hypertension, chronic kidney disease (CKD), and nephrolithiasis - is very high. Recent advances in genetics and molecular physiology have greatly enhanced the understanding of renal reabsorption and secretion of filtered urate. Moreover, baseline SUA appears to be set by the net balance of absorption and secretion across epithelial cells in the kidney and intestine. There have also been substantial advances in the management of gout in patients with CKD. The stage is set for an increasingly molecular understanding of baseline and regulated urate transport by the kidney and intestine. The increasing prevalence of gout with CKD will be balanced by an expanding spectrum of therapeutic options for this important disease.

Molecular Regulation of Phosphate Metabolism by Fibroblast Growth Factor-23–Klotho System

PubMed Central

Cheng, Chung-Yi; Kuro-o, Makoto; Razzaque, Mohammed S.

2011-01-01

Phosphorus is an essential nutrient and is routinely assimilated through consumption of food. The body’s need of phosphate is usually fulfilled by intestinal absorption of this element from the consumed food, whereas its serum level is tightly regulated by renal excretion or reabsorption. Sodium-dependent phosphate transporters, located in the luminal side of the proximal tubular epithelial cells, have a molecular control on renal phosphate excretion and reabsorption. The systemic regulation of phosphate metabolism is a complex multiorgan process, and the identification of fibroblast growth factor-23 (FGF23)–Klotho system as a potent phosphatonin has provided new mechanistic insights into the homeostatic control of phosphate. Hypophosphatemia as a result of an increase in urinary phosphate wasting after activation of the FGF23–Klotho system is a common phenomenon, observed in both animal and human studies, whereas suppression of the FGF23–Klotho system leads to the development of hyperphosphatemia. This article will briefly summarize how delicate interactions of the FGF23–Klotho system can regulate systemic phosphate homeostasis. PMID:21406293

Significant hyperkalemia and hyponatremia secondary to telmisartan/hydrochlorothiazide treatment.

PubMed

Cakir, Mehtap

2010-12-01

The renin-angiotensin-aldosterone system (RAAS) has crucial importance in maintaining blood pressure; thus blockade of RAAS is an effective antihypertensive treatment choice. The final step in RAAS stimulation is aldosterone secretion by angiotensin II, which leads to increased renal tubular sodium absorption and potassium secretion. Angiotensin II receptor blockers (ARBs) allow blockade of RAAS by blocking binding of angiotensin II to the AT(1) receptors. There are several fixed-dose combinations of ARBs with hydrochlorothiazide in the market, providing antihypertensive therapies with complimentary mechanisms of action. With such combinations, while ARB inhibits the vasoconstricting action and aldosterone-secreting effects of angiotensin II, hydrochlorothiazide affects the renal tubular mechanisms of electrolyte reabsorption and directly increases excretion of sodium and chloride in the distal tubule, and promotes water excretion. Also, hypokalemia, which may be triggered by increased urinary potassium loss induced by hydrochlorothiazide, is opposed by ARB use and hence ARB/hydrochlorothiazide combination is known to be safe in terms of potassium imbalance. In this case report, significant hyperkalemia and hyponatremia related to telmisartan/hydrochlorothiazide use in a diabetic patient has been presented.

Polonium assimilation and retention in mule deer and pronghorn antelope

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sejkora, K.J.

Excretion kinetics and tissue distribution of polonium-210 in mule deer and pronghorn were studied. Each animal in a captive herd of 7 mule deer and 2 pronghorn received an intraruminal injection of 4.4 ..mu..Ci of polonium chloride. Feces and urine were collected periodically over a 43-day period and daily excretion rate for each pathway was regressed as a function of time. Assimilation fractions of 0.40 and 0.51 were calculated for mule deer (n=2) and 0.60 for a pronghorn. Body burden retention functions were calculated from integrated excretion rate functions. Polonium burdens in muscle, liver, and kidney were calculated as amore » fraction of body burden from serially-sacrificed animals. Background tissue burdens in mule deer were comparable to those of other ruminants reported in the literature. Hypothetical cases were assumed which combined feeding rate of mule deer, forage concentrations of polonium, retention function, tissue burden fraction, and human intake to estimate human radiation dose. 26 references.« less

Fibroblast Growth Factor-23 in Bed Rest and Spaceflight

NASA Technical Reports Server (NTRS)

Bokhari, R.; Zwart, S. R; Fields, E.; Heer, M.; Sibonga, J.; Smith, S. M.

2014-01-01

Many nutritional factors influence bone, from the basics of calcium and vitamin D, to factors which influence bone through acid/base balance, including protein, sodium, and more. Fibroblast growth factor 23 (FGF23) is a recently identified factor, secreted from osteocytes, which is involved in classic (albeit complex) feedback loops controlling phosphorus homeostasis through both vitamin D and parathyroid hormone (PTH) (1, 2). As osteocytes are gravity sensing cells, it is important to determine if there are changes in FGF23 during spaceflight. In extreme cases, such as chronic kidney disease, FGF23 levels are highly elevated. FGF23 imbalances, secondary to dietary influences, may contribute to skeletal demineralization and kidney stone risk during spaceflight. Presented with an imbalanced dietary phosphorus to calcium ratio, increased secretion of FGF23 will inhibit renal phosphorus reabsorption, resulting in increased excretion and reduced circulating phosphorus. Increased intake and excretion of phosphorus is associated with increased kidney stone risk in both the terrestrial and microgravity environments. Highly processed foods and carbonated beverages are associated with higher phosphorus content. Ideally, the dietary calcium to phosphorus ratio should be at minimum 1:1. Nutritional requirements for spaceflight suggest that this ratio not be less than 0.67 (3), while the International Space Station (ISS) menu provides 1020 mg Ca and 1856 mg P, for a ratio of 0.55 (3). Subjects in NASA's bed rest studies, by design, have consumed intake ratios much closer to 1.0 (4). FGF23 also has an inhibitory influence on PTH secretion and 1(alpha)-hydroxylase, both of which are required for activating vitamin D with the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Decreased 1,25-dihydroxyvitamin D will result in decreased intestinal phosphorus absorption, and increased urinary phosphorus excretion (via decreased renal reabsorption). Should a decrease in 1,25- dihydroxyvitamin D be necessary to reduce intestinal phosphorus absorption, calcium absorption will also proportionally be reduced, potentially leading to skeletal demineralization. Demineralization of bone can increase kidney stone risk, a medical issue that could prove detrimental to mission success. Given the interrelationships described above, we sought to determine circulating FGF23 concentrations in spaceflight and ground analog studies to better understand the potential effects of dietary phosphorus on bone and calcium metabolism. We analyzed serum from ISS astronauts participating in studies of bone biochemistry, including the Nutrition SMO and Pro K experiments, and we also evaluated FGF23 during extended-duration bed rest. Serum intact FGF23 levels were determined using an ELISA kit from Kainos laboratories in Japan. While initial evaluation of the data showed no changes over time during flight or bed rest, evaluation continues of FGF23 data in light of dietary factors, PTH, vitamin D status, and other biochemical and endocrine factors.

Melatonin reduces lead levels in blood, brain and bone and increases lead excretion in rats subjected to subacute lead treatment.

PubMed

Hernández-Plata, Everardo; Quiroz-Compeán, Fátima; Ramírez-Garcia, Gonzalo; Barrientos, Eunice Yáñez; Rodríguez-Morales, Nadia M; Flores, Alberto; Wrobel, Katarzina; Wrobel, Kazimierz; Méndez, Isabel; Díaz-Muñoz, Mauricio; Robles, Juvencio; Martínez-Alfaro, Minerva

2015-03-04

Melatonin, a hormone known for its effects on free radical scavenging and antioxidant activity, can reduce lead toxicity in vivo and in vitro.We examined the effects of melatonin on lead bio-distribution. Rats were intraperitoneally injected with lead acetate (10, 15 or 20mg/kg/day) with or without melatonin (10mg/kg/day) daily for 10 days. In rats intoxicated with the highest lead doses, those treated with melatonin had lower lead levels in blood and higher levels in urine and feces than those treated with lead alone, suggesting that melatonin increases lead excretion. To explore the mechanism underlying this effect, we first assessed whether lead/melatonin complexes were formed directly. Electronic density functional (DFT) calculations showed that a lead/melatonin complex is energetically feasible; however, UV spectroscopy and NMR analysis showed no evidence of such complexes. Next, we examined the liver mRNA levels of metallothioneins (MT) 1 and 2. Melatonin cotreatment increased the MT2 mRNA expression in the liver of rats that received the highest doses of lead. The potential effects of MTs on the tissue distribution and excretion of lead are not well understood. This is the first report to suggest that melatonin directly affects lead levels in organisms exposed to subacute lead intoxication. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Supplementing a low-protein diet with dibasic amino acids increases urinary calcium excretion in young women.

PubMed

Bihuniak, Jessica D; Sullivan, Rebecca R; Simpson, Christine A; Caseria, Donna M; Huedo-Medina, Tania B; O'Brien, Kimberly O; Kerstetter, Jane E; Insogna, Karl L

2014-03-01

Increasing dietary protein within a physiologic range stimulates intestinal calcium absorption, but it is not known if specific amino acids or dietary protein as a whole are responsible for this effect. Therefore, we selectively supplemented a low-protein (0.7 g/kg) diet with either the calcium-sensing receptor-activating amino acids (CaSR-AAAs) L-tryptophan, L-phenylalanine, and L-histidine, or the dibasic amino acids (DAAs) L-arginine and L-lysine, to achieve intakes comparable to the content of a high-protein diet (2.1 g/kg) and measured intestinal calcium absorption. Fourteen young women took part in a placebo-controlled, double-blind, crossover feeding trial in which each participant ingested a 6-d low-protein diet supplemented with CaSR-AAAs, DAAs, or methylcellulose capsules (control) after an 11-d adjustment period. All participants ingested all 3 diets in random order. Intestinal calcium absorption was measured between days 5 and 6 using dual-stable calcium isotopes ((42)Ca, (43)Ca, and (44)Ca). There was no difference in calcium absorption between the diet supplemented with CaSR-AAAs (22.9 ± 2.0%) and the control diet (22.3 ± 1.4%) (P = 0.64). However, calcium absorption tended to be greater during the DAA supplementation period (25.2 ± 1.4%) compared with the control diet period (22.3 ± 1.4%) (P < 0.10). Larger and longer clinical trials are needed to clarify the possible benefit of arginine and lysine on calcium absorption.

Effect of abomasal infusion of oligofructose on portal-drained visceral ammonia and urea-nitrogen fluxes in lactating Holstein cows.

PubMed

Røjen, B A; Larsen, M; Kristensen, N B

2012-12-01

The effects of abomasal infusion of oligofructose in lactating dairy cows on the relationship between hindgut fermentation and N metabolism, and its effects on NH(3) absorption and transfer of blood urea-N across the portal-drained viscera versus ruminal epithelia were investigated. Nine lactating Holstein cows fitted with ruminal cannulas and permanent indwelling catheters in major splanchnic blood vessels were used in an unbalanced crossover design with 14-d periods. Treatments were continuous abomasal infusion of water or 1,500 g/d of oligofructose. The same basal diet was fed with both treatments. Eight sample sets of arterial, portal, hepatic, and ruminal vein blood, ruminal fluid, and urine were obtained at 0.5h before the morning feeding and at 0.5, 1.5, 2.5, 3.5, 4.5, 5.5, and 6.5 h after feeding. It was hypothesized that an increased supply of fermentable substrate to the hindgut would increase the uptake of urea-N from blood to the hindgut at the expense of urea-N uptake to the forestomach. The study showed that abomasal oligofructose infusion decreased the total amount of urea-N transferred from the blood to the gut, NH(3) absorption, and arterial blood urea-N concentration. Subsequently, hepatic NH(3) uptake and urea-N production also decreased with oligofructose infusion. Additionally, urea-N concentration in milk and urinary N excretion decreased with oligofructose treatment. The oligofructose infusion did not affect ruminal NH(3) concentrations or any other ruminal variables, nor did it affect ruminal venous - arterial concentration differences for urea-N and NH(3). The oligofructose treatment did not affect milk yield, but did decrease apparent digestibility of OM, N, and starch. Nitrogen excreted in the feces was greater with the oligofructose infusion. In conclusion, the present data suggest that increased hindgut fermentation did not upregulate urea-N transfer to the hindgut at the expense of urea-N uptake by the rumen, and the observed reduction in arterial blood urea-N concentration appeared not to be due to increased urea-N transport, but rather could be explained by reduced NH(3) input to hepatic urea-N synthesis caused by increased sequestration of NH(3) in the hindgut and excretion in feces. Increasing the hindgut fermentation in lactating dairy cows by abomasal infusion of 1,500 g/d of oligofructose shifted some N excretion from the urine to feces and possibly reduced manure NH(3) volatilization without impairing rumen fermentation. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

FAF-Drugs2: free ADME/tox filtering tool to assist drug discovery and chemical biology projects.

PubMed

Lagorce, David; Sperandio, Olivier; Galons, Hervé; Miteva, Maria A; Villoutreix, Bruno O

2008-09-24

Drug discovery and chemical biology are exceedingly complex and demanding enterprises. In recent years there are been increasing awareness about the importance of predicting/optimizing the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of small chemical compounds along the search process rather than at the final stages. Fast methods for evaluating ADMET properties of small molecules often involve applying a set of simple empirical rules (educated guesses) and as such, compound collections' property profiling can be performed in silico. Clearly, these rules cannot assess the full complexity of the human body but can provide valuable information and assist decision-making. This paper presents FAF-Drugs2, a free adaptable tool for ADMET filtering of electronic compound collections. FAF-Drugs2 is a command line utility program (e.g., written in Python) based on the open source chemistry toolkit OpenBabel, which performs various physicochemical calculations, identifies key functional groups, some toxic and unstable molecules/functional groups. In addition to filtered collections, FAF-Drugs2 can provide, via Gnuplot, several distribution diagrams of major physicochemical properties of the screened compound libraries. We have developed FAF-Drugs2 to facilitate compound collection preparation, prior to (or after) experimental screening or virtual screening computations. Users can select to apply various filtering thresholds and add rules as needed for a given project. As it stands, FAF-Drugs2 implements numerous filtering rules (23 physicochemical rules and 204 substructure searching rules) that can be easily tuned.

Open Source Bayesian Models. 1. Application to ADME/Tox and Drug Discovery Datasets.

PubMed

Clark, Alex M; Dole, Krishna; Coulon-Spektor, Anna; McNutt, Andrew; Grass, George; Freundlich, Joel S; Reynolds, Robert C; Ekins, Sean

2015-06-22

On the order of hundreds of absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) models have been described in the literature in the past decade which are more often than not inaccessible to anyone but their authors. Public accessibility is also an issue with computational models for bioactivity, and the ability to share such models still remains a major challenge limiting drug discovery. We describe the creation of a reference implementation of a Bayesian model-building software module, which we have released as an open source component that is now included in the Chemistry Development Kit (CDK) project, as well as implemented in the CDD Vault and in several mobile apps. We use this implementation to build an array of Bayesian models for ADME/Tox, in vitro and in vivo bioactivity, and other physicochemical properties. We show that these models possess cross-validation receiver operator curve values comparable to those generated previously in prior publications using alternative tools. We have now described how the implementation of Bayesian models with FCFP6 descriptors generated in the CDD Vault enables the rapid production of robust machine learning models from public data or the user's own datasets. The current study sets the stage for generating models in proprietary software (such as CDD) and exporting these models in a format that could be run in open source software using CDK components. This work also demonstrates that we can enable biocomputation across distributed private or public datasets to enhance drug discovery.

Open Source Bayesian Models. 1. Application to ADME/Tox and Drug Discovery Datasets

PubMed Central

2015-01-01

On the order of hundreds of absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) models have been described in the literature in the past decade which are more often than not inaccessible to anyone but their authors. Public accessibility is also an issue with computational models for bioactivity, and the ability to share such models still remains a major challenge limiting drug discovery. We describe the creation of a reference implementation of a Bayesian model-building software module, which we have released as an open source component that is now included in the Chemistry Development Kit (CDK) project, as well as implemented in the CDD Vault and in several mobile apps. We use this implementation to build an array of Bayesian models for ADME/Tox, in vitro and in vivo bioactivity, and other physicochemical properties. We show that these models possess cross-validation receiver operator curve values comparable to those generated previously in prior publications using alternative tools. We have now described how the implementation of Bayesian models with FCFP6 descriptors generated in the CDD Vault enables the rapid production of robust machine learning models from public data or the user’s own datasets. The current study sets the stage for generating models in proprietary software (such as CDD) and exporting these models in a format that could be run in open source software using CDK components. This work also demonstrates that we can enable biocomputation across distributed private or public datasets to enhance drug discovery. PMID:25994950

Handling of computational in vitro/in vivo correlation problems by Microsoft Excel II. Distribution functions and moments.

PubMed

Langenbucher, Frieder

2003-01-01

MS Excel is a useful tool to handle in vitro/in vivo correlation (IVIVC) distribution functions, with emphasis on the Weibull and the biexponential distribution, which are most useful for the presentation of cumulative profiles, e.g. release in vitro or urinary excretion in vivo, and differential profiles such as the plasma response in vivo. The discussion includes moments (AUC and mean) as summarizing statistics, and data-fitting algorithms for parameter estimation.

Effect of dietary fiber and crude protein content in feed on nitrogen retention in pigs.

PubMed

Patrás, P; Nitrayová, S; Brestenský, M; Heger, J

2012-12-01

Eight gilts (29.9 ± 1.7 kg initial BW) were used to evaluate effects of dietary (crude) fiber on N excretion via feces and urine at 2 levels of dietary CP. Pigs were fed 4 dietary treatments according to a double 4 × 4 Latin square. Treatments were low (14%) CP and low (3.25%) (crude) fiber (LPAA), low CP and high (4.46%) fiber (LPAABP), high (18.8%) CP and low fiber (HP), and high CP and high fiber (HPBP). Diets were based on soybean (Glycine max) meal, wheat (Triticum aestivum), and maize (Zea mays) and were supplemented with crystalline AA. High fiber diets contained 15% dried beet (Beta vulgaris) pulp. Pigs were housed in metabolic cages and fed 2 equal meals at 0700 and 1700 h at a daily rate of 90 g/kg BW(0.75). Water was offered ad libitum. Each experimental period consisted of a 6-d adaptation followed by a 4-d collection of feces and urine (bladder catheters). Data were analyzed using ANOVA. Differences between means (P < 0.05) were assessed using Fisher's LSD procedure. The N intake, fecal N excretion and absorption, and N retention increased (P < 0.05) in pigs fed high-CP diets with added fiber (HP vs. HPBR). With added fiber, urinary N excretion (g/d) was reduced (P < 0.02) only for the low-CP diet. Urinary N as a percentage of N intake was reduced (P < 0.01) in both groups fed high-fiber diets irrespective of dietary CP content. Dietary fiber level did not affect DMI. Fecal DM excretion (g/d) was higher (P < 0.02) in pigs fed diets with high CP and high fiber content than in pigs fed diets with high CP and low fiber content. In conclusion, beet pulp fiber added to diets increased fecal N and reduced urinary N and in diets with higher CP content increased overall N retention.

A compartmental model of uranium in human hair for protracted ingestion of natural uranium in drinking water.

PubMed

Li, W B; Karpas, Z; Salonen, L; Kurttio, P; Muikku, M; Wahl, W; Höllriegl, V; Hoeschen, C; Oeh, U

2009-06-01

To predict uranium in human hair due to chronic exposure through drinking water, a compartment representing human hair was added into the uranium biokinetic model developed by the International Commission on Radiological Protection (ICRP). The hair compartmental model was used to predict uranium excretion in human hair as a bioassay indicator due to elevated uranium intakes. Two excretion pathways, one starting from the compartment of plasma and the other from the compartment of intermediate turnover soft tissue, are assumed to transfer uranium to the compartment of hair. The transfer rate was determined from reported uranium contents in urine and in hair, taking into account the hair growth rate of 0.1 g d(-1). The fractional absorption in the gastrointestinal tract of 0.6% was found to fit best to describe the measured uranium levels among the users of drilled wells in Finland. The ingestion dose coefficient for (238)U, which includes its progeny of (234)Th, (234m)Pa, and (234)Pa, was calculated equal to 1.3 x 10(-8) Sv Bq(-1) according to the hair compartmental model. This estimate is smaller than the value of 4.5 x 10(-8) Sv Bq(-1) published by ICRP for the members of the public. In this new model, excretion of uranium through urine is better represented when excretion to the hair compartment is accounted for and hair analysis can provide a means for assessing the internal body burden of uranium. The model is applicable for chronic exposure as well as for an acute exposure incident. In the latter case, the hair sample can be collected and analyzed even several days after the incident, whereas urinalysis requires sample collection shortly after the exposure. The model developed in this study applies to ingestion intakes of uranium.

SN2-Palmitate Reduces Fatty Acid Excretion in Chinese Formula-fed Infants

PubMed Central

Bar-Yoseph, Fabiana; Lifshitz, Yael; Cohen, Tzafra; Malard, Patrice; Xu, Chungdi

2016-01-01

ABSTRACT Objectives: Palmitic acid (PA) comprises 17% to 25% of human milk fatty acids, of which 70% to 75% are esterified to the SN2 position of the triglyceride (SN2-palmitate). In vegetable oils, which are commonly used in infant formulas, palmitate is primarily esterified to other positions, resulting in reduced calcium and fat absorption and hard stools. The aim of this study was to elucidate the effects of SN2-palmitate on nutrient excretion. Methods: In total, 171 Chinese infants were included (within 14 days of birth) in this multicenter study. Formula-fed infants were randomly assigned to receive either SN2-palmitate formula (INFAT, n = 57) or control formula (n = 57). The formulas (Biostime, China) differed only in their SN2 PA proportions. Stool was collected at 6 postnatal weeks. Results: The stool dry weight and fat content of the SN2-palmitate group were lower compared with the control group (dry weight 4.25 g vs 7.28 g, P < 0.05; fat 0.8 g vs 1.2 g, P < 0.05). The lipid component was also significantly lower for the SN2-palmitate group (0.79 g vs 1.19 g, P < 0.05). PA, representing ∼50% of the saponified fatty acids, was significantly lower in the SN2-palmitate group compared with the control group (0.3 g vs 0.7 g, P < 0.01). Breast-fed infants had a significantly lower stool dry weight, fat content, and saponified fat excretion compared with formula-fed infants (P < 0.01). Conclusions: Similar to breast milk, the SN2-palmitate infant formula primarily reduced calcium-saponified fat excretion. The results of this study further emphasize the nutritional importance of SN2-palmitate structured fat for infants. PMID:26334255

CONGENER-DEPENDENT DISTRIBUTION AND EXCRETION: A COMPARISON OF BDES 47, 99, 100, AND 153 TOXICOKINETICS.

EPA Science Inventory

Polybrominated diphenyl ethers (PBDEs) represent a novel class of chemicals used as flame retardants predominantly in textiles, furniture, and electronics. Evidence demonstrating the bioaccumulation of these brominated flame retardants in humans has spurred research into potenti...