Transdermal permeation of drugs with differing lipophilicity: Effect of penetration enhancer camphor.

PubMed

Xie, Feng; Chai, Jia-Ke; Hu, Quan; Yu, Yong-Hui; Ma, Li; Liu, Ling-Ying; Zhang, Xu-Long; Li, Bai-Ling; Zhang, Dong-Hai

2016-06-30

The aim of the present study was to investigate the potential application of (+)-camphor as a penetration enhancer for the transdermal delivery of drugs with differing lipophilicity. The skin irritation of camphor was evaluated by in vitro cytotoxicity assays and in vivo transdermal water loss (TEWL) measurements. A series of model drugs with a wide span of lipophilicity (logP value ranging from 3.80 to -0.95), namely indometacin, lidocaine, aspirin, antipyrine, tegafur and 5-fluorouracil, were tested using in vitro transdermal permeation experiments to assess the penetration-enhancing profile of camphor. Meanwhile, the in vivo skin microdialysis was carried out to further investigate the enhancing effect of camphor on the lipophilic and hydrophilic model drugs (i.e. lidocaine and tegafur). SC (stratum corneum)/vehicle partition coefficient and Fourier transform infrared spectroscopy (FTIR) were performed to probe the regulation action of camphor in the skin permeability barrier. It was found that camphor produced a relatively low skin irritation, compared with the frequently-used and standard penetration enhancer laurocapram. In vitro skin permeation studies showed that camphor could significantly facilitate the transdermal absorption of model drugs with differing lipophilicity, and the penetration-enhancing activities were in a parabola curve going downwards with the drug logP values, which displayed the optimal penetration-enhancing efficiency for the weak lipophilic or hydrophilic drugs (an estimated logP value of 0). In vivo skin microdialysis showed that camphor had a similar penetration behavior on transdermal absorption of model drugs. Meanwhile, the partition of lipophilic drugs into SC was increased after treatment with camphor, and camphor also produced a shift of CH2 vibration of SC lipid to higher wavenumbers and decreased the peak area of the CH2 vibration, probably resulting in the alteration of the skin permeability barrier. This suggests that camphor might be a safe and effective penetration enhancer for transdermal drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Evaluation of Organogel Nanoparticles as Drug Delivery System for Lipophilic Compounds.

PubMed

Martin, Baptiste; Brouillet, Fabien; Franceschi, Sophie; Perez, Emile

2017-05-01

The purpose of the study was to evaluate organogel nanoparticles as a drug delivery system by investigating their stability, according to the formulation strategy, and their release profile. The gelled nanoparticles were prepared by hot emulsification (above the gelation temperature) of an organogel in water, and cooling at room temperature. In the first step, we used DLS and DSC to select the most suitable formulations by optimizing the proportion of ingredients (HSA, PVA, castor oil) to obtain particles of the smallest size and greatest stability. Then, two lipophilic drug models, indomethacin and ketoconazole were entrapped in the nanoparticles made of castor oil gelled by 12-hydroxystearic acid. Thermal studies (DSC) confirmed that there was no significant alteration of gelling due to the entrapped drugs, even at 3% w/w. Very stable dispersions were obtained (>3 months), with gelled oil nanoparticles presenting a mean diameter between 250 and 300 nm. High encapsulation efficiency (>98%) was measured for indomethacin and ketoconazole. The release profile determined by in vitro dialysis showed an immediate release of the drug from the organogel nanoparticles, due to rapid diffusion. The study demonstrates the interest of these gelled oil nanoparticles for the encapsulation and the delivery of lipophilic active compounds.

Ocular Drug Delivery through pHEMA-Hydrogel Contact Lenses Co-Loaded with Lipophilic Vitamins

NASA Astrophysics Data System (ADS)

Lee, Dasom; Cho, Seungkwon; Park, Hwa Sung; Kwon, Inchan

2016-09-01

Ocular drug delivery through hydrogel contact lenses has great potential for the treatment of ocular diseases. Previous studies showed that the loading of lipophilic vitamin E to silicone-hydrogel contact lenses was beneficial in ocular drug delivery. We hypothesized that vitamin E loading to another type of popular hydrogel contact lenses, pHEMA-hydrogel contact lenses, improves ocular drug delivery by increasing the drug loading or the duration of drug release. Loading of vitamin E to pHEMA-hydrogel contact lenses significantly increased the loading of a hydrophilic drug surrogate (Alexa Fluor 488 dye) and two hydrophilic glaucoma drugs (timolol and brimonidine) to the lenses by 37.5%, 19.1%, and 18.7%, respectively. However, the release duration time was not significantly altered. Next, we hypothesized that the lipophilic nature of vitamin E attributes to the enhanced drug loading. Therefore, we investigated the effects of co-loading of another lipophilic vitamin, vitamin A, on drug surrogate delivery. We found out that vitamin A loading also increased the loading of the drug surrogate to pHEMA-hydrogel contact lenses by 30.3%. Similar to vitamin E loading, vitamin A loading did not significantly alter the release duration time of the drug or drug surrogate.

Lung Surfactant Microbubbles Increase Lipophilic Drug Payload for Ultrasound-Targeted Delivery

PubMed Central

Sirsi, Shashank R.; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y.; Mountford, Paul A.; Borden, Mark A.

2013-01-01

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta®, Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload. PMID:23781287

Lung surfactant microbubbles increase lipophilic drug payload for ultrasound-targeted delivery.

PubMed

Sirsi, Shashank R; Fung, Chinpong; Garg, Sumit; Tianning, Mary Y; Mountford, Paul A; Borden, Mark A

2013-01-01

The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta(®), Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload.

Effect of lipophilicity on microneedle-mediated iontophoretic transdermal delivery across human skin in vitro.

PubMed

Pawar, Kasturi R; Smith, Forrest; Kolli, Chandra Sekhar; Babu, R Jayachandra

2013-10-01

The effect of lipophilicity of drug on the microneedle (MN)-mediated iontophoretic delivery across dermatomed human skin was studied. Beta blockers with similar pKa but varied log P values were selected as model drugs in this study. Iontophoresis (ITP) or MNs, when used independently, increased the transdermal flux of beta blockers as compared with passive delivery (PD). ITP across the MN-treated skin (MN + ITP) increased the permeation rate of all beta blockers as compared with PD (p < 0.001). The enhancement ratios (ER) for hydrophilic molecules (atenolol and sotalol) were 71- and 78-fold higher for ITP + MN as compared with PD. However, for lipophilic molecule such as propranolol, there was 10-fold increase in the ER as compared with PD. These observations were further substantiated by the skin retention data; an inverse relationship between the skin retention and the hydrophilicity of the drug was observed. The results in the present study point out that the lipophilicity of the molecule plays a significant role on the electrically assisted transdermal delivery of drugs across the microporated skin. Using the combination of ITP + MN, hydrophilic drugs (atenolol and sotalol) were delivered at a much higher rate as compared with lipophilic molecules (propranolol and acebutolol). © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

Small molecule absorption by PDMS in the context of drug response bioassays.

PubMed

van Meer, B J; de Vries, H; Firth, K S A; van Weerd, J; Tertoolen, L G J; Karperien, H B J; Jonkheijm, P; Denning, C; IJzerman, A P; Mummery, C L

2017-01-08

The polymer polydimethylsiloxane (PDMS) is widely used to build microfluidic devices compatible with cell culture. Whilst convenient in manufacture, PDMS has the disadvantage that it can absorb small molecules such as drugs. In microfluidic devices like "Organs-on-Chip", designed to examine cell behavior and test the effects of drugs, this might impact drug bioavailability. Here we developed an assay to compare the absorption of a test set of four cardiac drugs by PDMS based on measuring the residual non-absorbed compound by High Pressure Liquid Chromatography (HPLC). We showed that absorption was variable and time dependent and not determined exclusively by hydrophobicity as claimed previously. We demonstrated that two commercially available lipophilic coatings and the presence of cells affected absorption. The use of lipophilic coatings may be useful in preventing small molecule absorption by PDMS. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study.

PubMed

Haag, M D M; Hofman, A; Koudstaal, P J; Stricker, B H C; Breteler, M M B

2009-01-01

Cross-sectional reports suggest that statin users are less likely to have Alzheimer disease (AD). Prospective studies have provided inconsistent evidence. Moreover, it is unclear whether the association differs for lipophilic statins, those that could more easily pass the blood-brain barrier and hydrophilic statins. To prospectively evaluate whether use of statins is associated with the risk of AD, and to determine whether associations differ for lipophilic and hydrophilic statins. 6992 participants of the prospective, population-based Rotterdam Study were followed, from baseline (1990-1993) until January 2005 for incident AD. Data on all filled prescriptions came from pharmacy records. For each date on which each event occurred, cholesterol-lowering drug use for the person who experienced the event and all remaining persons in the cohort was categorised as "any" or "never" use. A distinction was made between statin, lipophilic and hydrophilic statins, and non-statin cholesterol-lowering drugs. Data were analysed with the Cox regression analysis, adjusting for sex, age and potential confounders. During follow-up (mean 9 years), 582 persons developed AD. Compared with never use of cholesterol-lowering drugs, statin use was associated with a decreased risk of AD (HR 0.57; 95% CI 0.37 to 0.90), but non-statin cholesterol-lowering drug use was not (HR 1.05; 95% CI 0.45 to 2.44). HRs were equal for lipophilic (HR 0.54; 95% CI 0.32 to 0.89) and hydrophilic statins (HR 0.54; 95% CI 0.26 to 1.11). In the general population, the use of statins, but not of non-statin cholesterol-lowering drugs, was associated with a lower risk of AD compared with never use of cholesterol-lowering drugs. The protective effect was independent of the lipophilicity of statins.

Design and Synthesis of High Affinity Inhibitors of Plasmodium falciparum and Plasmodium vivax N-Myristoyltransferases Directed by Ligand Efficiency Dependent Lipophilicity (LELP)

PubMed Central

2014-01-01

N-Myristoyltransferase (NMT) is an essential eukaryotic enzyme and an attractive drug target in parasitic infections such as malaria. We have previously reported that 2-(3-(piperidin-4-yloxy)benzo[b]thiophen-2-yl)-5-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)-1,3,4-oxadiazole (34c) is a high affinity inhibitor of both Plasmodium falciparum and P. vivax NMT and displays activity in vivo against a rodent malaria model. Here we describe the discovery of 34c through optimization of a previously described series. Development, guided by targeting a ligand efficiency dependent lipophilicity (LELP) score of less than 10, yielded a 100-fold increase in enzyme affinity and a 100-fold drop in lipophilicity with the addition of only two heavy atoms. 34c was found to be equipotent on chloroquine-sensitive and -resistant cell lines and on both blood and liver stage forms of the parasite. These data further validate NMT as an exciting drug target in malaria and support 34c as an attractive tool for further optimization. PMID:24641010

Effect of Lipophilicity and Drug Ionization on Permeation Across Porcine Sublingual Mucosa.

PubMed

Goswami, Tarun; Li, Xiaoling; Jasti, Bhaskara R

2017-01-01

Sublingual route is one of the oldest alternative routes studied for the administration of drugs. However, the effect of physical-chemical properties on drug permeation via this route has not been systemically investigated. The objective of this study was to determine the effect of two key physicochemical properties, lipophilicity and ionization, on the transport of drugs across porcine sublingual mucosa. A series of β-blockers were used to study the effect of lipophilicity on drug permeation across the sublingual mucosa, while nimesulide (pKa 6.5) was used as a model drug to study the effect of degree of ionization on sublingual mucosa permeation of ionized and unionized species. Permeation of β-blockers increased linearly with an increase in the lipophilicity for the range of compounds studied. The permeability of nimesulide across sublingual mucosa decreased with an increase of pH. The flux of ionized and unionized forms of nimesulide was determined to delineate the contribution of ionized and unionized species to the total flux. At low pH, the apparent flux was primarily contributed by unionized species; however, when the pH is increased beyond its pKa, the primary contributor to the apparent flux, nimesulide, is ionized species. The contribution of each species to the apparent flux was shown to be determined by the thermodynamic activity of ionized or unionized species. This study identified the roles of lipophilicity and thermodynamic activity in drug permeation across the sublingual mucosa. The findings can help guide the design of sublingual drug delivery systems with optimal pH and solubility.

Co-delivery of antigen and a lipophilic anti-inflammatory drug to cells via a tailorable nanocarrier emulsion.

PubMed

Chuan, Yap Pang; Zeng, Bi Yun; O'Sullivan, Brendan; Thomas, Ranjeny; Middelberg, Anton P J

2012-02-15

Nanotechnology promises new drug carriers that can be tailored to specific applications. Here we report a new approach to drug delivery based on tailorable nanocarrier emulsions (TNEs), motivated by a need to co-deliver a protein antigen and a lipophilic drug for specific inhibition of nuclear factor kappa B (NF-κB) in antigen presenting cells (APCs). Co-delivery for NF-κB inhibition holds promise as a strategy for the treatment of rheumatoid arthritis. We used a highly surface-active peptide (SAP) to prepare a nanosized emulsion having defined surface properties predictable from the SAP sequence. Incorporating the lipophilic drug into the oil phase at the time of emulsion formation enabled its facile packaging. The SAP is depleted from bulk during emulsification, allowing simple subsequent addition of the drug-loaded oil-in-water emulsion to a solution of protein antigen. Decoration of emulsion surface with antigen was achieved via electrostatic deposition. In vitro data showed that the TNE prepared this way was internalized and well-tolerated by model APCs, and that good suppression of NF-κB expression was achieved. This work reports a new type of nanotechnology-based carrier, a TNE, which can potentially be tailored for co-delivery of multiple therapeutic components, and can be made using simple methods using only biocompatible materials. Copyright © 2011 Elsevier Inc. All rights reserved.

Insights on novel particulate self-assembled drug delivery beads based on partial inclusion complexes between triglycerides and cyclodextrins.

PubMed

Aburahma, Mona Hassan

2016-09-01

Most of the newly designed drug molecules are lipophilic in nature and often encounter erratic absorption and low bioavailability after oral administration. Finding ways to enhance the absorption and bioavailability of these lipophilic drugs is one of the major challenges that face pharmaceutical industry nowadays. In view of that, the purpose of this review is to shed some light on a novel particulate self-assembling system named "beads" than can act as a safe carrier for delivering lipophilic drugs. The beads are prepared simply by mixing oils with cyclodextrin (CD) aqueous solution in mild conditions. A unique interaction between oil components and CD molecules occurs to form in situ surface-active complexes which are prerequisites for beads formation. This review mainly focuses on the fundamentals of beads preparation through reviewing present, yet scarce, literature. The key methods used for beads characterization are discussed in details. Also, the potential mechanisms by which beads increase the bioavailability of lipophilic drugs are illustrated. Finally, the related research areas that needs to be addressed in future for optimizing this promising delivery system are briefly outlined.

Ion-pair partition of quarternary ammonium drugs: the influence of counter ions of different lipophilicity, size, and flexibility.

PubMed

Takács-Novák, K; Szász, G

1999-10-01

The ion-pair partition of quaternary ammonium (QA) pharmacons with organic counter ions of different lipophilicity, size, shape and flexibility was studied to elucidate relationships between ion-pair formation and chemical structure. The apparent partition coefficient (P') of 4 QAs was measured in octanol/pH 7.4 phosphate buffer system by the shake-flask method as a function of molar excess of ten counter ions (Y), namely: mesylate (MES), acetate (AC), pyruvate (PYRU), nicotinate (NIC), hydrogenfumarate (HFUM), hydrogenmaleate (HMAL), p-toluenesulfonate (PTS), caproate (CPR), deoxycholate (DOC) and prostaglandin E1 anion (PGE1). Based on 118 of highly precise logP' values (SD< 0.05), the intrinsic lipophilicity (without external counter ions) and the ion-pair partition of QAs (with different counter ions) were characterized. Linear correlation was found between the logP' of ion-pairs and the size of the counter ions described by the solvent accessible surface area (SASA). The lipophilicity increasing effect of the counter ions were quantified and the following order was established: DOC approximate to PGE1 > CPR approximate to PTS > NIC approximate to HMAL > PYRU approximate to AC approximate to MES approximate to HFUM. Analyzing the lipophilicity/molar ratio (QA:Y) profile, the differences in the ion-pair formation were shown and attributed to the differences in the flexibility/rigidity and size both of QA and Y. Since the largest (in average, 300 X) lipophilicity enhancement was found by the influence of DOC and PGE1 and considerable (on average 40 X) increase was observed by CPR and PTS, it was concluded that bile acids and prostaglandin anions may play a significant role in the ion-pair transport of quaternary ammonium drugs and caproic acid and p-toluenesulfonic acid may be useful salt forming agents to improve the pharmacokinetics of hydrophilic drugs.

Heuristic lipophilicity potential for computer-aided rational drug design.

PubMed

Du, Q; Arteca, G A; Mezey, P G

1997-09-01

In this contribution we suggest a heuristic molecular lipophilicity potential (HMLP), which is a structure-based technique requiring no empirical indices of atomic lipophilicity. The input data used in this approach are molecular geometries and molecular surfaces. The HMLP is a modified electrostatic potential, combined with the averaged influences from the molecular environment. Quantum mechanics is used to calculate the electron density function rho(r) and the electrostatic potential V(r), and from this information a lipophilicity potential L(r) is generated. The HMLP is a unified lipophilicity and hydrophilicity potential. The interactions of dipole and multipole moments, hydrogen bonds, and charged atoms in a molecule are included in the hydrophilic interactions in this model. The HMLP is used to study hydrogen bonds and water-octanol partition coefficients in several examples. The calculated results show that the HMLP gives qualitatively and quantitatively correct, as well as chemically reasonable, results in cases where comparisons are available. These comparisons indicate that the HMLP has advantages over the empirical lipophilicity potential in many aspects. The HMLP is a three-dimensional and easily visualizable representation of molecular lipophilicity, suggested as a potential tool in computer-aided three-dimensional drug design.

Development and validation of a general derivatization HPLC method for the trace analysis of acyl chlorides in lipophilic drug substances.

PubMed

Zheng, Xiangyuan; Luo, Lan; Zhou, Jie; Ruan, Xiaoling; Liu, Wenyuan; Zheng, Feng

2017-06-05

Acyl chlorides are important acylating agents in the synthesis of active pharmaceutical ingredients. Determining the residual acyl chlorides in drug substances is a challenge due to their high reactivity and the matrix interferences from drug substances and their related impurities. This paper describes a general derivatization HPLC method for the determination of aromatic and aliphatic acyl chlorides in lipophilic drug substances. Since most drug substances have weak absorptions in the visible range (above 380nm), the nitro-substituted anilines and nitro-substituted phenylhydrazines were selected as the derivatization reagents due to their weak basicity and red-shift of UV absorption spectra. The maximum wavelength and absorption intensity of nitro-substituted anilines decreased after derivatization with acyl chlorides, whereas the derivatization products of nitro-substituted phenylhydrazines showed the slight increases of maximum wavelength and absorbance intensity. Hence, 2-nitrophenylhydrazine was selected as the suitable derivatization reagent because the derivatives have the maximum UV wavelength absorbance at 395nm, which could largely minimize the matrix interferences. The optimization of the concentration of 2-nitrophenylhydrazine is important for the sensitivity and stability of derivatives. Other reaction conditions including reaction temperature, time and the influence of three competitive solvents (water, methanol and ethanol) on the reaction efficiency were also studied. After derivatization with 100μgmL -1 2-nitrophenylhydrazine at room temperature for 30min, the method was validated for high specificity and sensitivity with the detection limits in the range of 0.01-0.03μgmL -1 . The proposed method was applied as a generic method to determine the residual acyl chlorides in lipophilic drug substances. Copyright © 2017 Elsevier B.V. All rights reserved.

The Brown Alga Stypopodium zonale (Dictyotaceae): A Potential Source of Anti-Leishmania Drugs

PubMed Central

Soares, Deivid Costa; Szlachta, Marcella Macedo; Teixeira, Valéria Laneuville; Soares, Angelica Ribeiro; Saraiva, Elvira Maria

2016-01-01

This study evaluated the anti-Leishmania amazonensis activity of a lipophilic extract from the brown alga Stypopodium zonale and atomaric acid, its major compound. Our initial results revealed high inhibitory activity for intracellular amastigotes in a dose-dependent manner and an IC50 of 0.27 μg/mL. Due to its high anti-Leishmania activity and low toxicity toward host cells, we fractionated the lipophilic extract. A major meroditerpene in this extract, atomaric acid, and its methyl ester derivative, which was obtained by a methylation procedure, were identified by nuclear magnetic resonance (NMR) spectroscopy. Both compounds inhibited intracellular amastigotes, with IC50 values of 20.2 μM (9 μg/mL) and 22.9 μM (10 μg/mL), and selectivity indexes of 8.4 μM and 11.5 μM. The leishmanicidal activity of both meroditerpenes was independent of nitric oxide (NO) production, but the generation of reactive oxygen species (ROS) may be at least partially responsible for the amastigote killing. Our results suggest that the lipophilic extract of S. zonale may represent an important source of compounds for the development of anti-Leishmania drugs. PMID:27618071

Effect of a high-fat meal on absorption and disposition of lipophilic compounds: the importance of degree of association with triglyceride-rich lipoproteins.

PubMed

Gershkovich, Pavel; Hoffman, Amnon

2007-09-01

Following a high-fat meal, triglyceride-rich lipoproteins (TRL) are assembled in the gut and absorbed via the lymph into the blood circulation, producing a temporal hyperlipidemia. The purpose of this study is to verify the hypothesis that this transient acute postprandial hyperlipidemia affects the pharmacokinetics of lipophilic drugs on both absorption and disposition levels by the same underlying mechanism, namely the association of active lipophilic compounds with TRL in the plasma (disposition) or within the enterocyte (lymphatic transport). This concept was assessed in rats using two model compounds, DDT with high affinity to chylomicrons and diazepam which does not bind to chylomicrons. Oral administration of peanut oil significantly increased the AUC of plasma DDT concentrations following its IV bolus administration in comparison to a water treated group. On the other hand, the AUC of diazepam following IV bolus administration was the same in oil and water treated rats. While DDT is known to have significant lymphatic bioavailability, diazepam has negligible intestinal lymphatic transport (0.014+/-0.004% of a given dose). In conclusion, lipophilic molecules that bind extensively to TRL will be prone to both intestinal lymphatic transport and to post-absorptive changes in disposition (decrease in clearance and volume of distribution) following a high-fat meal.

Extravascular transport of drugs in tumor tissue: effect of lipophilicity on diffusion of tirapazamine analogues in multicellular layer cultures.

PubMed

Pruijn, Frederik B; Sturman, Joanna R; Liyanage, H D Sarath; Hicks, Kevin O; Hay, Michael P; Wilson, William R

2005-02-24

The extravascular diffusion of antitumor agents is a key determinant of their therapeutic activity, but the relationships between physicochemical properties of drugs and their extravascular transport are poorly understood. It is well-known that drug lipophilicity plays an important role in transport across biological membranes, but the net effect of lipophilicity on transport through multiple layers of tumor cells is less clear. This study examines the influence of lipophilicity (measured as the octanol-water partition coefficient P) on the extravascular transport properties of the hypoxic cytotoxin tirapazamine (TPZ, 1) and a series of 13 neutral analogues, using multicellular layers (MCLs) of HT29 human colon carcinoma cells as an in vitro model for the extravascular compartment of tumors. Flux of drugs across MCLs was determined using diffusion chambers, with the concentration-time profile on both sides of the MCL measured by HPLC. Diffusion coefficients in the MCLs (D(MCL)) were inversely proportional to M(r)(0.5) (M(r), relative molecular weight), although this was a minor contributor to differences between compounds over the narrow M(r) range investigated. Differences in lipophilicity had a larger effect, with a sigmoidal dependence of D(MCL) on log P. Correcting for M(r) differences, lipophilic compounds (log P > 1.5) had ca. 15-fold higher D(MCL) than hydrophilic compounds (log P < -1). Using a pharmacokinetic/pharmacodynamic (PK/PD) model in which diffusion in the extravascular compartment of tumors is considered explicitly, we demonstrated that hypoxic cell kill is very sensitive to changes in extravascular diffusion coefficient of TPZ analogues within this range. This study shows that simple monosubstitution of TPZ can alter log P enough to markedly improve extravascular transport and activity against target cells, especially if rates of metabolic activation are also optimized.

The connection Between Plasma Protein Binding and Acute Toxicity as Determined by the LD50 Value.

PubMed

Svennebring, Andreas

2016-02-01

Preclinical Research A dataset of three drug classes (acids, bases, and neutrals) with LD50 values in mice was analysed to investigate a possible connection between high plasma protein binding and acute toxicity. Initially, it was found that high plasma protein binding was associated with toxicity for acids and neutrals, but after compensating for differences in lipophilicity, plasma protein binding was found not to be associated with toxicity. The therapeutic index established by the quotient between mouse LD50 and the defined daily dose was unaffected by both lipophilicity and plasma protein binding. © 2015 Wiley Periodicals, Inc.

Drug delivery properties of macroporous polystyrene solid foams.

PubMed

Canal, Cristina; Aparicio, Rosa Maria; Vilchez, Alejandro; Esquena, Jordi; García-Celma, Maria José

2012-01-01

Polymeric porous foams have been evaluated as possible new pharmaceutical dosage forms. These materials were obtained by polymerization in the continuous phase of highly concentrated emulsions prepared by the phase inversion temperature method. Their porosity, specific surface and surface topography were characterized, and the incorporation and release of active principles was studied using ketoprofen as model lipophilic molecule. Solid foams with very high pore volume, mainly inside macropores, were obtained by this method. The pore morphology of the materials was characterized, and very rough topography was observed, which contributed to their nearly superhydrophobic properties. These solid foams could be used as delivery systems for active principles with pharmaceutical interest, and in the present work ketoprofen was used as a model lipophilic molecule. Drug incorporation and release was studied from solid foam disks, using different concentrations of the loading solutions, achieving a delayed release with short lag-time.

Influence of Drug Solubility and Lipophilicity on Transscleral Retinal Delivery of Six Corticosteroids

PubMed Central

Thakur, Ashish; Kadam, Rajendra S.

2011-01-01

The influence of drug properties including solubility, lipophilicity, tissue partition coefficients, and in vitro transscleral permeability on ex vivo and in vivo transscleral delivery from corticosteroid suspensions was determined. Solubility, tissue/buffer partition coefficients for bovine sclera and choroid-retinal pigment epithelium (CRPE), and in vitro bovine sclera and sclera-choroid-retinal pigment epithelium (SCRPE) transscleral transport were determined at pH 7.4 for triamcinolone, prednisolone, dexamethasone, fluocinolone acetonide, triamcinolone acetonide, and budesonide in solution. Ex vivo and in vivo transscleral delivery was assessed in Brown Norway rats after posterior subconjunctival injection of a 1 mg/ml suspension of each corticosteroid. Corticosteroid solubility and partition coefficients ranged from ∼17 to 300 μg/ml and 3.0 to 11.4 for sclera and from 7.1 to 35.8 for CRPE, respectively, with the more lipophilic molecules partitioning more into both tissues. Transport across sclera and SCRPE was in the range of 3.9 to 10.7% and 0.3 to 1.8%, respectively, with the transport declining with an increase in lipophilicity. Ex vivo and in vivo transscleral delivery indicated tissue distribution in the order CRPE ≥ sclera > retina > vitreous. Tissue partitioning showed a positive correlation with drug lipophilicity (R2 = 0.66–0.96). Ex vivo and in vivo sclera, CRPE, retina, and vitreous tissue levels of all corticosteroids showed strong positive correlation with drug solubility (R2 = 0.91–1.0) but not lipophilicity (R2 = 0.24–0.41) or tissue partitioning (R2 = 0.24–0.46) when delivered as suspensions. In vivo delivery was lower in all eye tissues assessed than ex vivo delivery, with the in vivo/ex vivo ratios being the lowest in the vitreous (0.085–0.212). Upon exposure to corticosteroid suspensions ex vivo or in vivo, transscleral intraocular tissue distribution was primarily driven by the drug solubility. PMID:21346004

Nanostructured lipid carrier-loaded hyaluronic acid microneedles for controlled dermal delivery of a lipophilic molecule

PubMed Central

Lee, Sang Gon; Jeong, Jae Han; Lee, Kyung Min; Jeong, Kyu Ho; Yang, Huisuk; Kim, Miroo; Jung, Hyungil; Lee, Sangkil; Choi, Young Wook

2014-01-01

Nanostructured lipid carriers (NLCs) were employed to formulate a lipophilic drug into hydrophilic polymeric microneedles (MNs). Hyaluronic acid (HA) was selected as a hydrophilic and bioerodible polymer to fabricate MNs, and nile red (NR) was used as a model lipophilic molecule. NR-loaded NLCs were consolidated into the HA-based MNs to prepare NLC-loaded MNs (NLC-MNs). A dispersion of NLCs was prepared by high-pressure homogenization after dissolving NR in Labrafil and mixing with melted Compritol, resulting in 268 nm NLCs with a polydispersity index of 0.273. The NLC dispersion showed a controlled release of NR over 24 hours, following Hixson–Crowell’s cube root law. After mixing the NLC dispersion with the HA solution, the drawing lithography method was used to fabricate NLC-MNs. The length, base diameter, and tip diameter of the NLC-MNs were approximately 350, 380, and 30 μm, respectively. Fluorescence microscopic imaging of the NLC-MNs helped confirm that the NR-loaded NLCs were distributed evenly throughout the MNs. In a skin permeation study performed using a Franz diffusion cell with minipig dorsal skin, approximately 70% of NR was localized in the skin after 24-hour application of NLC-MNs. Confocal laser scanning microscopy (z-series) of the skin at different depths showed strong fluorescence intensity in the epidermal layer, which appeared to spread out radially with the passage of time. This study indicated that incorporation of drug-loaded NLCs into MNs could represent a promising strategy for controlled dermal delivery of lipophilic drugs. PMID:24403833

Adsorption of drugs onto a pH responsive poly(N,N-dimethyl aminoethyl methacrylate) grafted anion-exchange membrane in vitro.

PubMed

Karppi, Jouni; Akerman, Satu; Akerman, Kari; Sundell, Annika; Nyyssönen, Kristiina; Penttilä, Ilkka

2007-06-29

The influence of charge and lipophilicity of acidic and basic model drugs on their adsorption onto poly(N,N-dimethyl aminoethyl methacrylic acid) grafted poly(vinylidene fluoride) (DMAEMA-PVDF) membranes was evaluated. The effect of serum proteins (albumin, IgG) and hormones (cortisol, free thyroxine (T(4)F) and thyrotropin (TSH)) on drug adsorption was also studied. Acidic model drugs (antiepileptics and benzodiazepies) adsorbed to a greater extent onto the membrane from Hepes buffer at ionic strength of 25mM and pH 7.0 than basic drugs (antidepressants) did. Adsorption of acidic model drugs was based on electrostatic interactions between positively charged tertiary amino groups of DMAEMA side-chain and acidic negatively charged drug. Albumin diminished the adsorption of drugs from serum onto the membrane. Lipophilicity was related to the adsorption of acidic model drugs from serum onto the membrane. The degree of grafting had the greatest effect on adsorption of lipophilic drugs, but no influence was observed on adsorption of hydrophilic drugs. The present results showed that acidic drugs and albumin adsorbed onto the membrane, which suggests that the PVDF-DMAEMA membrane may be suitable for separating acidic drugs from protein-free substances for subsequent monitoring and evaluation.

[Effects of sub-micro emulsion composition on cellular disposition of incorporated lipophilic drug].

PubMed

Sun, Xiao-Yi; Xiang, Zhi-Qiang; Wu, Shuo; Lv, Yuan-Yuan; Liang, Wen-Quan

2013-09-01

To investigate the effects of sub-micro emulsion composition on cellular uptake and disposition of incorporated lipophilic drug. Sub-micro emulsions containing 10 % oil, 1.2 % lecithin and 2.25 % glycerol were prepared, and the fluorescent agent coumarin 6 was used as a model drug. The effects of oil types, co-surfactants and cationic lipid on uptake and elimination kinetics of 6-coumarin in HeLa cells were studied. The uptake mechanism of sub-micro emulsions was further investigated. Oil type and Tweens had no influence on the cellular uptake. Modifications of surfactants with Span series increased the cellular influx, among which Span 20 with hydrophilic-lipophilic balance (HLB) value of 8.6 was the best enhancer. The intracellular drug level reached up to (46.09 ± 1.98)ng/μg protein which had significant difference with control group [(38.54 ± 0.34)ng/μg protein]. The positively charged emulsions significantly increased the uptake rate constant and elimination rate constant which were 4 times and 1.5 times of those in anionic groups, respectively. The uptake enhancement was also observed in cationic emulsions, cellular concentrations at plateau were (42.73 ± 0.84)ng/μg protein, which was about 3 times of that in anionic emulsions [(15.71 ± 0.74)ng/μg protein], when extracellular drug concentration kept at 100 ng/ml. Cationic emulsions delivered the payload mainly by direct drug transfer to contacted cells, while the negative ones depended on both drug passive diffusion and clathrin-mediated endocytosis of drug containing oil droplets which accounted for 20% of the intracellular drug. Interfacial characteristic of sub-micro emulsions such as co-surfactants HLB as well as zeta potentials can influence lipophilic drug both in cellular uptake and elimination.

Octanol/water partitioning simulation by RP-HPLC for structurally diverse acidic drugs: comparison of three columns in the presence and absence of n-octanol as the mobile phase additive.

PubMed

Giaginis, Costas; Theocharis, Stamatios; Tsantili-Kakoulidou, Anna

2013-12-01

The advantageous effect of n-octanol as a mobile phase additive for lipophilicity assessment of structurally diverse acidic drugs both in the neutral and ionized form was explored. Two RP C18 columns, ABZ+ and Aquasil, were used for the determination of logkw indices, and the results were compared with those previously reported on a base-deactivated silica column. At pH 2.5, the use of n-octanol-saturated buffer as the mobile phase aqueous component led to high-quality 1:1 correlation between logkw and logP for the ABZ+ column, while inferior statistics were obtained for Aquasil. At physiological pH, the correlations were significantly improved if strongly ionized acidic drugs were treated separately from weakly ionized ones. In the latter case, 1:1 correlations between logD7.4 and logkw(oct) indices were obtained in the presence of 0.25% n-octanol. Concerning strongly ionized compounds, adequate correlations were established under the same conditions; however, slopes were significantly lower than unity, while large negative intercepts were obtained. According to the absolute difference (diff = logD7.4 – logkw) pattern, base-deactivated silica showed a better performance than ABZ+, however, the latter seems more efficient for the lipophilicity assessment of highly lipophilic acidic compounds. Aquasil may be the column of choice if logD7.4<3 with the limitation, however, that very hydrophilic compounds cannot be measured.

Assessing the lipophilicity of fragments and early hits

NASA Astrophysics Data System (ADS)

Mortenson, Paul N.; Murray, Christopher W.

2011-07-01

A key challenge in many drug discovery programs is to accurately assess the potential value of screening hits. This is particularly true in fragment-based drug design (FBDD), where the hits often bind relatively weakly, but are correspondingly small. Ligand efficiency (LE) considers both the potency and the size of the molecule, and enables us to estimate whether or not an initial hit is likely to be optimisable to a potent, druglike lead. While size is a key property that needs to be controlled in a small molecule drug, there are a number of additional properties that should also be considered. Lipophilicity is amongst the most important of these additional properties, and here we present a new efficiency index (LLEAT) that combines lipophilicity, size and potency. The index is intuitively defined, and has been designed to have the same target value and dynamic range as LE, making it easily interpretable by medicinal chemists. Monitoring both LE and LLEAT should help both in the selection of more promising fragment hits, and controlling molecular weight and lipophilicity during optimisation.

Amphiphilic naproxen prodrugs: differential scanning calorimetry study on their interaction with phospholipid bilayers.

PubMed

Giuffrida, Maria Chiara; Pignatello, Rosario; Castelli, Francesco; Sarpietro, Maria Grazia

2017-09-01

Naproxen, a nonsteroid anti-inflammatory drug studied for Alzheimer's disease, was conjugated with lipoamino acids (LAA) directly or through a diethylamine (EDA) spacer to improve the drug lipophilicity and the interaction with phospholipid bilayers. The interaction of naproxen and its prodrugs with biomembrane models consisting of dimyristoylphosphatidylcholine multilamellar vesicles was studied by differential scanning calorimetry. The transfer of prodrugs from a lipophilic carrier to a biomembrane model was also studied. Naproxen conjugation to lipoamino acids improves its interaction with biomembrane models and affects the transfer from a lipophilic carrier to biomembrane model. LAA portion may localize between the phospholipid chains; the entity of the interaction depends not only on the presence of the spacer but also on the LAA chain length. Variation of LAA portion can modulate the naproxen prodrugs affinity towards the biological membrane as well as towards the lipophilic carrier. © 2017 Royal Pharmaceutical Society.

Heuristic lipophilicity potential for computer-aided rational drug design

NASA Astrophysics Data System (ADS)

Du, Qishi; Arteca, Gustavo A.; Mezey, Paul G.

1997-09-01

In this contribution we suggest a heuristic molecular lipophilicitypotential (HMLP), which is a structure-based technique requiring noempirical indices of atomic lipophilicity. The input data used in thisapproach are molecular geometries and molecular surfaces. The HMLP is amodified electrostatic potential, combined with the averaged influences fromthe molecular environment. Quantum mechanics is used to calculate theelectron density function ρ(r) and the electrostatic potential V(r), andfrom this information a lipophilicity potential L(r) is generated. The HMLPis a unified lipophilicity and hydrophilicity potential. The interactions ofdipole and multipole moments, hydrogen bonds, and charged atoms in amolecule are included in the hydrophilic interactions in this model. TheHMLP is used to study hydrogen bonds and water-octanol partitioncoefficients in several examples. The calculated results show that the HMLPgives qualitatively and quantitatively correct, as well as chemicallyreasonable, results in cases where comparisons are available. Thesecomparisons indicate that the HMLP has advantages over the empiricallipophilicity potential in many aspects. The HMLP is a three-dimensional andeasily visualizable representation of molecular lipophilicity, suggested asa potential tool in computer-aided three-dimensional drug design.

Advances in visual representation of molecular potentials.

PubMed

Du, Qi-Shi; Huang, Ri-Bo; Chou, Kuo-Chen

2010-06-01

The recent advances in visual representations of molecular properties in 3D space are summarized, and their applications in molecular modeling study and rational drug design are introduced. The visual representation methods provide us with detailed insights into protein-ligand interactions, and hence can play a major role in elucidating the structure or reactivity of a biomolecular system. Three newly developed computation and visualization methods for studying the physical and chemical properties of molecules are introduced, including their electrostatic potential, lipophilicity potential and excess chemical potential. The newest application examples of visual representations in structure-based rational drug are presented. The 3D electrostatic potentials, calculated using the empirical method (EM-ESP), in which the classical Coulomb equation and traditional atomic partial changes are discarded, are highly consistent with the results by the higher level quantum chemical method. The 3D lipophilicity potentials, computed by the heuristic molecular lipophilicity potential method based on the principles of quantum mechanics and statistical mechanics, are more accurate and reliable than those by using the traditional empirical methods. The 3D excess chemical potentials, derived by the reference interaction site model-hypernetted chain theory, provide a new tool for computational chemistry and molecular modeling. For structure-based drug design, the visual representations of molecular properties will play a significant role in practical applications. It is anticipated that the new advances in computational chemistry will stimulate the development of molecular modeling methods, further enriching the visual representation techniques for rational drug design, as well as other relevant fields in life science.

Evaluation of γ-cyclodextrin effect on permeation of lipophilic drugs: application of cellophane/fused octanol membrane.

PubMed

Muankaew, Chutimon; Jansook, Phatsawee; Loftsson, Thorsteinn

2017-06-01

According to the Biopharmaceutics Classification System, oral bioavailability of drugs is determined by their aqueous solubility and the ability of the dissolved drug molecules to permeate lipophilic biological membranes. Similarly topical bioavailability of ophthalmic drugs is determined by their solubility in the aqueous tear fluid and their ability to permeate the lipophilic cornea. Enabling pharmaceutical excipients such as cyclodextrins can have profound effect on the drug bioavailability. However, to fully appreciate such enabling excipients, the relationship between their effects and the physicochemical properties of the permeating drug needs to be known. In this study, the permeation enhancing effect of γ-cyclodextrin (γCD) on saturated drug solutions containing hydrocortisone (HC), irbesartan (IBS), or telmisartan (TEL) was evaluated using cellophane and fused cellulose-octanol membranes in a conventional Franz diffusion cell system. The flux (J), the flux ratio (J R ) and the apparent permeability coefficients (P app ) demonstrate that γCD increases drug permeability. However, its efficacy depends on the drug properties. Addition of γCD increased P app of HC (unionized) and IBS (partially ionized) through the dual membrane but decreased the P app of TEL (fully ionized) that displays low complexation efficacy. The dual cellophane-octanol membrane system was simple to use and gave reproducible results.

Fatty Acid Binding Proteins Expressed at the Human Blood-Brain Barrier Bind Drugs in an Isoform-Specific Manner.

PubMed

Lee, Gordon S; Kappler, Katharina; Porter, Christopher J H; Scanlon, Martin J; Nicolazzo, Joseph A

2015-10-01

To examine the expression of fatty acid binding proteins (FABPs) at the human blood-brain barrier (BBB) and to assess their ability to bind lipophilic drugs. mRNA and protein expression of FABP subtypes in immortalized human brain endothelial (hCMEC/D3) cells were examined by RT-qPCR and Western blot, respectively. FABPs that were found in hCMEC/D3 cells (hFABPs) were recombinantly expressed and purified from Escherichia coli C41(DE3) cells. Drug binding to these hFABPs was assessed using a fluorescence assay, which measured the ability of a panel of lipophilic drugs to displace the fluorescent probe compound 1-anilinonaphthalene-8-sulfonic acid (ANS). hFABP3, 4 and 5 were expressed in hCMEC/D3 cells at the mRNA and protein level. The competitive ANS displacement assay demonstrated that, in general, glitazones preferentially bound to hFABP5 (Ki: 1.0-28 μM) and fibrates and fenamates preferentially bound to hFABP4 (Ki: 0.100-17 μM). In general, lipophilic drugs appeared to show weaker affinities for hFABP3 relative to hFABP4 and hFABP5. No clear correlation was observed between the molecular structure or physicochemical properties of the drugs and their ability to displace ANS from hFABP3, 4 and 5. hFABP3, 4 and 5 are expressed at the human BBB and bind differentially to a diverse range of lipophilic drugs. The unique expression and binding patterns of hFABPs at the BBB may therefore influence drug disposition into the brain.

Cyclodextrins in eye drop formulations: enhanced topical delivery of corticosteroids to the eye.

PubMed

Loftsson, Thorsteinn; Stefánsson, Einar

2002-04-01

Cyclodextrins are cylindrical oligosaccharides with a lipophilic central cavity and hydrophilic outer surface. They can form water-soluble complexes with lipophilic drugs, which 'hide' in the cavity. Cyclodextrins can be used to form aqueous eye drop solutions with lipophilic drugs, such as steroids and some carbonic anhydrase inhibitors. The cyclodextrins increase the water solubility of the drug, enhance drug absorption into the eye, improve aqueous stability and reduce local irritation. Cyclodextrins are useful excipients in eye drop formulations of various drugs, including steroids of any kind, carbonic anhydrase inhibitors, pilocarpine, cyclosporins, etc. Their use in ophthalmology has already begun and is likely to expand the selection of drugs available as eye drops. In this paper we review the properties of cyclodextrins and their application in eye drop formulations, of which their use in the formulation of dexamethasone eye drops is an example. Cyclodextrins have been used to formulate eye drops containing corticosteroids, such as dexamethasone, with levels of concentration and ocular absorption which, according to human and animal studies, are many times those seen with presently available formulations. Cyclodextrin-based dexamethasone eye drops are well tolerated in the eye and seem to provide a higher degree of bioavailability and clinical efficiency than the steroid eye drop formulations presently available. Such formulations offer the possibility of once per day application of corticosteroid eye drops after eye surgery, and more intensive topical steroid treatment in severe inflammation. While cyclodextrins have been known for more than a century, their use in ophthalmology is just starting. Cyclodextrins are useful excipients in eye drop formulations for a variety of lipophilic drugs. They will facilitate eye drop formulations for drugs that otherwise might not be available for topical use, while improving absorption and stability and decreasing local irritation.

Reduction in lipophilicity improved the solubility, plasma–protein binding, and permeability of tertiary sulfonamide RORc inverse agonists

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

Fauber, Benjamin P.; René, Olivier; de Leon Boenig, Gladys

2014-08-01

Using structure-based drug design principles, we identified opportunities to reduce the lipophilicity of our tertiary sulfonamide RORc inverse agonists. The new analogs possessed improved RORc cellular potencies with >77-fold selectivity for RORc over other nuclear receptors in our cell assay suite. The reduction in lipophilicity also led to an increased plasma–protein unbound fraction and improvements in cellular permeability and aqueous solubility.

Troxacitabine prodrugs for pancreatic cancer.

PubMed

Adema, A D; Radi, M; Daft, J; Narayanasamy, J; Hoebe, E K; Alexander, L E; Chu, C K; Peters, G J

2007-01-01

Troxacitabine is a cytotoxic deoxycytidine analogue with an unnatural L-configuration, which is activated by deoxycytidine kinase (dCK). The configuration is responsible for differences in the uptake and metabolism of troxacitabine compared to other deoxynucleoside analogues. The main drawback in the use of most nucleoside anticancer agents originates from their hydrophilic nature, which property requires a high and frequent dosage for an intravenous administration. To overcome this problem several troxacitabine prodrugs modified in the aminogroup with a linear aliphatic chain with a higher lipophilicity were developed. To determine whether these prodrugs have an advantage over Troxacitabine pancreatic cancer cell lines were exposed to Troxacitabine and the lipophilic prodrugs. The addition of linear aliphatic chains to troxacitabine increased sensitivity of pancreatic cancer cell lines to the drug > 100-fold, possibly due to a better uptake and retention of the drug.

Parallel screening of drug-like natural compounds using Caco-2 cell permeability QSAR model with applicability domain, lipophilic ligand efficiency index and shape property: A case study of HIV-1 reverse transcriptase inhibitors

NASA Astrophysics Data System (ADS)

Patel, Rikin D.; Kumar, Sivakumar Prasanth; Patel, Chirag N.; Shankar, Shetty Shilpa; Pandya, Himanshu A.; Solanki, Hitesh A.

2017-10-01

The traditional drug design strategy centrally focuses on optimizing binding affinity with the receptor target and evaluates pharmacokinetic properties at a later stage which causes high rate of attrition in clinical trials. Alternatively, parallel screening allows evaluation of these properties and affinity simultaneously. In a case study to identify leads from natural compounds with experimental HIV-1 reverse transcriptase (RT) inhibition, we integrated various computational approaches including Caco-2 cell permeability QSAR model with applicability domain (AD) to recognize drug-like natural compounds, molecular docking to study HIV-1 RT interactions and shape similarity analysis with known crystal inhibitors having characteristic butterfly-like model. Further, the lipophilic properties of the compounds refined from the process with best scores were examined using lipophilic ligand efficiency (LLE) index. Seven natural compound hits viz. baicalien, (+)-calanolide A, mniopetal F, fagaronine chloride, 3,5,8-trihydroxy-4-quinolone methyl ether derivative, nitidine chloride and palmatine, were prioritized based on LLE score which demonstrated Caco-2 well absorption labeling, encompassment in AD structural coverage, better receptor affinity, shape adaptation and permissible AlogP value. We showed that this integrative approach is successful in lead exploration of natural compounds targeted against HIV-1 RT enzyme.

Encapsulation of porphyrins and chlorins in biodegradable nanoparticles: the effect of dye lipophilicity on the extravasation and the photothrombic activity. A comparative study.

PubMed

Pegaz, Bernadette; Debefve, Elodie; Borle, Francois; Ballini, Jean-Pierre; van den Bergh, Hubert; Kouakou-Konan, Yvette Niamien

2005-07-01

In the present work, we performed a preclinical inter-comparison study using several photosensitizers with the goal of optimizing photodynamic therapy (PDT) for the treatment of choroidal neovascularization (CNV) associated with age-related macular degeneration. The tested molecules were the porphyrins meso-tetraphenylporphyrin (TPP) and meso-tetra-(4-carboxyphenyl)-porphyrin (TCPP), and the chlorins pheophorbide-a (Pheo-a) and chlorin e(6) (Ce(6)). Each of these molecules was entrapped in biodegradable nanoparticles (NP) based on poly(d,l-lactic acid). The influence of the degree of lipophilicity on the incorporation efficiency of the drug in the NPs, and on the dye leakage from blood vessels as well as on the photothrombic efficiency was investigated using the chick chorioallantoic membrane (CAM) as in vivo model. NP characterization showed that the dye was more effectively entrapped in the polymeric matrix when its degree of lipophilicity increased. While less lipophilic compounds (TCPP, Ce(6)) extravasate rather easily, the more lipophilic dyes (TPP, Pheo-a) tend to remain inside the blood vessels. After injection of a drug dose of 1 mg/kg body weight and a drug-light application interval of 1 min, irradiation with light doses ranging from 5 to 20 J/cm(2) led to the highest photothrombic efficiency when using the NPs loaded with the most lipophilic molecule (TPP). The latter induced vascular damage, which was significantly higher than that observed with the other molecules tested. Thus, in addition to minimal leakage from blood vessels, the TPP in NP formulation exhibited photothrombic efficiency similar to Visudyne which was also tested in the CAM model.

Effect of O-acylmenthol on transdermal delivery of drugs with different lipophilicity.

PubMed

Zhao, Ligang; Fang, Liang; Xu, Yongnan; Zhao, Yanyan; He, Zhonggui

2008-03-20

To develop more effective compounds as enhancers, O-acylmenthol derivatives which were expected to be enzymatically hydrolyzed into nontoxic metabolites by esterases in the living epidermis were synthesized from l-menthol and pharmaceutical excipient acids (lactic acid, cinnamic acid, salicylic acid and oleic acid) in this study. Their promoting activity on the percutaneous absorption of five model drugs, 5-fluorouracil (5-FU), isosorbide dinitrate (ISDN), lidocaine (LD), ketoprofen (KP), and indomethacin (IM), which were selected based on their lipophilicity represented by log K(O/W), were tested in vitro across full thickness rat skin with each of the evaluated drugs in saturated donor solution. 2-Isopropyl-5-methylcyclohexyl 2-hydroxypanoate (M-LA) provided the highest increase of accumulation of 5-FU (3.74-fold) and LD (4.19-fold) in the receptor phase while 2-isopropyl-5-methylcyclohexyl cinnamate (M-CA) was ineffective for most of the drugs; Both 2-isopropyl-5-methylcyclohexyl 2-hydroxybenzoate (M-SA) and (E)-2-isopropyl-5-methylcyclohexyl octadec-9-enoate (M-OA) had better promoting effects on the drugs with low water-solubility. The four O-acylmenthol enhancers produced parabolic relationship between the lipophilicity (log K(O/W)) of the model drugs (5-FU, ISDN, KP, IM) and their enhancement ratio of the permeation coefficient (ER(P)), indicating that the lipophilicity of the penetrants has significant effect on the permeation results, r = 0.989 (P=0.144) for M-LA, r = 0.965 (P = 0.216) for M-CA, r = 0.786 (P = 0.630) for M-SA, and r = 0.996 (P = 0.088) for M-OA.

Enantio-selective optrode for optical isomers of biologically active amines using a new lipophilic aromatic carrier

NASA Astrophysics Data System (ADS)

He, Huarui; Uray, Georg; Wolfbeis, Otto S.

1991-09-01

This paper presents a method for optically sensing enantiomers (optical isomers) of biological amines such as norephedrine, and drugs such as the (Beta) -blocker propranolol. It is based on the use of a new lipophilic aromatic ammonium ion carrier (DODD) and a highly fluorescent lipophilic proton carrier (DZ 49) dissolved in a pvc membrane. Recognition of one of the enantiomers is accomplished by specific interaction of the amine with the optically active lipophilic substrate in a pvc membrane. The amine, which is present as an ammonium ion at physiological pH, is carried into the pvc membranes. Simultaneously, a proton is released from the proton carrier (a lipophilic xanthene dye) that thereby undergoes a change in both color and fluorescence intensity. The sensors respond to three analytes in the concentration range from 0.01 to 10 mM for propranolol, 0.3 to 100 mM for norephedrine, and 1 to 100 mM for 1-phenylethylamine. The selectivity coefficients (Kopt) are 0.8, 0.7, and 0.8 for propranolol, norephedrine,a nd 1-phenylethylamine, respectively. It is of potential utility for specifically recognizing one out of several isomers, in particular bioactive amines, where one form usually is active only. The carrier showed stronger affinity for compounds which contain naphthyl rather than phenyl substituents.

Preparation and pharmaceutical evaluation of new sustained-release capsule including starch-sponge matrix (SSM).

PubMed

Shibata, Nobuhito; Nishumura, Asako; Naruhashi, Kazumasa; Nakao, Yurie; Miura, Rieko

2010-05-01

The focus of current study was to demonstrate a new sustained-release capsule including starch-sponge matrix (SSM) and to investigate how the pharmaceutical properties of SSM affect the drug release or its pharmacokinetic properties. Three representative drugs (uranine [UN], indomethacin [IMC] and nifedipine [NFP]) with different physicochemical properties (LogP(ow): 0.10, 1.18 and 3.23, respectively) were selected as model drugs. Model drug was dispersioned in pastelike cornstarch (starch glue) after heating 2.0-3.0% cornstarch suspension with electromagnetic wave at 2450 MHz (700 W) for l min. Then the drug mixture was encapsulated into a gratin capsule by a syringe, and the SSM including drug was prepared by means of a freeze-dried method. Essentially, drug-free SSM has a porous and netlike structure, and the distribution aspect of model drugs in the SSM depends on physicochemical properties between cornstarch glue and drugs. UN with much lower lipophilicity exists in continues phase of SSM, and IMC or NFP with a moderate or a higher lipophilicity exist in continues phase or porous space of the SSM. In the in vitro dissolution study, the release rate of drug from the SSM was mainly dependent on the lipophilicities of drugs, showing a rank order of the release rate of UN>IMC>NFP. In addition, the in vitro release rate for each drug was well regulated by changing the initial concentration of cornstarch suspension. In vivo absorption studies after intraduodenal administration of SSM capsule including model drug revealed that the sustained-release effects also could be regulated by the initial concentration of starch suspension. Moreover, the sustained-release effect of SSM capsule was enhanced with an increase in the lipophilicity of drug, and local-residential and mucoadhesive properties of SSM in the intestine provided stable supply of drugs from the SSM. The SSM capsule we developed here shows promising results as an oral drug delivery system for sustained-release regulation or target specificity. 2009 Elsevier Masson SAS. All rights reserved.

Effect of lipophilicity on the bioavailability of drugs after percutaneous administration by dissolving microneedles.

PubMed

Ito, Yukako; Yoshimura, Masahiro; Tanaka, Tsutomu; Takada, Kanji

2012-03-01

To elucidate drug lipophilicity effects on the bioavailability (BA) of drugs from skin after administration by dissolving microneedles, nine compounds with different lipophilicity indexes (log p value) were formulated into two-layered dissolving microneedles and administered percutaneously to rat skin: desmopressin (DDAVP), sumatriptan (ST), fluorescein (FL), granisetron (GRN), pindolol (PDL), pravastatin (PRV), rhodamine 123 (Rho), rifampicin (RFP), and salmeterol (SLM). Plasma drug concentrations were measured using liquid chromatography-tandem mass spectrometry and spectrofluorometry. In vivo dissolution and diffusion in both horizontal and vertical directions of FL and RH in the skin were studied using fluorescence microscopy. Respective BAs were 95.1 ± 7.9% (DDAVP), 84.2 ± 2.7% (ST), 82.3 ± 7.2% (FL), 82.7 ± 6.7% (GRN), 71.6 ± 3.8% (PDL), 63.6 ± 7.5% (PRV), 53.7 ± 8.3% (Rho), 46.2 ± 6.1% (RFP), and 38.4 ± 2.7% (SM). BA decreased as the lipophilicity index, log p value, of the drug increased from-1.95 to 1.73. The respective remaining percentages in skin tissue were 1.4 ± 0.7% (DDAVP), 0.9 ± 0.1% (ST), 1.0 ± 0.2% (FL), 3.4 ± 1.2% (GRN), 14.5 ± 3.7% (PDL), 23.4 ± 5.2% (PRV), 32.2 ± 6.0% (Rho), 40.7 ± 4.9% (RFP), and 40.6 ± 5.1% (SLM), dependent on log p. Fluorescence microscopy showed no FL or Rho in skin tissue within 4 and 24 h after administration, respectively. The BA of drugs delivered by dissolving microneedles depends on the drug solubility in the skin epidermis and dermis. Copyright © 2011 Wiley Periodicals, Inc.

Dependence of the kinetic and thermodynamic parameters on hydrophilic-lipophilic character of alprazolam, clonazepam, diazepam, doxepin and haloperidol in alkaline environment.

PubMed

Maślanka, Anna; Krzek, Jan; Szlósarczyk, Marek; Żmudzki, Paweł; Wach, Katarzyna

2013-10-15

Examination of the stability of clonazepam, diazepam, alprazolam, haloperidol, and doxepin in basic solutions was performed, together with an assessment of the kinetic (k, t0.1i t0.5) and thermodynamic (Ea, ΔH(++)i ΔS(++)) stability-indicating parameters, which were compared with the lipophilicity (logP) of the studied drugs. It was observed that the calculated values of Ea, ΔH(++) and ΔS(++) for the studied drugs increased from 41.04 kJ/mol to 125.50 kJ/mol, from 37.82 kJ/mol to 122.24 kJ/mol and from -167.09 J/Kmol to 53.02 J/Kmol, respectively, along with an increase of lipophilicity (logP) from 2.12 to 4.30 for the most hydrophilic alprazolam to the most lipophilic haloperidol. The degradation products were identified using UPLC/MS/MS method. Copyright © 2013 Elsevier B.V. All rights reserved.

Modeling the drug transport in the anterior segment of the eye.

PubMed

Avtar, Ram; Tandon, Deepti

2008-10-02

The aim of the present work is the development of a simple mathematical model for the time course concentration profile of topically administered drugs in the anterior chamber aqueous humor and investigation of the effects of various model parameters on the aqueous humor concentration of lipophilic and hydrophilic drugs. A simple pharmacokinetic model for the transient drug transport in the anterior segment has been developed by using the conservation of mass in the precorneal tear film, Fick's law of diffusion and Michaelis-Menten kinetics of drug metabolism in cornea, and the conservation of mass in the anterior chamber. An analytical solution describing the drug concentration in the anterior chamber has been obtained. The model predicts that an increase in the drug metabolic (consumption) rate in the corneal epithelium reduces the drug concentration in the anterior chamber for both lipophilic and hydrophilic molecules. A decrease in the clearance rate and distribution volume of the drug in the anterior chamber raises the aqueous humor concentration significantly. It is also observed that decay rate of drug concentration in the anterior chamber is higher for lipophilic molecules than that for hydrophilic molecules. The bioavailability of drugs applied topically to the eye may be improved by a rise in the precorneal tear volume, diffusion coefficient in corneal epithelium and distribution coefficient across the endothelium anterior chamber interface, and by reducing the drug metabolism, drug clearance rate and distribution volume in anterior chamber.

[Bioavailability of antiglaucoma drugs].

PubMed

Demailly, P

2000-05-01

The biodisponibility of antiglaucoma drugs, generally delivered in an aqueous eye-drop solution depends on their capacity to cross the cornea. The structure of the cornea forms a barrier to strongly lipophilic substances and the continuous renewal of the lacrimal film creates a major obstacle, preventing active substances from penetrating the eye. Active substances must thus be delivered in highly concentrated solutions. The systemic bioavailability of antiglaucoma drugs taken orally, for example beta-blockers, is well known, their behavior after eye-drop administration remains poorly elucidated and highly dependent on individual susceptibility. We reviewed the literature on pilocarpine, beta-blockers, adrenergic drugs (dipivalyl-epinephrine, apraclonidine, brimonidine), carbon anhydrase inhibitors (acetazolamide, dorzolamide).

Controlled crystallization of the lipophilic drug fenofibrate during freeze-drying: elucidation of the mechanism by in-line Raman spectroscopy.

PubMed

de Waard, Hans; De Beer, Thomas; Hinrichs, Wouter L J; Vervaet, Chris; Remon, Jean-Paul; Frijlink, Henderik W

2010-12-01

We developed a novel process, "controlled crystallization during freeze-drying" to produce drug nanocrystals of poorly water-soluble drugs. This process involves freeze-drying at a relatively high temperature of a drug and a matrix material from a mixture of tertiary butyl alcohol and water, resulting in drug nanocrystals incorporated in a matrix. The aim of this study was to elucidate the mechanisms that determine the size of the drug crystals. Fenofibrate was used as a model lipophilic drug. To monitor the crystallization during freeze-drying, a Raman probe was placed just above the sample in the freeze-dryer. These in-line Raman spectroscopy measurements clearly revealed when the different components crystallized during freeze-drying. The solvents crystallized only during the freezing step, while the solutes only crystallized after the temperature was increased, but before drying started. Although the solutes crystallized only after the freezing step, both the freezing rate and the shelf temperature were critical parameters that determined the final crystal size. At a higher freezing rate, smaller interstitial spaces containing the freeze-concentrated fraction were formed, resulting in smaller drug crystals (based on dissolution data). On the other hand, when the solutes crystallized at a lower shelf temperature, the degree of supersaturation is higher, resulting in a higher nucleation rate and consequently more and therefore smaller crystals. In conclusion, for the model drug fenofibrate, a high freezing rate and a relatively low crystallization temperature resulted in the smallest crystals and therefore the highest dissolution rate.

Development of a high-throughput brain slice method for studying drug distribution in the central nervous system.

PubMed

Fridén, Markus; Ducrozet, Frederic; Middleton, Brian; Antonsson, Madeleine; Bredberg, Ulf; Hammarlund-Udenaes, Margareta

2009-06-01

New, more efficient methods of estimating unbound drug concentrations in the central nervous system (CNS) combine the amount of drug in whole brain tissue samples measured by conventional methods with in vitro estimates of the unbound brain volume of distribution (V(u,brain)). Although the brain slice method is the most reliable in vitro method for measuring V(u,brain), it has not previously been adapted for the needs of drug discovery research. The aim of this study was to increase the throughput and optimize the experimental conditions of this method. Equilibrium of drug between the buffer and the brain slice within the 4 to 5 h of incubation is a fundamental requirement. However, it is difficult to meet this requirement for many of the extensively binding, lipophilic compounds in drug discovery programs. In this study, the dimensions of the incubation vessel and mode of stirring influenced the equilibration time, as did the amount of brain tissue per unit of buffer volume. The use of cassette experiments for investigating V(u,brain) in a linear drug concentration range increased the throughput of the method. The V(u,brain) for the model compounds ranged from 4 to 3000 ml . g brain(-1), and the sources of variability are discussed. The optimized setup of the brain slice method allows precise, robust estimation of V(u,brain) for drugs with diverse properties, including highly lipophilic compounds. This is a critical step forward for the implementation of relevant measurements of CNS exposure in the drug discovery setting.

Analysis of Physicochemical Properties for Drugs of Natural Origin.

PubMed

Camp, David; Garavelas, Agatha; Campitelli, Marc

2015-06-26

The impact of time, therapy area, and route of administration on 13 physicochemical properties calculated for 664 drugs developed from a natural prototype was investigated. The mean values for the majority of properties sampled over five periods from pre-1900 to 2013 were found to change in a statistically significant manner. In contrast, lipophilicity and aromatic ring count remained relatively constant, suggesting that these parameters are the most important for successful prosecution of a natural product drug discovery program if the route of administration is not focused exclusively on oral availability. An examination by therapy area revealed that anti-infective agents had the most differences in physicochemical property profiles compared with other areas, particularly with respect to lipophilicity. However, when this group was removed, the variation between the mean values for lipophilicity and aromatic ring count across the remaining therapy areas was again found not to change in a meaningful manner, further highlighting the importance of these two parameters. The vast majority of drugs with a natural progenitor were formulated for either oral and/or injectable administration. Injectables were, on average, larger and more polar than drugs developed for oral, topical, and inhalation routes.

Prediction of Log "P": ALOGPS Application in Medicinal Chemistry Education

ERIC Educational Resources Information Center

Kujawski, Jacek; Bernard, Marek K.; Janusz, Anna; Kuzma, Weronika

2012-01-01

Molecular hydrophobicity (lipophilicity), usually quantified as log "P" where "P" is the partition coefficient, is an important molecular characteristic in medicinal chemistry and drug design. The log "P" coefficient is one of the principal parameters for the estimation of lipophilicity of chemical compounds and pharmacokinetic properties. The…

SC lipid model membranes designed for studying impact of ceramide species on drug diffusion and permeation--part II: diffusion and permeation of model drugs.

PubMed

Ochalek, M; Podhaisky, H; Ruettinger, H-H; Wohlrab, J; Neubert, R H H

2012-10-01

The barrier function of two quaternary stratum corneum (SC) lipid model membranes, which were previously characterized with regard to the lipid organization, was investigated based on diffusion studies of model drugs with varying lipophilicities. Diffusion experiments of a hydrophilic drug, urea, and more lipophilic drugs than urea (i.e. caffeine, diclofenac sodium) were conducted using Franz-type diffusion cells. The amount of permeated drug was analyzed using either HPLC or CE technique. The subjects of interest in the present study were the investigation of the influence of physicochemical properties of model drugs on their diffusion and permeation through SC lipid model membranes, as well as the study of the impact of the constituents of these artificial systems (particularly ceramide species) on their barrier properties. The diffusion through both SC lipid model membranes and the human SC of the most hydrophilic model drug, urea, was faster than the permeation of the more lipophilic drugs. The slowest rate of permeation through SC lipid systems occurred in the case of caffeine. The composition of SC lipid model membranes has a significant impact on their barrier function. Model drugs diffused and permeated faster through Membrane II (presence of Cer [EOS]). In terms of the barrier properties, Membrane II is much more similar to the human SC than Membrane I. Copyright © 2012 Elsevier B.V. All rights reserved.

Drug delivery strategies for poorly water-soluble drugs.

PubMed

Fahr, Alfred; Liu, Xiangli

2007-07-01

The drug candidates coming from combinatorial chemistry research and/or the drugs selected from biologically based high-throughput screening are quite often very lipophilic, as these drug candidates exert their pharmacological action at or in biological membranes or membrane-associated proteins. This challenges drug delivery institutions in industry or academia to develop carrier systems for the optimal oral and parenteral administration of these drugs. To mention only a few of the challenges for this class of drugs: their oral bioavailability is poor and highly variable, and carrier development for parenteral administration is faced with problems, including the massive use of surface-active excipients for solubilisation. Formulation specialists are confronted with an even higher level of difficulties when these drugs have to be delivered site specifically. This article addresses the emerging formulation designs for delivering of poorly water-soluble drugs.

Modulating lipophilicity of rohitukine via prodrug approach: Preparation, characterization, and in vitro enzymatic hydrolysis in biorelevant media.

PubMed

Kumar, Vikas; Bharate, Sonali S; Vishwakarma, Ram A

2016-09-20

Rohitukine is a medicinally important natural product which has inspired the discovery of two anticancer clinical candidates. Rohitukine is highly hydrophilic in nature which hampers its oral bioavailability. Thus, herein our objective was to improve the drug-like properties of rohitukine via prodrug-strategy. Various ester prodrugs were synthesized and studied for solubility, lipophilicity, chemical stability and enzymatic hydrolysis in plasma/esterase. All prodrugs displayed lower aqueous solubility and improved lipophilicity compared with rohitukine, which was in accordance with the criteria of compounds in drug-discovery. The stability of synthesized prodrugs was evaluated in buffers at different pH, SGF, SIF, rat plasma and in esterase enzyme. The rate of hydrolysis in all incubation media was dependent primarily on the acyl promoieties. Hexanoyl ester prodrug of rohitukine, 3d, was stable under chemical conditions; however it was completely hydrolyzed to rohitukine, in plasma and in esterase in 4h. Hexanoate ester 3d appeared to be the most promising prodrug as it remained intact at gastric/intestinal pH and was completely transformed to the parent compound in plasma as desired for an ideal prodrug. The data presented herein, will help in designing prodrugs with desired physicochemical properties in future in structurally similar chemotypes. Copyright © 2016 Elsevier B.V. All rights reserved.

Drug release studies from lipid nanoparticles in physiological media by a new DSC method.

PubMed

Roese, Elin; Bunjes, Heike

2017-06-28

Lipid nanoparticles are an interesting parenteral delivery system for poorly water-soluble drugs. In order to approach physiological conditions when conducting release studies from such systems the release media should preferentially contain lipophilic acceptor compartments such as lipoproteins or other colloidal lipophilic components. In practice, drug release studies under such close to physiological conditions may be complicated by the small size of lipid nanoparticles, which is in the same range as that of the potential acceptor particles. This study describes a novel differential scanning calorimetry (DSC) method for drug release measurements which works without separation of donor and acceptor particles. The technique is based on measuring the crystallization temperature of trimyristin nanoparticles by DSC. The crystallization temperature of the nanoparticles decreases proportionally with the amount of active ingredient incorporated and thus increases as a result of drug release. Liquid trimyristin nanoparticles loaded with fenofibrate, orlistat, tocopherol acetate and ubidecarenone were studied in three different release media with increasing complexity and comparability to physiological conditions: a rapeseed oil nanoemulsion, porcine serum and porcine blood. Using the new method, a correlation between release behavior and drug lipophilicity was observed: the higher the logP value of the drug, the slower the release. The extent of drug release was influenced by partition equilibrium as indicated by increased drug release in the rapeseed oil nanoemulsion compared to porcine serum and blood. Copyright © 2017 Elsevier B.V. All rights reserved.

Hydrotropic Solubilization of Lipophilic Drugs for Oral Delivery: The Effects of Urea and Nicotinamide on Carbamazepine Solubility–Permeability Interplay

PubMed Central

Beig, Avital; Lindley, David; Miller, Jonathan M.; Agbaria, Riad; Dahan, Arik

2016-01-01

Hydrotropy refers to increasing the water solubility of otherwise poorly soluble compound by the presence of small organic molecules. While it can certainly increase the apparent solubility of a lipophilic drug, the effect of hydrotropy on the drugs’ permeation through the intestinal membrane has not been studied. The purpose of this work was to investigate the solubility–permeability interplay when using hydrotropic drug solubilization. The concentration-dependent effects of the commonly used hydrotropes urea and nicotinamide, on the solubility and the permeability of the lipophilic antiepileptic drug carbamazepine were studied. Then, the solubility–permeability interplay was mathematically modeled, and was compared to the experimental data. Both hydrotropes allowed significant concentration-dependent carbamazepine solubility increase (up to ∼30-fold). A concomitant permeability decrease was evident both in vitro and in vivo (∼17-fold for nicotinamide and ∼9-fold for urea), revealing a solubility–permeability tradeoff when using hydrotropic drug solubilization. A relatively simplified simulation approach based on proportional opposite correlation between the solubility increase and the permeability decrease at a given hydrotrope concentration allowed excellent prediction of the overall solubility–permeability tradeoff. In conclusion, when using hydrotropic drug solubilization it is prudent to not focus solely on solubility, but to account for the permeability as well; achieving optimal solubility–permeability balance may promote the overall goal of the formulation to maximize oral drug exposure. PMID:27826241

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.

Clinical relevance of drug binding to plasma proteins

NASA Astrophysics Data System (ADS)

Ascenzi, Paolo; Fanali, Gabriella; Fasano, Mauro; Pallottini, Valentina; Trezza, Viviana

2014-12-01

Binding to plasma proteins highly influences drug efficacy, distribution, and disposition. Serum albumin, the most abundant protein in plasma, is a monomeric multi-domain macromolecule that displays an extraordinary ligand binding capacity, providing a depot and carrier for many endogenous and exogenous compounds, such as fatty acids and most acidic drugs. α-1-Acid glycoprotein, the second main plasma protein, is a glycoprotein physiologically involved in the acute phase reaction and is the main carrier for basic and neutral drugs. High- and low-density lipoproteins play a limited role in drug binding and are natural drug delivery system only for few lipophilic drugs or lipid-based formulations. Several factors influence drug binding to plasma proteins, such as pathological conditions, concurrent administration of drugs, sex, and age. Any of these factors, in turn, influences drug efficacy and toxicity. Here, biochemical, biomedical, and biotechnological aspects of drug binding to plasma proteins are reviewed.

Measurement of diffusion coefficients of parabens and steroids in water and 1-octanol.

PubMed

Seki, Toshinobu; Mochida, Junko; Okamoto, Maiko; Hosoya, Osamu; Juni, Kazuhiko; Morimoto, Kazuhiro

2003-06-01

Diffusion coefficients (D) of parabens and steroids in water and 1-octanol were determined by using the chromatographic broadening method at 37 degrees C, and the relationships between the D values and the physicochemical properties of the drugs were discussed. The D values in 1-octanol were lower than those in water because of the higher viscosity of 1-octanol. The D values depend on not only the molecular weight (MW), but also the lipophilicity of the drugs in water and on the ability for hydrogen-bonding in 1-octanol. When the lipophilic index (LI), calculated from the retention time using in a reverse-phase column, was used as a parameter of drug lipophilicity, the following equation was obtained for D in water (D(w)); log D(w)=-0.215.log MW-0.077.log LI-4.367. When the hydrogen bond index (HI), the logarithm of the ratio of the partition coefficient of the drugs in 1-octanol and cyclohexane, was used as an index of hydrogen-bonding, the following equation was obtained for D in 1-octanol (D(o)); log D(o)=-0.690.log MW-0.074.log HI-4.085.

Fabrication of doxorubicin nanoparticles by controlled antisolvent precipitation for enhanced intracellular delivery.

PubMed

Tam, Yu Tong; To, Kenneth Kin Wah; Chow, Albert Hee Lum

2016-03-01

Over-expression of ATP-binding cassette transporters is one of the most important mechanisms responsible for multidrug resistance. Here, we aimed to develop a stable polymeric nanoparticle system by flash nanoprecipitation (FNP) for enhanced anticancer drug delivery into drug resistant cancer cells. As an antisolvent precipitation process, FNP works best for highly lipophilic solutes (logP>6). Thus we also aimed to evaluate the applicability of FNP to drugs with relatively low lipophilicity (logP=1-2). To this end, doxorubicin (DOX), an anthracycline anticancer agent and a P-gp substrate with a logP of 1.3, was selected as a model drug for the assessment. DOX was successfully incorporated into the amphiphilic diblock copolymer, polyethylene glycol-b-polylactic acid (PEG-b-PLA), by FNP using a four-stream multi-inlet vortex mixer. Optimization of key processing parameters and co-formulation with the co-stabilizer, polyvinylpyrrolidone, yielded highly stable, roughly spherical DOX-loaded PEG-b-PLA nanoparticles (DOX.NP) with mean particle size below 100nm, drug loading up to 14%, and drug encapsulation efficiency up to 49%. DOX.NP exhibited a pH-dependent drug release profile with higher cumulative release rate at acidic pHs. Surface analysis of DOX.NP by XPS revealed an absence of DOX on the particle surface, indicative of complete drug encapsulation. While there were no significant differences in cytotoxic effect on P-gp over-expressing LCC6/MDR cell line between DOX.NP and free DOX in buffered aqueous media, DOX.NP exhibited a considerably higher cellular uptake and intracellular retention after efflux. The apparent lack of cytotoxicity enhancement with DOX.NP may be attributable to its slow DOX release inside the cells. Copyright © 2015 Elsevier B.V. All rights reserved.

Using lidocaine and benzocaine to link sodium channel molecular conformations to state-dependent antiarrhythmic drug affinity.

PubMed

Hanck, Dorothy A; Nikitina, Elena; McNulty, Megan M; Fozzard, Harry A; Lipkind, Gregory M; Sheets, Michael F

2009-08-28

Lidocaine and other antiarrhythmic drugs bind in the inner pore of voltage-gated Na channels and affect gating use-dependently. A phenylalanine in domain IV, S6 (Phe1759 in Na(V)1.5), modeled to face the inner pore just below the selectivity filter, is critical in use-dependent drug block. Measurement of gating currents and concentration-dependent availability curves to determine the role of Phe1759 in coupling of drug binding to the gating changes. The measurements showed that replacement of Phe1759 with a nonaromatic residue permits clear separation of action of lidocaine and benzocaine into 2 components that can be related to channel conformations. One component represents the drug acting as a voltage-independent, low-affinity blocker of closed channels (designated as lipophilic block), and the second represents high-affinity, voltage-dependent block of open/inactivated channels linked to stabilization of the S4s in domains III and IV (designated as voltage-sensor inhibition) by Phe1759. A homology model for how lidocaine and benzocaine bind in the closed and open/inactivated channel conformation is proposed. These 2 components, lipophilic block and voltage-sensor inhibition, can explain the differences in estimates between tonic and open-state/inactivated-state affinities, and they identify how differences in affinity for the 2 binding conformations can control use-dependence, the hallmark of successful antiarrhythmic drugs.

Evaluation of in silico pharmacokinetic properties and in vitro cytotoxic activity of selected newly synthesized N-succinimide derivatives.

PubMed

Milosevic, Natasa P; Kojic, Vesna; Curcic, Jelena; Jakimov, Dimitar; Milic, Natasa; Banjac, Nebojsa; Uscumlic, Gordana; Kaliszan, Roman

2017-04-15

Design of a new drug entity is usually preceded by analysis of quantitative structure activity (properties) relationships, QSA(P)R. Six newly synthesized succinimide derivatives have been determined for (i) in silico physico-chemical descriptors, pharmacokinetic and toxicity predictors, (ii) in vitro biological activity on four different carcinoma cell lines and on normal fetal lung cells and (iii) lipophilicity on liquid chromatography. All compounds observed were predicted for good permeability and solubility, good oral absorption rate and moderate volume of distribution as well as for modest blood brain permeation, followed by acceptable observed toxicity. In silico determined lipophilicity, permeability through jejunum and aqueous solubility were correlated with experimentally obtained lipophilic constants (by use of high pressure liquid chromatography) and linear correlations were obtained. Absorption rate and volume of distribution were predicted by chromatographic lipophilicity measurements while permeation through blood bran barrier was predicted dominantly by molecular size defined with molecular weight. Five compounds have demonstrated antiproliferative activity toward cervix carcinoma HeLa cell lines; three were cytotoxic against breast carcinoma MCF-7 cells, while one inhibited proliferation of colon carcinoma HT-29 cell lines. Only one compound was cytotoxic toward normal cell lines, while other compounds were proven as safe. Antiproliferative potential against HeLa cells was described as exponential function of lipophilicity. Based on obtained results, lead compounds were selected. Copyright © 2017 Elsevier B.V. All rights reserved.

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity.

PubMed

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M

2016-07-20

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (sc) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. Their ease and efficiency make double-click helix stabilization chemistries a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control sc absorption and clearance rates to customize plasma pharmacokinetics.

Microfluidics based manufacture of liposomes simultaneously entrapping hydrophilic and lipophilic drugs.

PubMed

Joshi, Sameer; Hussain, Maryam T; Roces, Carla B; Anderluzzi, Giulia; Kastner, Elisabeth; Salmaso, Stefano; Kirby, Daniel J; Perrie, Yvonne

2016-11-30

Despite the substantial body of research investigating the use of liposomes, niosomes and other bilayer vesicles for drug delivery, the translation of these systems into licensed products remains limited. Indeed, recent shortages in the supply of liposomal products demonstrate the need for new scalable production methods for liposomes. Therefore, the aim of our research has been to consider the application of microfluidics in the manufacture of liposomes containing either or both a water soluble and a lipid soluble drug to promote co-delivery of drugs. For the first time, we demonstrate the entrapment of a hydrophilic and a lipophilic drug (metformin and glipizide respectively) both individually, and in combination, using a scalable microfluidics manufacturing system. In terms of the operating parameters, the choice of solvents, lipid concentration and aqueous:solvent ratio all impact on liposome size with vesicle diameter ranging from ∼90 to 300nm. In terms of drug loading, microfluidics production promoted high loading within ∼100nm vesicles for both the water soluble drug (20-25% of initial amount added) and the bilayer embedded drug (40-42% of initial amount added) with co-loading of the drugs making no impact on entrapment efficacy. However, co-loading of glipizide and metformin within the same liposome formulation did impact on the drug release profiles; in both instances the presence of both drugs in the one formulation promoted faster (up to 2 fold) release compared to liposomes containing a single drug alone. Overall, these results demonstrate the application of microfluidics to prepare liposomal systems incorporating either or both an aqueous soluble drug and a bilayer loaded drug. Copyright © 2016 Elsevier B.V. All rights reserved.

The development of structure-activity relationships for mitochondrial dysfunction: uncoupling of oxidative phosphorylation.

PubMed

Naven, Russell T; Swiss, Rachel; Klug-McLeod, Jacquelyn; Will, Yvonne; Greene, Nigel

2013-01-01

Mitochondrial dysfunction has been implicated as an important factor in the development of idiosyncratic organ toxicity. An ability to predict mitochondrial dysfunction early in the drug development process enables the deselection of those drug candidates with potential safety liabilities, allowing resources to be focused on those compounds with the highest chance of success to the market. A database of greater than 2000 compounds was analyzed to identify structural and physicochemical features associated with the uncoupling of oxidative phosphorylation (herein defined as an increase in basal respiration). Many toxicophores associated with potent uncoupling activity were identified, and these could be divided into two main mechanistic classes, protonophores and redox cyclers. For the protonophores, potent uncoupling activity was often promoted by high lipophilicity and apparent stabilization of the anionic charge resulting from deprotonation of the protonophore. The potency of redox cyclers did not appear to be prone to variations in lipophilicity. Only 11 toxicophores were of sufficient predictive performance that they could be incorporated into a structural-alert model. Each alert was associated with one of three confidence levels (high, medium, and low) depending upon the lipophilicity-activity profile of the structural class. The final model identified over 68% of those compounds with potent uncoupling activity and with a value for specificity above 99%. We discuss the advantages and limitations of this approach and conclude that although structural alert methodology is useful for identifying toxicophores associated with mitochondrial dysfunction, they are not a replacement for the mitochondrial dysfunction assays in early screening paradigms.

Effect of solute lipophilicity on penetration through canine skin.

PubMed

Mills, P C; Magnusson, B M; Cross, S E

2003-12-01

To investigate the effect of lipophilicity on the percutaneous penetration of a homologous series of alcohols through canine skin. Skin harvested from Greyhound thorax was placed in Franz-type diffusion cells and the in vitro passage of radiolabelled (14C) alcohols (ethanol, butanol, hexanol and octanol (Log P 0.19-3.0)) through separate skin sections was measured in replicates of five. Permeability coefficient (kP, cm/h), maximum flux (Jmax, mol/cm2/h) and residue remaining within the skin were determined. The kP increased with increasing lipophilicity (6.2 x 10(-4) +/- 1.6 x 10(-4) cm/h for ethanol to 1.8 x 10(-2) +/- 3.6 x 10(-3) cm/h for octanol). Alcohol residues remaining within each skin sample followed a similar pattern. An exponential decrease in Jmax with increasing lipophilicity was observed. Changes in canine skin permeability occur with increasing alcohol lipophilicity. This finding has practical consequences for the design of topical formulations and optimisation of drug delivery through animal skin.

Interrogating the relationship between rat in vivo tissue distribution and drug property data for >200 structurally unrelated molecules

PubMed Central

Harrell, Andrew W; Sychterz, Caroline; Ho, May Y; Weber, Andrew; Valko, Klara; Negash, Kitaw

2015-01-01

The ability to explain distribution patterns from drug physicochemical properties and binding characteristics has been explored for more than 200 compounds by interrogating data from quantitative whole body autoradiography studies (QWBA). These in vivo outcomes have been compared to in silico and in vitro drug property data to determine the most influential properties governing drug distribution. Consistent with current knowledge, in vivo distribution was most influenced by ionization state and lipophilicity which in turn affected phospholipid and plasma protein binding. Basic and neutral molecules were generally better distributed than acidic counterparts demonstrating weaker plasma protein and stronger phospholipid binding. The influence of phospholipid binding was particularly evident in tissues with high phospholipid content like spleen and lung. Conversely, poorer distribution of acidic drugs was associated with stronger plasma protein and weaker phospholipid binding. The distribution of a proportion of acidic drugs was enhanced, however, in tissues known to express anionic uptake transporters such as the liver and kidney. Greatest distribution was observed into melanin containing tissues of the eye, most likely due to melanin binding. Basic molecules were consistently better distributed into parts of the eye and skin containing melanin than those without. The data, therefore, suggest that drug binding to macromolecules strongly influences the distribution of total drug for a large proportion of molecules in most tissues. Reducing lipophilicity, a strategy often used in discovery to optimize pharmacokinetic properties such as absorption and clearance, also decreased the influence of nonspecific binding on drug distribution. PMID:26516585

Effect of borneol on the transdermal permeation of drugs with differing lipophilicity and molecular organization of stratum corneum lipids.

PubMed

Yi, Qi-Feng; Yan, Jin; Tang, Si-Yuan; Huang, Hui; Kang, Li-Yang

2016-01-01

The aim of the present paper was to investigate the promoting activity of borneol on the transdermal permeation of drugs with differing lipophilicity, and probe its alterations in molecular organization of stratum corneum (SC) lipids. The toxicity of borneol was evaluated in epidermal keratinocyte HaCaT and dermal fibroblast CCC-HSF-1 cell cultures and compared to known enhancers, and its irritant profile was also assessed by transepidermal water loss (TEWL) evaluation. The promoting effect of borneol on the transdermal permeation of five model drugs, namely 5-fluorouracil, antipyrine, aspirin, salicylic acid and ibuprofen, which were selected based on their lipophilicity denoted by logp value, were performed using in vitro skin permeation studies. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) was employed to monitor the borneol-induced alteration in molecular organization of SC lipids. The enhancer borneol displayed lower cytotoxicity or irritation in comparison to the well-established and standard enhancer Azone. Borneol could effectively promote the transdermal permeation of five model drugs, and its enhancement ratios were found to be parabolic curve with the logp values of drugs, which exhibited the optimum permeation activity for relatively hydrophilic drugs (an estimated logp value of -0.5 ∼0.5). The molecular mechanism studies suggested that borneol could perturb the structure of SC lipid alkyl chains, and extract part of SC lipids, resulting in the alteration in the skin permeability barrier.

Development and characterization of polymer-oil nanostructured carrier (PONC) for controlled delivery of all-trans retinoic acid (ATRA)

NASA Astrophysics Data System (ADS)

Narvekar, Mayuri M.

The commonly used PLGA-based delivery systems are often limited by their inadequate drug loading and release properties. This study reports the integration of oil into PLGA to form the prototype of a hybrid drug carrier PONC. Our primary goal is to confer the key strength of lipid-based drug carriers, i.e. efficient encapsulation of lipophilic compounds, to a PLGA system without taking away its various useful qualities. The PONC were formulated by emulsification solvent evaporation technique, which were then characterized for particle size, encapsulation efficiency, drug release and anticancer efficacy. The ATRA loaded PONC showed excellent encapsulation efficiency and release kinetics. Even after surface functionalization with PEG , controlled drug release kinetics was maintained, with 88.5% of the encapsulated ATRA released from the PEG-PONC in a uniform manner over 120 hours. It also showed favorable physicochemical properties and serum stability. PEG-PONC has demonstrated substantially superior activity over the free ATRA in ovarian cancer cells that are non-responsive to the standard chemotherapy. The newly developed PEG-PONC significantly reduced the IC50 values (p<0.05) in the chemoresistant cells in both MTT and colony formation assays. Hence, this new ATRA-nanoformulation may offer promising means for the delivery of lipophilic compounds like all-trans retinoic acid to treat highly resistant ovarian cancer.

Effect of n-octanol in the mobile phase on lipophilicity determination by reversed-phase high-performance liquid chromatography on a modified silica column.

PubMed

Benhaim, Deborah; Grushka, Eli

2008-10-31

In this study, we show that the addition of n-octanol to the mobile phase improves the chromatographic determination of lipophilicity parameters of xenobiotics (neutral solutes, acidic, neutral and basic drugs) on a Phenomenex Gemini C18 column. The Gemini C18 column is a new generation hybrid silica-based column with an extended pH range capability. The wide pH range (2-12) afforded the examination of basic drugs and acidic drugs in their neutral form. Extrapolated retention factor values, [Formula: see text] , obtained on the above column with the n-octanol-modified mobile phase were very well correlated (1:1 correlation) with literature values of logP (logarithm of the partition coefficient in n-octanol/water) of neutral compounds and neutral drugs (69). In addition, we found good linear correlations between measured [Formula: see text] values and calculated values of the logarithm of the distribution coefficient at pH 7.0 (logD(7.0)) for ionized acidic and basic drugs (r(2)=0.95). The Gemini C18 phase was characterized using the linear solvation energy relationship (LSER) model of Abraham. The LSER system constants for the column were compared to the LSER constants of n-octanol/water extraction system using the Tanaka radar plots. The comparison shows that the two methods are nearly equivalent.

Lipophilicity assessment of basic drugs (log P(o/w) determination) by a chromatographic method.

PubMed

Pallicer, Juan M; Sales, Joaquim; Rosés, Martí; Ràfols, Clara; Bosch, Elisabeth

2011-09-16

A previously reported chromatographic method to determine the 1-octanol/water partition coefficient (log P(o/w)) of organic compounds is used to estimate the hydrophobicity of bases, mainly commercial drugs with diverse chemical nature and pK(a) values higher than 9. For that reason, mobile phases buffered at high pH to avoid the ionization of the solutes and three different columns (Phenomenex Gemini NX, Waters XTerra RP-18 and Waters XTerra MS C(18)) with appropriate alkaline-resistant stationary phases have been used. Non-ionizable substances studied in previous works were also included in the set of compounds to evaluate the consistency of the method. The results showed that all the columns provide good estimations of the log P(o/w) for most of the compounds included in this study. The Gemini NX column has been selected to calculate log P(o/w) values of the set of studied drugs, and really good correlations between the determined log P(o/w) values and those considered as reference were obtained, proving the ability of the procedure for the lipophilicity assessment of bioactive compounds with very different structures and functionalities. Copyright © 2011 Elsevier B.V. All rights reserved.

Influence of Lipophilicity on Drug Partitioning into Sclera, Choroid-Retinal Pigment Epithelium, Retina, Trabecular Meshwork, and Optic Nerve

PubMed Central

Kadam, Rajendra S.

2010-01-01

In vitro bovine eye tissue/phosphate-buffered saline, pH 7.4, partition coefficients (Kt:b), in vitro binding to natural melanin, and in vivo delivery at 1 h after posterior subconjunctival injection in Brown Norway rats were determined for eight β-blockers. The Kt:b was in the order intact tissue, dry weight method ≥ intact tissue, wet weight method corrected for tissue water and drug in tissue water ≫ intact tissue, wet weight method > homogenized tissue. In intact tissue methods, Kt:b followed the order choroid-retinal pigment epithelium (RPE) > trabecular meshwork > retina > sclera ∼ optic nerve; propranolol > betaxolol > pindolol ∼ timolol ∼ metoprolol > sotalol ∼ atenolol ∼ nadolol. Intact tissue, wet weight log (Kt:b) correlated positively with log D for all tissues (R2 of 0.7–0.9). Log (melanin binding capacity) correlated positively with choroid-RPE log (Kt:b) (R2 of 0.5). With an increase in concentration, Kt:b decreased in trabecular meshwork for all β-blockers and for some lipophilic β-blockers in choroid-RPE and sclera. With an increase in drug lipophilicity, in vivo tissue distribution increased in choroid-RPE, iris-ciliary body, sclera, and cornea but exhibited a declining trend in retina, vitreous, and lens. In vitro bovine intact tissue, wet weight Kt:b correlated positively with rat in vivo tissue/vitreous humor distribution for sclera, choroid-RPE, and retina (R2 of 0.985–0.993). In vitro tissue partition coefficients might be useful in predicting in vivo drug distribution after trans-scleral delivery. Less lipophilic solutes exhibiting limited nonproductive binding in choroid-RPE might exhibit greater trans-scleral delivery to the retina and vitreous. PMID:19926800

Mechanism of transdermal permeation promotion of lipophilic drugs by ethosomes.

PubMed

Yang, Li; Wu, Lifang; Wu, Dongze; Shi, Deshun; Wang, Tai; Zhu, Xiaoliang

2017-01-01

Ethosomes can promote the penetration of lipophilic drugs into the skin, but the underlying mechanism is still unknown. The purpose of this study was to investigate the mechanism of transdermal permeation promotion of lipophilic drugs by ethosomes. The formulation of ethosomes was optimized using the Box-Behnken experimental design, in which Rhodamine B and 1-palmitoyl-2-{12-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl}- sn -glycero-3-phosphocholine were used to simulate a model lipophilic drug and act as a fluorescent tracer of ethosomal phospholipids, respectively. Liposomes with the same phospholipid concentration and a hydroethanolic solution with the same ethanol concentration were also prepared as controls. The percutaneous progression of the above fluorescent preparations was observed by confocal laser scanning microscopy, and the fluorescence intensity of the images was analyzed. The optimized ethosome formulation consisted of 2.45% yolk phospholipids, 30% ethanol, and 67.55% distilled water. The percutaneous permeation of Rhodamine B in the optimized ethosomes was superior to that in hydroethanolic solution ( P <0.05) and liposomes ( P <0.05). The ethosomes could penetrate the skin via the percutaneous pathway of the hair follicle and stratum corneum, while during the process of penetration, the vesicles were broken and the phospholipids were retained in the upper epidermis, with the test compounds penetrating gradually. The superior percutaneous penetration of ethosomes was linked to the synergistic effects of their ingredients. The percutaneous pathways of ethosomes included open hair follicles and stratum corneum pathways. In addition, the vesicles might break up during percutaneous penetration in the superficial layer of the skin, allowing the test compounds to keep permeating into the deeper layer alone, while the phospholipid was retained in the upper epidermis.

pH-Dependent dissolving nano- and microparticles for improved peroral delivery of a highly lipophilic compound in dogs.

PubMed

De Jaeghere, F; Allémann, E; Cerny, R; Galli, B; Steulet, A F; Müller, I; Schütz, H; Doelker, E; Gurny, R

2001-01-01

RR01, a new highly lipophilic drug showing extremely low water solubility and poor oral bioavailability, has been incorporated into pH-dependent dissolving particles made of a poly(methacrylic acid-co-ethylacrylate) copolymer. The physicochemical properties of the particles were determined using laser-light-scattering techniques, scanning electron microscopy, high-performance liquid chromatography, and x-ray powder diffraction. Suspension of the free drug in a solution of hydroxypropylcellulose (reference formulation) and aqueous dispersions of pH-sensitive RR01-loaded nanoparticles or microparticles were administered orally to Beagle dogs according to a 2-block Latin square design (n = 6). Plasma samples were obtained over the course of 48 hours and analyzed by gas chromatography/mass spectrometry. The administration of the reference formulation resulted in a particularly high interindividual variability of pharmacokinetic parameters, with low exposure to compound RR01 (AUC0-48h of 6.5 microg x h/mL and coefficient of variation (CV) of 116%) and much higher Tmax, as compared to both pH-sensitive formulations. With respect to exposure and interindividual variability, nanoparticles were superior to microparticles (AUC0-48h of 27.1 microg x h/mL versus 17.7 microg x h/mL with CV of 19% and 40%, respectively), indicating that the particle size may play an important role in the absorption of compound RR01. The performance of pH-sensitive particles is attributed to their ability to release the drug selectively in the upper part of the intestine in a molecular or amorphous form. In conclusion, pH-dependent dissolving particles have a great potential as oral delivery systems for drugs with low water solubility and acceptable permeation properties.

Cyclodextrins in delivery systems: Applications

PubMed Central

Tiwari, Gaurav; Tiwari, Ruchi; Rai, Awani K.

2010-01-01

Cyclodextrins (CDs) are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. CD molecules are relatively large with a number of hydrogen donors and acceptors and, thus in general, they do not permeate lipophilic membranes. In the pharmaceutical industry, CDs have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs and to increase their bioavailability and stability. CDs are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current CD-based therapeutics is described and possible future applications are discussed. CD-containing polymers are reviewed and their use in drug delivery is presented. Of specific interest is the use of CD-containing polymers to provide unique capabilities for the delivery of nucleic acids. Studies in both humans and animals have shown that CDs can be used to improve drug delivery from almost any type of drug formulation. Currently, there are approximately 30 different pharmaceutical products worldwide containing drug/CD complexes in the market. PMID:21814436

Using Lidocaine and Benzocaine to Link Sodium Channel Molecular Conformations to State-Dependent Antiarrhythmic Drug Affinity

PubMed Central

Hanck, Dorothy A.; Nikitina, Elena; McNulty, Megan M.; Fozzard, Harry A.; Lipkind, Gregory M.; Sheets, Michael F.

2009-01-01

Rationale Lidocaine and other antiarrhythmic drugs bind in the inner pore of voltage-gated Na channels and affect gating use-dependently. A phenylalanine in domain IV, S6 (Phe1759 in NaV1.5), modeled to face the inner pore just below the selectivity filter, is critical in use-dependent drug block. Objective Measurement of gating currents and concentration-dependent availability curves to determine the role of Phe1759 in coupling of drug binding to the gating changes. Methods & Results The measurements showed that replacement of Phe1759 with a non-aromatic residue permits clear separation of action of lidocaine and benzocaine into two components that can be related to channel conformations. One component represents the drug acting as a voltage-independent, low-affinity blocker of closed channels (designated as lipophilic block), and the second represents high-affinity, voltage-dependent block of open/inactivated channels linked to stabilization of the S4's in domains III and IV (designated as voltage-sensor inhibition) by Phe1759. A homology model for how lidocaine and benzocaine bind in the closed and open/inactivated channel conformation is proposed. Conclusions These two components, lipophilic block and voltage-sensor inhibition, can explain the differences in estimates between tonic and open-state/inactivated-state affinities, and they identify how differences in affinity for the two binding conformations can control use-dependence, the hallmark of successful antiarrhythmic drugs. PMID:19661462

[Antibiotic diffusion to central nervous system].

PubMed

Cabrera-Maqueda, J M; Fuentes Rumí, L; Valero López, G; Baidez Guerrero, A E; García Molina, E; Díaz Pérez, J; García-Vázquez, E

2018-02-01

Central nervous system (CNS) infections caused by pathogens with a reduced sensitivity to drugs are a therapeutic challenge. Transport of fluid and solutes is tightly controlled within CNS, where vasculature exhibits a blood-brain barrier (BBB).The entry of drugs, including antibiotics, into the cerebro-spinal fluid (CSF) is governed by molecular size, lipophilicity, plasma protein binding and their affinity to transport systems at the BBB. The ratio of the AUCCSF (Area under the curve in CSF)/AUCS (Area under the curve in serum) is the most accurate parameter to characterize drug penetration into the CSF. Linezolid, some fluoroquinolones and metronidazole get high CSF concentrations and are useful for treating susceptible pathogens. Some highly active antibiotic compounds with low BBB permeability can be directly administered into the ventricles together with concomitant intravenous therapy. The ideal antibiotic to treat CNS infections should be that with a small moderately lipophilic molecule, low plasma protein binding and low affinity to efflux pumps at BBB. Knowledge of the pharmacokinetics and pharmacodynamics of antibiotics at the BBB will assist to optimize antibiotic treatment in CNS infections. This article reviews the physicochemical properties of the main groups of antibiotics to assess which compounds are most promising for the treatment of CNS infections and how to use them in the daily clinical practice. © The Author 2018. Published by Sociedad Española de Quimioterapia.

Excipient foods: designing food matrices that improve the oral bioavailability of pharmaceuticals and nutraceuticals.

PubMed

McClements, David Julian; Xiao, Hang

2014-07-25

The oral bioavailability of many lipophilic bioactive agents (pharmaceuticals and nutraceuticals) is limited due to various physicochemical and physiological processes: poor release from food or drug matrices; low solubility in gastrointestinal fluids; metabolism or chemical transformation within the gastrointestinal tract; low epithelium cell permeability. The bioavailability of these agents can be improved by specifically designing food matrices that control their release, solubilization, transport, metabolism, and absorption within the gastrointestinal tract. This article discusses the impact of food composition and structure on oral bioavailability, and how this knowledge can be used to design excipient foods for improving the oral bioavailability of lipophilic bioactives. Excipient foods contain ingredients or structures that may have no bioactivity themselves, but that are able to promote the bioactivity of co-ingested bioactives. These bioactives may be lipophilic drugs in pharmaceutical preparations (such as capsules, pills, or syrups) or nutraceuticals present within food matrices (such as natural or processed foods and beverages).

Machine learning models for lipophilicity and their domain of applicability.

PubMed

Schroeter, Timon; Schwaighofer, Anton; Mika, Sebastian; Laak, Antonius Ter; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-01-01

Unfavorable lipophilicity and water solubility cause many drug failures; therefore these properties have to be taken into account early on in lead discovery. Commercial tools for predicting lipophilicity usually have been trained on small and neutral molecules, and are thus often unable to accurately predict in-house data. Using a modern Bayesian machine learning algorithm--a Gaussian process model--this study constructs a log D7 model based on 14,556 drug discovery compounds of Bayer Schering Pharma. Performance is compared with support vector machines, decision trees, ridge regression, and four commercial tools. In a blind test on 7013 new measurements from the last months (including compounds from new projects) 81% were predicted correctly within 1 log unit, compared to only 44% achieved by commercial software. Additional evaluations using public data are presented. We consider error bars for each method (model based error bars, ensemble based, and distance based approaches), and investigate how well they quantify the domain of applicability of each model.

The effect of oral castor oil on the disposition of methyprylon in intoxicated dogs.

PubMed

Gwilt, P R; Pankaskie, M C; Mitala, J J

1982-07-01

Clinical observations indicate that large oral doses of castor oil are effective in reducing the time of coma resulting from acute intoxication with lipophilic drugs. It has been further suggested that the rate of removal of these drugs from the body is increased by castor oil. In order to investigate the effect of castor oil on the disposition of lipophilic drugs, five dogs were given toxic doses of methyprylon by intravenous infusion. Each dog was treated with a large oral dose of castor oil in a cross-over fashion. No significant difference was observed in the sleep times of the dogs treated with castor oil, or in the methyprylon pharmacokinetics compared to controls. It was concluded that castor oil does not affect the disposition of methyprylon.

Electrochemical study of the anticancer drug daunorubicin at a water/oil interface: drug lipophilicity and quantification.

PubMed

Ribeiro, José A; Silva, F; Pereira, Carlos M

2013-02-05

In this work, the ion transfer mechanism of the anticancer drug daunorubicin (DNR) at a liquid/liquid interface has been studied for the first time. This study was carried out using electrochemical techniques, namely cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The lipophilicity of DNR was investigated at the water/1,6-dichlorohexane (DCH) interface, and the results obtained were presented in the form of an ionic partition diagram. The partition coefficients of both neutral and ionic forms of the drug were determined. The analytical parameter for the detection of DNR was also investigated in this work. An electrochemical DNR sensor is proposed by means of simple ion transfer at the water/DCH interface, using DPV as the quantification technique. Experimental conditions for the analytical determination of DNR were established, and a detection limit of 0.80 μM was obtained.

Fast gradient HPLC method to determine compounds binding to human serum albumin. Relationships with octanol/water and immobilized artificial membrane lipophilicity.

PubMed

Valko, Klara; Nunhuck, Shenaz; Bevan, Chris; Abraham, Michael H; Reynolds, Derek P

2003-11-01

A fast gradient HPLC method (cycle time 15 min) has been developed to determine Human Serum Albumin (HSA) binding of discovery compounds using chemically bonded protein stationary phases. The HSA binding values were derived from the gradient retention times that were converted to the logarithm of the equilibrium constants (logK HSA) using data from a calibration set of molecules. The method has been validated using literature plasma protein binding data of 68 known drug molecules. The method is fully automated, and has been used for lead optimization in more than 20 company projects. The HSA binding data obtained for more than 4000 compounds were suitable to set up global and project specific quantitative structure binding relationships that helped compound design in early drug discovery. The obtained HSA binding of known drug molecules were compared to the Immobilized Artificial Membrane binding data (CHI IAM) obtained by our previously described HPLC-based method. The solvation equation approach has been used to characterize the normal binding ability of HSA, and this relationship shows that compound lipophilicity is a significant factor. It was found that the selectivity of the "baseline" lipophilicity governing HSA binding, membrane interaction, and octanol/water partition are very similar. However, the effect of the presence of positive or negative charges have very different effects. It was found that negatively charged compounds bind more strongly to HSA than it would be expected from the lipophilicity of the ionized species at pH 7.4. Several compounds showed stronger HSA binding than can be expected from their lipophilicity alone, and comparison between predicted and experimental binding affinity allows the identification of compounds that have good complementarities with any of the known binding sites. Copyright 2003 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2236-2248, 2003

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity

PubMed Central

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M.

2016-01-01

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (SC) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. The ease and efficiency of double-click helix stabilization chemistries is a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control SC absorption and clearance rates to customize plasma pharmacokinetics. PMID:27327034

Analytical requirements, perspectives and limits of immunological methods for drugs in hair.

PubMed

Cassani, M; Spiehler, V

1993-12-01

The analytical requirements for analysis of drugs in hair are sensitivity in the range of picograms per milligram of hair, specificity for lipophilic drugs and absence of matrix effects with hair digests. These requirements are met by immunoassays which are also inexpensive, rapid and easy to use. However, in applying immunoassays to hair testing, certain limitations of the assay and of interpretation of assay results should be kept in perspective. These limitations are illustrated in this review with examples of the analysis of opiates in hair from patients and opiate addicts. The first requirement for immunological analysis of hair digests is that the digest must not denature the antibody proteins of the immunoassay reagents. For this reason enzymatic digests are better for immunological assay than chemical digests. Strongly acidic or alkaline digests must be brought to a neutral pH before immunoassay. Immunoassays used for analysis of hair should be calibrated with spiked hair digest standards to correct for possible matrix effects. The second requirement is that the immunoassay have the sensitivity and specificity to detect the drug in hair. Drugs of abuse are found in hair in the range of 10 pg-10 ng/mg hair. Radioimmunoassays are capable of detection and quantitation in this concentration range. Although the mechanism of drug incorporation into hair is not known, it is now apparent that primarily the parent drug and lipophilic metabolites are found in hair. For example, the ratio of cocaine/benzoylecgonine averages 10 (range 2-50) in published reports of analysis of hair from cocaine users. Therefore, immunoassays which are highly sensitive for the parent drug are required and results of immunoassays should be expressed as equivalents. When spiking standards for calibration of hair digest immunoassays, parent drug known to be present in hair should be used, e.g. cocaine not benzoylecgonine. With immunoassays which are specific for the lipophilic metabolite found in hair such as 6-MAM, differential radioimmunoassay can be used to discriminate between medical and illicit sources for the opiate drugs found in hair. Because of the low concentrations of drugs encountered in hair, immunoassays for hair have been used at cutoff concentrations at their limits of detection. The limit of detection (LOD) has been determined by calculating the mean and standard deviation (S.D.) for the assay response for a number of negative hair samples. The cutoff was then set at a distance of 2, 3, or 5 S.D.s from the mean response.(ABSTRACT TRUNCATED AT 400 WORDS)

Study on the Preparation and Antileukemic Activity of New Lipophilic 1-β-D-arabinofuranosylcytosine Derivatives

NASA Astrophysics Data System (ADS)

Chu, Yanyan; Tian, Zhenhua; Hou, Yingwei; Li, Wenbao

2018-04-01

Cytarabine (1-β-D-arabinofuranosylcytosine, Ara-C), isolated from a Caribbean sponge species Tethyacrypta, is the first antitumor drug from a marine resource. In 1980, the US Food and Drug Administration approved this drug for the treatment of different types of leukemia. This drug has a short plasma half-life, low stability, limited bioavailability, and severe side effects. To improve stability and bioavailability, we synthesized nine novel derivatives by blocking the cytarabine metabolic sites and improving lipophilicity. The cLogP values of the newly synthesized compounds were calculated. All the synthesized compounds were more lipophilic than cytarabine, resulting in membrane permeability and bioavailability improvement. The antitumor activities against leukemia cell line HL-60 were evaluated by using the MTT assay. The bioassay results revealed that the IC50 values of compounds 5, 8 and 9 were 0.080, 0.090 and 0.057 μmol L-1, respectively, which was similar with that of cytarabine (0.056 μmol L-1). In comparison, compound 4 with a phosphate group at O5' was inactive. Because phosphoester bonds are easily hydrolyzed by alkaline phosphatase and are commonly used in producing prodrug strategies, compound 4 might also be metabolized in vivo and generate compound 3 or even cytarabine through a multi-step reaction. Thus, compound 4 might be a promising compound to be developed as a prodrug.

Suprachoroidal delivery in a rabbit ex vivo eye model: influence of drug properties, regional differences in delivery, and comparison with intravitreal and intracameral routes

PubMed Central

Kadam, Rajendra S.; Williams, Jason; Tyagi, Puneet; Edelhauser, Henry F.

2013-01-01

Purpose First, to determine the influence of drug lipophilicity (using eight beta-blockers) and molecular weight (using 4 kDa and 40 kDa fluoroscein isothiocyanate [FITC]-dextrans) on suprachoroidal delivery to the posterior segment of the eye by using a rabbit ex vivo eye model. Second, to determine whether drug distribution differs between the dosed and undosed side of the eye following suprachoroidal delivery. Third, to compare the suprachoroidal delivery of sodium fluorescein (NaF) with the intracameral and intravitreal routes by using noninvasive fluorophotometry. Methods Using a small hypodermic 26G needle (3/8”) with a short bevel (250 µm), location of the suprachoroidal injection in an ex vivo New Zealand white rabbit eye model was confirmed with India ink. Ocular tissue distribution of NaF (25 µl of 1.5 µg/ml) at 37 °C was monitored noninvasively using the Fluorotron MasterTM at 0, 1, and 3 h following suprachoroidal, intravitreal, or intracameral injections in ex vivo rabbit eyes. For assessing the influence of lipophilicity and molecular size, 25 µl of a mixture of eight beta-blockers (250 µg/ml each) or FITC-dextran (4 kDa and 40 kDa, 30 mg/ml) was injected into the suprachoroidal space of excised rabbit eyes and incubated at 37 °C. Eyes were incubated for 1 and 3 h, and frozen at the end of incubation. Ocular tissues were isolated in frozen condition. Beta-blocker and FITC-dextran levels in excised ocular tissue were measured by liquid chromatography–tandem mass spectrometry and spectrofluorometry, respectively. Results Histological sections of India ink-injected albino rabbit eye showed the localization of dye as a black line in the suprachoroidal space. Suprachoroidal injection of NaF showed signal localization to the choroid and retina at 1 and 3 h post injection when compared with intravitreal and intracameral injections. Drug delivery to the vitreous after suprachoroidal injection decreased with an increase in solute lipophilicity and molecular weight. With an increase in drug lipophilicity, drug levels in the choroid–retinal pigment epithelium (RPE) and retina generally increased with some exceptions. Beta-blockers and FITC-dextrans were localized more to the dosed side when compared to the opposite side of the sclera, choroid–RPE, retina, and vitreous. These differences were greater for FITC-dextrans as compared to the beta-blockers. Conclusions The suprachoroidal route of injection allows localized delivery to the choroid–RPE and retina for small as well as large molecules. Suprachoroidal drug delivery to the vitreous declines with an increase in drug lipophilicity and molecular weight. Drug delivery differs between the dosed and opposite sides following suprachoroidal injection, at least up to 3 h. PMID:23734089

Confocal observation of hydrophilic and lipophilic photosensitizers in endothelial cells, lumen of the vessels, interstitium, and tumor cells using the chicken chorioallantoic membrane

NASA Astrophysics Data System (ADS)

Rueck, Angelika C.; Akguen, Nermin; Heckelsmiller, K.; Beck, Gerd C.; Genze, Felicitas; Steiner, Rudolf W.

1998-05-01

The dynamic behavior of lipophilic and hydrophilic sensitizers in cell cultures and non animal in vivo systems with varying incubation but also during the photodynamic therapy will be summarized within the presentation. As an appropriate in vivo system we used the chorioallantoic membrane (CAM) of fertilized eggs, which served as a substrate for tumor cells. Because the CAM is a transparent membrane it is possible to view individual blood vessels and to examine tumor cells as well as structural changes of the supplying vasculature. To adapt this system to high magnification microscopy, we established a new technique for in vivo observation of the CAM tissue. This technique enables online investigations of alterations at cellular level induced by drugs with confocal laser scanning microscopy. The localization of the drugs with clinical importance was observed after different application times in the lumen of the vessels, the endothelial cells and the tumor cells. In addition light induced subcellular Ca2+-changes were observed and correlated with the photodynamic process.

Alternative measures of lipophilicity: from octanol-water partitioning to IAM retention.

PubMed

Giaginis, Costas; Tsantili-Kakoulidou, Anna

2008-08-01

This review describes lipophilicity parameters currently used in drug design and QSAR studies. After a short historical overview, the complex nature of lipophilicity as the outcome of polar/nonpolar inter- and intramolecular interactions is analysed and considered as the background for the discussion of the different lipophilicity descriptors. The first part focuses on octanol-water partitioning of neutral and ionisable compounds, evaluates the efficiency of predictions and provides a short description of the experimental methods for the determination of distribution coefficients. A next part is dedicated to reversed-phase chromatographic techniques, HPLC and TLC in lipophilicity assessment. The two methods are evaluated for their efficiency to simulate octanol-water and the progress achieved in the refinement of suitable chromatographic conditions, in particular in the field of HPLC, is outlined. Liposomes as direct models of biological membranes are examined and phospolipophilicity is compared to the traditional lipophilicity concept. Difficulties associated with liposome-water partitioning are discussed. The last part focuses on Immobilised Artificial Membrane (IAM) chromatography as an alternative which combines membrane simulation with rapid measurements. IAM chromatographic retention is compared to octanol-water and liposome-water partitioning as well as to reversed-phase retention and its potential to predict biopartitioning and biological activities is discussed.

Mesoporous materials and nanocrystals for enhancing the dissolution behavior of poorly water-soluble drugs.

PubMed

Santos, Helder A; Peltonen, Leena; Limnell, Tarja; Hirvonen, Jouni

2013-01-01

Advanced drug delivery formulations are presently recognized as promising tools for overcoming the adverse physicochemical properties of conventional drug molecules, such as poor water solubility, which often leads to poor drug bioavailability. Oral drug delivery is considered as the easiest and most convenient route of drug administration. However, via the current trends utilizing combinatorial chemistry and high throughput screening in drug development, new drug molecules are moving towards lipophilic and poorly water-soluble large molecules, and the oral delivery route is becoming increasingly challenging. In this context, formulation of poorly soluble and/or permeable drugs using mesoporous materials and nanocrystals technology have proven to be highly successful due to the greater surface/volume ratio of these systems, resulting in improvements in dissolution and bioavailability, as well as enhanced drug permeability. This review addresses the issues of poorly water-soluble drugs with a major focus on recent developments in the application of the mesoporous materials (e.g., porous silicon and silica) and nanocrystals in drug delivery applications. In addition, we present several recent examples of the significant potential of these materials for the pharmaceutical field.

Differences in lung local dosimetry of the carcinogens benzo(a)pyrene and NNK

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

Dahl, A.R.; Muggenburg, B.A.; Thornton-Manning, J.R.

1996-12-31

A diffusion model predicts that highly lipophilic toxicants penetrate the comparatively thick epithelium of the conducting airways much more slowly than less lipophilic toxicants. To validate this model, the tracheal walls of a Beagle dog were sprayed with very small quantities of tritiated, highly lipophilic benzo(a)pyrene (BaP), moderately lipophilic pyrene, or slightly lipophilic 4-(methylnitrosamino)-1-(3 pyridyl)-1-butanone-(NNK). The concentration of the hydrocarbons and their metabolites were measured in the circulating blood for up to 6 hr, and tissue retention was determined at the end of the experiment. Differences in absorption of these compounds into blood were manifested in several independent measurements. Themore » highly lipophilic toxicant manifested: (1) a much slower penetration into azygous vein blood, the principal drainage system from the exposed area of the trachea; (2) a much slower appearance in the systemic circulation and (3) a much greater retention in the tracheal tissues at the end of the exposure. Increased retention mm in the airway mucosa allowed a grew fraction of lipophilic toxicants to be metabolized locally in the airway walls. This finding led us to conclude that, for example, if the carcinogens BaP and NNK are deposited at the same surface density on the airway mucosa, the highly lipophilic BaP will reach a far higher concentration in the airway epithelium than will the less lipophilic NNK. Such sharp differences in local dosimetry should be considered in order to improve the accuracy of risk assessment models for inhalants.« less

Heterogeneous transport of digitalis-like compounds by P-glycoprotein in vesicular and cellular assays.

PubMed

Gozalpour, Elnaz; Wilmer, Martijn J; Bilos, Albert; Masereeuw, Rosalinde; Russel, Frans G M; Koenderink, Jan B

2016-04-01

Digitalis-like compounds (DLCs), the ancient medication of heart failure and Na,K-ATPase inhibitors, are characterized by their toxicity. Drug-drug interactions (DDIs) at absorption and excretion levels play a key role in their toxicity, hence, knowledge about the transporters involved might prevent these unwanted interactions. In the present study, the transport of fourteen DLCs with human P-glycoprotein (P-gp; ABCB1) was studied using a liquid chromatography-mass spectrometry (LC-MS) quantification method. DLC transport by P-gp overexpressing Madin-Darby canine kidney (MDCK) and immortalized human renal cells (ciPTEC) was compared to vesicular DLC transport. Previously, we identified convallatoxin as a substrate using membrane vesicles overexpressing P-gp; however, we could not measure transport of other DLCs in this assay (Gozalpour et al., 2014a). Here, we showed that lipophilic digitoxin, digoxigenin, strophanthidin and proscillaridin A are P-gp substrates in cellular accumulation assays, whereas the less lipophilic convallatoxin was not. P-gp function in the cellular accumulation assays depends on the entrance of lipophilic compounds by passive diffusion, whereas the vesicular transport assay is more appropriate for hydrophilic substrates. In conclusion, we identified digitoxin, digoxigenin, strophanthidin and proscillaridin A as P-gp substrates using cellular accumulation assays and recognized lipophilicity as an important factor in selecting a suitable transport assay. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimization of the qualitative composition of liposomal drugs based on natural organomineral formations

NASA Astrophysics Data System (ADS)

Chzhu, O. P.; Shubenkova, E. G.

2017-08-01

Liposomal structures were developed on the basis of oil and water extracts of natural organomineral formations. These structures are natural compositions. The content of the main components in the preparations varies within the range of 20-25% of the lipophilic phase, 64-74% of the hydrophilic phase, 5-10% of the auxiliary component and the stabilizer on the phospholipid base is 1%. Phospholipids of natural origin were used as surface-active substances. The influence of hydrophilic and lipophilic auxiliary components on the content of neutral lipids in the surface lipid layer of the skin was studied. The developed preparations can be used as carriers of both hydrophilic and lipophilic active substances in pharmaceutical compositions, cosmetic and veterinary products on a natural basis.

In Silico Study of Chromatographic Lipophilicity Parameters of 3-(4-Substituted Benzyl)-5-Phenylhydantoins.

PubMed

Sekulic, Tatjana Djakovic; Keleman, Svetlana; Tot, Kristina; Tot, Jadranka; Trisovic, Nemanja; Uscumlic, Gordana

2016-01-01

New synthesized compounds, particularly those with biological activity, are potential drug candidates. This article describes experimental studies performed to estimate lipophilicity parameters of new 3-(4-substituted benzyl)-5-phenylhydantoins. Lipophilicity, as one of the most important molecular characteristics for the activity, was determined using the reversed-phase liquid chromatography (RP-18 stationary phase and methanol-water mobile phase). Molecular structures were used to generate in silico data which were used to estimate pharmacokinetic properties of the investigated compounds. The results show that generally, the investigated compounds attain good bioavailability properties. A more detailed analysis shows that the presence of a nitro, methoxy and tert-butyl group in the molecule is indicated as unfavorable for the oral bioavailability of hydantoins. Multivariate exploratory analysis was used in order to visualize grouping patterns among molecular descriptors as well as among the investigated compounds. Molecular docking study performed for two hydantoins with the highest bioavailability scores shows high binding affinity to tyrosine kinase receptor IGF-1R. The results achieved can be useful as a template for future development and further derivation or modification to obtain more potent and selective antitumor agents.

Eyelid skin as a potential site for drug delivery to conjunctiva and ocular tissues.

PubMed

See, Gerard Lee; Sagesaka, Ayano; Sugasawa, Satoko; Todo, Hiroaki; Sugibayashi, Kenji

2017-11-25

The feasibility of topical application onto the (lower) eyelid skin to deliver hydrophilic and lipophilic compounds into the conjunctiva and ocular tissues was evaluated by comparing with conventional eye drop application. Skin permeation and the concentration of several model compounds, and skin impedance were determined utilizing eyelid skin from hairless rats, as well as abdominal skin in the same animals for comparison. In vitro static diffusion cells were used to assess the skin permeation in order to provide key insights into the relationship between the skin sites and drugs. The obtained results revealed that drug permeation through the eyelid skin was much higher than that through abdominal skin regardless of the drug lipophilicity. Specifically, diclofenac sodium salt and tranilast exhibited approximately 6-fold and 11-fold higher permeability coefficients, respectively, through eyelid skin compared with abdominal skin. Histomorphological evaluation and in vivo distribution of model fluorescent dyes were also examined in the conjunctiva and skin after eyelid administration by conventional microscope and confocal laser scanning microscope analyses. The result revealed that eyelid skin has a thinner stratum corneum, thereby showing lower impedance, which could be the reason for the higher drug permeation through eyelid skin. Comparative evaluation of lipophilic and hydrophilic model compounds administered via the eyelid skin over 8h revealed stronger fluorescence intensity in the skin and surrounding tissues compared with eye drop administration. These results suggested that the (lower) eyelid skin is valuable as a prospective site for ophthalmic medicines. Copyright © 2017 Elsevier B.V. All rights reserved.

Development, characterization and in vivo evaluation of benzocaine-loaded liposomes.

PubMed

Mura, Paola; Maestrelli, Francesca; González-Rodríguez, Maria Luisa; Michelacci, Ilaria; Ghelardini, Carla; Rabasco, Antonio M

2007-08-01

This study reports the development and in vivo evaluation of a liposomal formulation of the local anaesthetic benzocaine. Multi-lamellar (MLV) and small uni-lamellar (SUV) vesicles entrapping benzocaine were prepared using 50:50 w/w phosphatidylcholine-cholesterol as lipophilic phase and 50:50 v/v ethanol-water as hydrophilic phase. Liposome size, Zeta-potential, encapsulation efficiency and skin penetration properties were determined. Drug permeation from liposomal dispersions, as such or formulated in Carbopol gel, was evaluated through artificial lipophilic membranes and excised abdominal rat skin, whereas in vivo anaesthetic effect was tested on rabbits. Interestingly, addition of the drug into the hydrophilic phase, rather than into the lipophilic one, during liposome preparation enabled an improvement of the MLV's entrapment efficiency from 29.7% to 82.3%. On the other hand, sonication conditions to obtain SUV influenced size and polydispersity index of the vesicles and reduced the entrapment efficiency by about 30%. All liposomal-benzocaine formulations showed sustained release properties and a more intense anaesthetic effect than plain drug. Permeation experiments from drug solutions in gel containing the same amount of ethanol as in the liposomal formulations made it possible to exclude a possible enhancer effect of this solvent, at least when not used in liposomal formulations. MLV with the drug added into the hydrophilic phase gave the most effective formulation, showing a permeability coefficient value 2.5 times higher than that of the plain drug and allowing a significant improvement (P<0.01) not only of intensity but also of duration of anaesthetic effect of benzocaine. These results suggest that a suitably developed liposomal formulation of benzocaine can be of actual value for improving its clinical effectiveness in topical anaesthesia.

Techniques for Loading Technetium-99m and Rhenium-186/188 Radionuclides into Preformed Liposomes for Diagnostic Imaging and Radionuclide Therapy.

PubMed

Goins, Beth; Bao, Ande; Phillips, William T

2017-01-01

Liposomes can serve as carriers of radionuclides for diagnostic imaging and therapeutic applications. Herein, procedures are outlined for radiolabeling liposomes with the gamma-emitting radionuclide, technetium-99m ( 99m Tc), for noninvasive detection of disease and for monitoring the pharmacokinetics and biodistribution of liposomal drugs, and/or with therapeutic beta-emitting radionuclides, rhenium-186/188 ( 186/188 Re), for radionuclide therapy. These efficient and practical liposome radiolabeling methods use a post-labeling mechanism to load 99m Tc or 186/188 Re into preformed liposomes prepared in advance of the labeling procedure. For all liposome radiolabeling methods described, a lipophilic chelator is used to transport 99m Tc or 186/188 Re across the lipid bilayer of the preformed liposomes. Once within the liposome interior, the pre-encapsulated glutathione or ammonium sulfate (pH) gradient provides for stable entrapment of the 99m Tc and 186/188 Re within the liposomes. In the first method, 99m Tc is transported across the lipid bilayer by the lipophilic chelator, hexamethylpropyleneamine oxime (HMPAO) and 99m Tc-HMPAO becomes trapped by interaction with the pre-encapsulated glutathione within the liposomes. In the second method, 99m Tc or 186/188 Re is transported across the lipid bilayer by the lipophilic chelator, N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA), and 99m Tc-BMEDA or 186/188 Re-BMEDA becomes trapped by interaction with pre-encapsulated glutathione within the liposomes. In the third method, an ammonium sulfate (pH) gradient loading technique is employed using liposomes with an extraliposomal pH of 7.4 and an interior pH of 5.1. BMEDA, which is lipophilic at pH 7.4, serves as a lipophilic chelator for 99m Tc or 186/188 Re to transport the radionuclides across the lipid bilayer. Once within the more acidic liposome interior, 99m Tc/ 186/188 Re-BMEDA complex becomes protonated and more hydrophilic, which results in stable entrapment of the 99m Tc/ 186/188 Re-BMEDA complex within the liposomes. Since many commercially available liposomal drugs use an ammonium sulfate (pH) gradient for drug loading, these liposomal drugs can be directly radiolabeled with 99m Tc-BMEDA for noninvasive monitoring of tissue distribution during treatment or with 186/188 Re-BMEDA for combination chemo-radionuclide therapy.

MLP Tools: a PyMOL plugin for using the molecular lipophilicity potential in computer-aided drug design

NASA Astrophysics Data System (ADS)

Oberhauser, Nils; Nurisso, Alessandra; Carrupt, Pierre-Alain

2014-05-01

The molecular lipophilicity potential (MLP) is a well-established method to calculate and visualize lipophilicity on molecules. We are here introducing a new computational tool named MLP Tools, written in the programming language Python, and conceived as a free plugin for the popular open source molecular viewer PyMOL. The plugin is divided into several sub-programs which allow the visualization of the MLP on molecular surfaces, as well as in three-dimensional space in order to analyze lipophilic properties of binding pockets. The sub-program Log MLP also implements the virtual log P which allows the prediction of the octanol/water partition coefficients on multiple three-dimensional conformations of the same molecule. An implementation on the recently introduced MLP GOLD procedure, improving the GOLD docking performance in hydrophobic pockets, is also part of the plugin. In this article, all functions of the MLP Tools will be described through a few chosen examples.

Improvement of lipophilicity and membrane transport of cefuroxime using in vitro models.

PubMed

Mrestani, Yahya; Mrestani-Klaus, Carmen; Bretschneider, Beate; Neubert, Reinhard H H

2004-11-01

Most beta-lactam antibiotics cannot be absorbed orally and, therefore, must be administered intravenously (i.v.) or intramuscularly (i.m.). Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability is receiving much attention in pharmaceutical research. Cefuroxime exhibiting significant advantages in the parental treatment of common infections, was used as model drug in the present study. The effect of the cationic absorption enhancers (four quaternary ammonium salts) on the lipophilicity of cefuroxime was investigated by means of the n-octanol/water system. The results on partitioning coefficients in the n-octanol/buffer system were confirmed using an in vitro transport model with artificial (dodecanol collodium membrane) and biological membranes (Charles-River guinea pig).

Molecular Insights into the Local Anesthetic Receptor within Voltage-Gated Sodium Channels Using Hydroxylated Analogs of Mexiletine

PubMed Central

Desaphy, Jean-François; Dipalma, Antonella; Costanza, Teresa; Carbonara, Roberta; Dinardo, Maria Maddalena; Catalano, Alessia; Carocci, Alessia; Lentini, Giovanni; Franchini, Carlo; Camerino, Diana Conte

2011-01-01

We previously showed that the β-adrenoceptor modulators, clenbuterol and propranolol, directly blocked voltage-gated sodium channels, whereas salbutamol and nadolol did not (Desaphy et al., 2003), suggesting the presence of two hydroxyl groups on the aromatic moiety of the drugs as a molecular requisite for impeding sodium channel block. To verify such an hypothesis, we synthesized five new mexiletine analogs by adding one or two hydroxyl groups to the aryloxy moiety of the sodium channel blocker and tested these compounds on hNav1.4 channels expressed in HEK293 cells. Concentration–response relationships were constructed using 25-ms-long depolarizing pulses at −30 mV applied from an holding potential of −120 mV at 0.1 Hz (tonic block) and 10 Hz (use-dependent block) stimulation frequencies. The half-maximum inhibitory concentrations (IC50) were linearly correlated to drug lipophilicity: the less lipophilic the drug, minor was the block. The same compounds were also tested on F1586C and Y1593C hNav1.4 channel mutants, to gain further information on the molecular interactions of mexiletine with its receptor within the sodium channel pore. In particular, replacement of Phe1586 and Tyr1593 by non-aromatic cysteine residues may help in the understanding of the role of π–π or π–cation interactions in mexiletine binding. Alteration of tonic block suggests that the aryloxy moiety of mexiletine may interact either directly or indirectly with Phe1586 in the closed sodium channel to produce low-affinity binding block, and that this interaction depends on the electrostatic potential of the drug aromatic tail. Alteration of use-dependent block suggests that addition of hydroxyl groups to the aryloxy moiety may modify high-affinity binding of the drug amine terminal to Phe1586 through cooperativity between the two pharmacophores, this effect being mainly related to drug lipophilicity. Mutation of Tyr1593 further impaired such cooperativity. In conclusion, these results confirm our former hypothesis by showing that the presence of hydroxyl groups to the aryloxy moiety of mexiletine greatly reduced sodium channel block, and provide molecular insights into the intimate interaction of local anesthetics with their receptor. PMID:22403541

Establishment of an evaluation method to detect drug distribution in hair follicles.

PubMed

Abe, Akinari; Saito, Miyuki; Kadhum, Wesam R; Todo, Hiroaki; Sugibayashi, Kenji

2018-05-05

Development of an appropriate method to evaluate drug disposition or targeting ability in hair follicles (HFs) is urgently needed in order to develop useful pharmaceutical products with pharmacological effects in HFs. In the present study, a cyanoacrylate biopsy (CB) method was used to measure drug disposition in HFs using a model hydrophilic drug, caffeine (CAF), and a lipophilic drug, 4-butylresorcinol (BR), in excised porcine skin. As a result, the height of HF replicas and the recovery ratio decreased with an increase in the application times of the CB method. HF replicas with a length of approximately 175 µm were obtained using a single application of the CB method. Drug distribution in the HF was detected even 5 min after topical application regardless of the lipophilicity of the drugs, although no drug disposition was observed in the deeper layers of the stratum corneum at the same time (5 min). Furthermore, significantly higher amounts of BR were observed in the stratum corneum and HF, compared with those of CAF. These results suggested that the CB method could be useful to evaluate the safety and efficacy as well as the disposition of topically applied chemicals, especially for HF-targeting drugs. Copyright © 2018 Elsevier B.V. All rights reserved.

Characterization of lipophilic pentasaccharides from beach morning glory (Ipomoea pes-caprae).

PubMed

Pereda-Miranda, Rogelio; Escalante-Sánchez, Edgar; Escobedo-Martínez, Carolina

2005-02-01

The hexane-soluble extract from the aerial parts of the herbal drug Ipomoea pes-caprae (beach morning-glory), through preparative-scale recycling HPLC, yielded six lipophilic glycosides, namely, five new pentasaccharides of jalapinolic acid, pescaproside A (1) and pescapreins I-IV (2-5), as well as the known stoloniferin III (6). Saponification of the crude resin glycoside mixture yielded simonic acid B (7) as the glycosidic acid component, whereas the esterifying residues of the natural oligosaccharides comprised five fatty acids: 2-methylpropanoic, (2S)-methylbutyric, n-hexanoic, n-decanoic, and n-dodecanoic acids. Pescaproside A (1), an acylated glycosidic acid methyl ester, is related structurally to the product obtained from the macrolactone hydrolysis of pescapreins I-IV (2-5). All the isolated compounds (1-6), characterized through high-field NMR spectroscopy, were found to be weakly cytotoxic to a small panel of cancer cell lines.

Human Intestinal Fluid Layer Separation: The Effect On Colloidal Structures & Solubility Of Lipophilic Compounds.

PubMed

Danny, Riethorst; Amitava, Mitra; Filippos, Kesisoglou; Wei, Xu; Jan, Tack; Joachim, Brouwers; Patrick, Augustijns

2018-05-23

In addition to individual intestinal fluid components, colloidal structures are responsible for enhancing the solubility of lipophilic compounds. The present study investigated the link between as well as the variability in the ultrastructure of fed state human intestinal fluids (FeHIF) and their solubilizing capacity for lipophilic compounds. For this purpose, FeHIF samples from 10 healthy volunteers with known composition and ultrastructure were used to determine the solubility of four lipophilic compounds. In light of the focus on solubility and ultrastructure, the study carefully considered the methodology of solubility determination in relation to colloid composition and solubilizing capacity of FeHIF. To determine the solubilizing capacity of human and simulated intestinal fluids, the samples were saturated with the compound of interest, shaken for 24 h, and centrifuged. When using FeHIF, solubilities were determined in the micellar layer of FeHIF, i.e. after removing the upper (lipid) layer (standard procedure), as well as in 'full' FeHIF (without removal of the upper layer). Compound concentrations were determined using HPLC-UV/fluorescence. To link the solubilizing capacity with the ultrastructure, all human and simulated fluids were imaged using transmission electron microscopy (TEM) before and after centrifugation and top layer (lipid) removal. Comparing the ultrastructure and solubilizing capacity of individual FeHIF samples demonstrated a high intersubject variability in postprandial intestinal conditions. Imaging of FeHIF after removal of the upper layer clearly showed that only micellar structures remain in the lower layer. This observation suggests that larger colloids such as vesicles and lipid droplets are contained in the upper, lipid layer. The solubilizing capacity of most FeHIF samples substantially increased with inclusion of this lipid layer. The relative increase in solubilizing capacity upon inclusion of the lipid layer was most pronounced in samples that contained mainly vesicles alongside the micelles. Current fed state simulated intestinal fluids do not contain the larger colloids observed in the lipid layer of FeHIF and can only simulate the solubilizing capacity of the micellar layer of FeHIF. While the importance of drug molecules solubilized in the micellar layer of postprandial intestinal fluids for absorption has been extensively demonstrated previously, the in-vivo relevance of drug solubilization in the lipid layer is currently unclear. In the dynamic environment of the human gastrointestinal tract, drug initially entrapped in larger postprandial colloids may become available for absorption upon lipid digestion and uptake. The current study, demonstrating the substantial solubilization of lipophilic compounds in the larger colloids of postprandial intestinal fluids, warrants further research in this field. Copyright © 2018. Published by Elsevier B.V.

Structural correlation between lipophilicity and lipopolysaccharide-sequestering activity in spermine-sulfonamide analogs.

PubMed

Burns, Mark R; Jenkins, Scott A; Vermeulen, Nicolas M; Balakrishna, Rajalakshmi; Nguyen, Thuan B; Kimbrell, Matthew R; David, Sunil A

2006-12-15

Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are outer-membrane constituents of Gram-negative bacteria, and play a key role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient. We had previously defined the pharmacophore necessary for small molecules to specifically bind and neutralize this complex carbohydrate. A series of aryl and aliphatic spermine-sulfonamide analogs were synthesized and tested in a series of binding and cell-based assays in order to probe the effect of lipophilicity on sequestration ability. A strong correlation was indeed found, supporting the hypothesis that endotoxin-neutralizing ability involves a lipophilic or membrane attachment event. The research discussed herein may be useful for the design of additional carbohydrate recognizing molecules and endotoxin-neutralizing drugs.

Relative contributions of active mediated transport and passive diffusion of fluoroquinolones with various lipophilicities in a Calu-3 lung epithelial cell model.

PubMed

Brillault, Julien; De Castro, Whocely Victor; Couet, William

2010-01-01

The transport characteristics of six fluoroquinolones (FQs) with various lipophilicities were compared in a Calu-3 cell model. For each FQ, an active polarized transport was observed in the direction of the apical side. However, the apparent permeability of FQs resulted from active transport and passive diffusion that were highly variable between compounds and mainly governed by lipophilicity. Therefore, active transport was predominant for compounds with relatively low lipophilicity but minor for FQs with higher lipophilicity.

Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability.

PubMed

Perrey, David A; Decker, Ann M; Zhang, Yanan

2018-03-21

Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX 1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX 1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX 1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX 1 potency ( K e = 5.7 nM) and selectivity (>1,760-fold over OX 2 ) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (>200 μM), good CNS permeability ( P app = 14.7 × 10 -6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3).

Structures of BmrR-Drug Complexes Reveal a Rigid Multidrug Binding Pocket And Transcription Activation Through Tyrosine Expulsion

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

Newberry, K.J.; Huffman, J.L.; Miller, M.C.

2009-05-22

BmrR is a member of the MerR family and a multidrug binding transcription factor that up-regulates the expression of the bmr multidrug efflux transporter gene in response to myriad lipophilic cationic compounds. The structural mechanism by which BmrR binds these chemically and structurally different drugs and subsequently activates transcription is poorly understood. Here, we describe the crystal structures of BmrR bound to rhodamine 6G (R6G) or berberine (Ber) and cognate DNA. These structures reveal each drug stacks against multiple aromatic residues with their positive charges most proximal to the carboxylate group of Glu-253 and that, unlike other multidrug binding pockets,more » that of BmrR is rigid. Substitution of Glu-253 with either alanine (E253A) or glutamine (E253Q) results in unpredictable binding affinities for R6G, Ber, and tetraphenylphosphonium. Moreover, these drug binding studies reveal that the negative charge of Glu-253 is not important for high affinity binding to Ber and tetraphenylphosphonium but plays a more significant, but unpredictable, role in R6G binding. In vitro transcription data show that E253A and E253Q are constitutively active, and structures of the drug-free E253A-DNA and E253Q-DNA complexes support a transcription activation mechanism requiring the expulsion of Tyr-152 from the multidrug binding pocket. In sum, these data delineate the mechanism by which BmrR binds lipophilic, monovalent cationic compounds and suggest the importance of the redundant negative electrostatic nature of this rigid drug binding pocket that can be used to discriminate against molecules that are not substrates of the Bmr multidrug efflux pump.« less

Transdermal absorption of memantin--effect of chemical enhancers, iontophoresis, and role of enhancer lipophilicity.

PubMed

del Rio-Sancho, S; Serna-Jiménez, C E; Calatayud-Pascual, M A; Balaguer-Fernández, C; Femenía-Font, A; Merino, V; López-Castellano, A

2012-09-01

The transdermal administration of memantine may have advantages with respect to oral therapy when treating advanced stages of Alzheimer's disease. With the ultimate objective of administrating memantine through a transdermal patch, the absorption of the drug across skin was evaluated by means of in vitro permeation studies. The effect of several chemical enhancers was studied in order to enhance percutaneous absorption of the memantine. The iontophoretic transdermal transport of memantine hydrochloride using a current density of 0.5 mA/cm(2) was also investigated. Results demonstrated that pre-treatment of the skin with R-(+)-limonene, laurocapram, decenoic acid, or oleic acid produced a statistically significant increment in the transdermal flux of memantine hydrochloride with respect to the control. Iontophoresis exhibited the greatest ability to enhance the flux of drug with respect to the control; nevertheless, the results obtained with R-(+)-limonene indicate that this compound could be of great use as a percutaneous enhancer in a memantine transdermal delivery system. In this study, the relationship between enhancement activity and lipophilicity was also studied. Satisfactory correlations have been obtained between the optimum lipophilicity of the enhancer and n-octanol/water partition coefficients of drugs. This relationship is a very useful tool that could allow to reduce time and to optimize the selection of appropriate enhancers for transdermal formulations. Copyright © 2012 Elsevier B.V. All rights reserved.

Development of a Predictive Model for the Stabilizer Concentration Estimation in Microreservoir Transdermal Drug Delivery Systems Using Lipophilic Pressure-Sensitive Adhesives as Matrix/Carrier.

PubMed

Chenevas-Paule, Clémence; Wolff, Hans-Michael; Ashton, Mark; Schubert, Martin; Dodou, Kalliopi

2017-05-01

Microreservoir-type transdermal drug delivery systems (MTDDS) can prevent drug crystallization; however, no current predictive model considers the impact of drug load and hydration on their physical stability. We investigated MTDDS films containing polyvinylpyrrolidone (PVP) as polymeric drug stabilizer in lipophilic pressure-sensitive adhesive (silicone). Medicated and unmedicated silicone films with different molar N-vinylpyrrolidone:drug ratios were prepared and characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, microscopy, dynamic vapor sorption (DVS), and stability testing for 4 months at different storage conditions. Homogeneously distributed drug-PVP associates were observed when nonaqueous emulsions, containing drug-PVP (inner phase) and silicone adhesive (outer phase), were dried to films. DVS data were essential to predict physical stability at different humidities. A predictive thermodynamic model was developed based on drug-polymer hydrogen-bonding interactions, using the Hoffman equation, to estimate the drug-PVP ratio needed to obtain stable MTDDS and to evaluate the impact of humidity on their physical stability. This new approach considers the impact of polymorphism on drug solubility by using easily accessible experimental data (T m and DVS) and avoids uncertainties associated with the solubility parameter approach. In conclusion, a good fit of predicted and experimental data was observed. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

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.

The influence of natural deep eutectic solvents on bioactive natural products: studying interactions between a hydrogel model and Schisandra chinensis metabolites.

PubMed

Liu, Yang; Zhang, Yu; Chen, Shao-Nong; Friesen, J Brent; Nikolić, Dejan; Choules, Mary P; McAlpine, James B; Lankin, David C; Gemeinhart, Richard A; Pauli, Guido F

2018-06-01

Natural Deep Eutectic Solvent (NADES) species can exhibit unexpected solubilizing power for lipophilic molecules despite their simple composition: hydrophilic organic molecules and water. In the present study, the unique properties of NADES species were applied in combination with a model polymer system: a hydrophilic chitosan/alginate hydrogel. Briefly, NADES species (e.g., mannose-dimethylurea-water, 2:5:5, mole/mole) formed matrices to 1) dissolve lipophilic molecules (e.g., curcumin), 2) load lipophilic molecule(s) into the hydrogel, and 3) spontaneously vacate from the system. NADES species ubiquitously occur in natural sources, and a crude extract is a mixture of the NADES species and bioactive metabolites. Based on these ideas, we hypothesized that the crude extract may also allow the loading of natural bioactive molecules from a natural NADES species into (bio)hydrogel systems. To evaluate this hypothesis in vitro, Schisandra chinensis fruit extract was chosen as a representative mixture of lipophilic botanical molecules and hydrophilic NADES species. The results showed that the NADES matrix of S. chinensis was capable of loading at least three bioactive lignans (i.e., gomisin A, gomisin J, and angeloylgomisin H) into the polymer system. The lipophilic metabolites can subsequently be released from the hydrogel. The outcomes suggest that a unique drug delivery mechanism may exist in nature, thereby potentially improving the bioavailability of lipophilic metabolites through physicochemical interactions with the NADES. Copyright © 2018 Elsevier B.V. All rights reserved.

Functional characteristics of a renal H+/lipophilic cation antiport system in porcine LLC-PK1 cells and rats.

PubMed

Matsui, Ryutaro; Hattori, Ryutaro; Usami, Youhei; Koyama, Masumi; Hirayama, Yuki; Matsuba, Emi; Hashimoto, Yukiya

2018-02-01

We have recently found an H + /quinidine (a lipophilic cation, QND) antiport system in Madin-Darby canine kidney (MDCK) cells. The primary aim of the present study was to evaluate whether the H + /lipophilic cation antiport system is expressed in porcine LLC-PK 1 cells. That is, we investigated uptake and/or efflux of QND and another cation, bisoprolol, in LLC-PK 1 cells. In addition, we studied the renal clearance of bisoprolol in rats. Uptake of QND into LLC-PK 1 cells was decreased by acidification of the extracellular pH or alkalization of the intracellular pH. Cellular uptake of QND from the apical side was much greater than from the basolateral side. In addition, apical efflux of QND from LLC-PK 1 cells was increased by acidification of the extracellular pH. Furthermore, lipophilic cationic drugs significantly reduced uptake of bisoprolol in LLC-PK 1 cells. Renal clearance of bisoprolol in rats was approximately 7-fold higher than that of creatinine, and was markedly decreased by alkalization of the urine pH. The present study suggests that the H + /lipophilic cation antiport system is expressed in the apical membrane of LLC-PK 1 cells. Moreover, the H + /lipophilic cation antiport system may be responsible for renal tubular secretion of bisoprolol in rats. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Solubility and transdermal permeation properties of a dehydroepiandrosterone cyclodextrin complex from hydrophilic and lipophilic vehicles.

PubMed

Ceschel, GianCarlo; Bergamante, Valentina; Maffei, Paola; Lombardi Borgia, Simone; Calabrese, Valeria; Biserni, Stefano; Ronchi, Celestino

2005-01-01

The permeation ability of a compound is due principally to its concentration in the vehicle and to its aptitude to cross the stratum corneum of the skin. In this work ex-vivo permeation studies on newly developed formulations containing dehydroepiandrosterone (DHEA) were carried out to investigate vehicles that increase drug permeation through the skin. To enhance the solubility of DHEA, its complex form with alpha-cyclodextrin was used. In addition, the two forms (pure drug and complex form) were introduced in hydrophilic (water), lipophilic (paraffin oil), and microemulsion vehicles to evaluate the synergic effect of cyclodextrins and microemulsion vehicles on solubility and permeation. From the results, DHEA solubility is notably conditioned by the type of the vehicle used: the highest solubilities (both for pure and complex drug forms) were obtained with microemulsion, followed by paraffin oil and water. Moreover, in all the studied vehicles, the c-DHEA was more soluble than DHEA. Permeation profile fluxes showed very interesting differences. That reflect the varying drug forms (pure drug and complex form), vehicles used, and drug concentrations in the vehicles. The major flux was obtained in complex of DHEA with alpha-cyclodextrins in the microemulsion vehicle. Therefore, this type of vehicle and drug form would be very useful in the development of a topical formulation containing DHEA.

Techniques for loading technetium-99m and rhenium-186/188 radionuclides into pre-formed liposomes for diagnostic imaging and radionuclide therapy.

PubMed

Goins, Beth; Bao, Ande; Phillips, William T

2010-01-01

Liposomes can serve as carriers of radionuclides for diagnostic imaging and therapeutic applications. Herein, procedures are outlined for radiolabeling liposomes with the gamma-emitting radionuclide, technetium-99m ((99m)Tc), for non-invasive detection of disease and for monitoring the pharmacokinetics and biodistribution of liposomal drugs, and/or with therapeutic beta-emitting radionuclides, rhenium-186/188 ((186/188)Re), for radionuclide therapy. These efficient and practical liposome radiolabeling methods use a post-labeling mechanism to load (99m)Tc or (186/188)Re into pre-formed liposomes prepared in advance of the labeling procedure. For all liposome radiolabeling methods described, a lipophilic chelator is used to transport (99m)Tc or (186/188)Re across the lipid bilayer of the pre-formed liposomes. Once within the liposome interior, the pre-encapsulated glutathione or ammonium sulfate (pH) gradient provides for stable entrapment of the (99m)Tc and (186/188)Re within the liposomes. In the first method, (99m)Tc is transported across the lipid bilayer by the lipophilic chelator, hexamethylpropyleneamine oxime (HMPAO) and (99m)Tc-HMPAO becomes trapped by interaction with the pre-encapsulated glutathione within the liposomes. In the second method, (99m)Tc or (186/188)Re is transported across the lipid bilayer by the lipophilic chelator, N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA), and (99m)Tc-BMEDA or (186/188)Re-BMEDA becomes trapped by interaction with pre-encapsulated glutathione within the liposomes. In the third method, an ammonium sulfate (pH) gradient loading technique is employed using liposomes with an extraliposomal pH of 7.4 and an interior pH of 5.1. BMEDA, which is lipophilic at pH 7.4, serves as a lipophilic chelator for (99m)Tc or (186/188)Re to transport the radionuclides across the lipid bilayer. Once within the more acidic liposome interior, (99m)Tc/(186/188)Re-BMEDA complex becomes protonated and more hydrophilic, which results in stable entrapment of the (99m)Tc/(186/188)Re-BMEDA complex within the liposomes. Since many commercially available liposomal drugs use an ammonium sulfate (pH) gradient for drug loading, these liposomal drugs can be directly radiolabeled with (99m)Tc-BMEDA for non-invasive monitoring of tissue distribution during treatment or with (186/188)Re-BMEDA for combination chemo-radionuclide therapy.

Insoluble drug delivery strategies: review of recent advances and business prospects

PubMed Central

Kalepu, Sandeep; Nekkanti, Vijaykumar

2015-01-01

The emerging trends in the combinatorial chemistry and drug design have led to the development of drug candidates with greater lipophilicity, high molecular weight and poor water solubility. Majority of the failures in new drug development have been attributed to poor water solubility of the drug. Issues associated with poor solubility can lead to low bioavailability resulting in suboptimal drug delivery. About 40% of drugs with market approval and nearly 90% of molecules in the discovery pipeline are poorly water-soluble. With the advent of various insoluble drug delivery technologies, the challenge to formulate poorly water soluble drugs could be achieved. Numerous drugs associated with poor solubility and low bioavailabilities have been formulated into successful drug products. Several marketed drugs were reformulated to improve efficacy, safety and patient compliance. In order to gain marketing exclusivity and patent protection for such products, revitalization of poorly soluble drugs using insoluble drug delivery technologies have been successfully adopted by many pharmaceutical companies. This review covers the recent advances in the field of insoluble drug delivery and business prospects. PMID:26579474

Model of transient drug diffusion across cornea.

PubMed

Zhang, Wensheng; Prausnitz, Mark R; Edwards, Aurélie

2004-09-30

A mathematical model of solute transient diffusion across the cornea to the anterior chamber of the eye was developed for topical drug delivery. Solute bioavailability was predicted given solute molecular radius and octanol-to-water distribution coefficient (Phi), ocular membrane ultrastructural parameters, tear fluid hydrodynamics, as well as solute distribution volume (Vd) and clearance rate (Cla) in the anterior chamber. The results suggest that drug bioavailability is primarily determined by solute lipophilicity. In human eyes, bioavailability is predicted to range between 1% and 5% for lipophilic molecules (Phi>1), and to be less than 0.5% for hydrophilic molecules (Phi<0.01). The simulations indicate that the distribution coefficient that maximizes bioavailability is on the order of 10. It was also found that the maximum solute concentration in the anterior chamber (Cmax) and the time needed to reach Cmax significantly depend on Phi, Vd, and Cla. Consistent with experimental findings, model predictions suggest that drug bioavailability can be increased by lowering the conjunctival-to-corneal permeability ratio and reducing precorneal solute drainage. Because of its mechanistic basis, this model will be useful to predict drug transport kinetics and bioavailability for new compounds and in diseased eyes.

Engineering and validation of a novel lipid thin film for biomembrane modeling in lipophilicity determination of drugs and xenobiotics

PubMed Central

Idowu, Sunday Olakunle; Adeyemo, Morenikeji Ambali; Ogbonna, Udochi Ihechiluru

2009-01-01

Background Determination of lipophilicity as a tool for predicting pharmacokinetic molecular behavior is limited by the predictive power of available experimental models of the biomembrane. There is current interest, therefore, in models that accurately simulate the biomembrane structure and function. A novel bio-device; a lipid thin film, was engineered as an alternative approach to the previous use of hydrocarbon thin films in biomembrane modeling. Results Retention behavior of four structurally diverse model compounds; 4-amino-3,5-dinitrobenzoic acid (ADBA), naproxen (NPX), nabumetone (NBT) and halofantrine (HF), representing 4 broad classes of varying molecular polarities and aqueous solubility behavior, was investigated on the lipid film, liquid paraffin, and octadecylsilane layers. Computational, thermodynamic and image analysis confirms the peculiar amphiphilic configuration of the lipid film. Effect of solute-type, layer-type and variables interactions on retention behavior was delineated by 2-way analysis of variance (ANOVA) and quantitative structure property relationships (QSPR). Validation of the lipid film was implemented by statistical correlation of a unique chromatographic metric with Log P (octanol/water) and several calculated molecular descriptors of bulk and solubility properties. Conclusion The lipid film signifies a biomimetic artificial biological interface capable of both hydrophobic and specific electrostatic interactions. It captures the hydrophilic-lipophilic balance (HLB) in the determination of lipophilicity of molecules unlike the pure hydrocarbon film of the prior art. The potentials and performance of the bio-device gives the promise of its utility as a predictive analytic tool for early-stage drug discovery science. PMID:19735551

Discovery of Clinical Candidate 1-{[(2 S ,3 S ,4 S )-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

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

Lee, Katherine L.; Ambler, Catherine M.; Anderson, David R.

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

Effect of cyclodextrin complexation on the aqueous solubility and solubility/dose ratio of praziquantel.

PubMed

Maragos, Stratos; Archontaki, Helen; Macheras, Panos; Valsami, Georgia

2009-01-01

Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound like PZQ could behave as BCS-Class I (highly soluble/highly permeable) drug. Phase solubility and the kneading and lyophilization techniques were used for inclusion complex preparation; solubility was determined by UV spectroscopy. The ability of the water soluble polymer polyvinylpyrolidone (PVP) to increase the complexation and solubilization efficiency of beta-CD and HP-beta-CD for PZQ was examined. Results showed significant improvement of PZQ solubility in the presence of both cyclodextrins but no additional effect in the presence of PVP. The solubility/dose ratios values of PZQ-cyclodextrin complexes calculated considering the low (150 mg) and the high dose (600 mg) of PZQ, used in practice, indicate that PZQ complexation with CDs may result in drug dosage forms that would behave as a BCS-Class I depending on the administered dose.

Formulation and evaluation of chitosan solid lipid nanoparticles of carbamazepine.

PubMed

Nair, Rahul; Kumar, Ashok C K; Priya, Vishnu K; Yadav, Chakrapani M; Raju, Prasanna Y

2012-06-13

The present work aims at preparing aqueous suspension of Solid lipid Nanoparticles containing Chitosan (CT) which is a biopolymer that exhibits a number of interesting properties which include controlled drug delivery. Carbamezapine (CBZ) is a lipophilic drug which shows it antiepileptic activity by inactivating sodium channels. The solid lipid Nanoparticles (SLN) of Chitosan-CBZ were prepared by using solvent injection method using ethanol as organic solvent. The prepared SLN formulations exhibited high encapsulation efficiency, high physical stability. The drug incorporated SLNs have demonstrated that the controlled release patterns of the drug for prolonged period. The prepared SLNs were characterized for surface morphology by SEM analysis, entrapment efficiency, zeta potential, FTIR, DSC and In-vitro diffusion studies. The hydrodynamic mean diameter and zeta potential were 168.7 ± 1.8 nm and -28.9 ± 2.0 mV for SLN-chitosan-CBZ respectively. Therefore chitosan-SLN can be good candidates to encapsulate CBZ and to increase its therapeutic efficacy in the treatment of Epilepsy.

Formulation and evaluation of chitosan solid lipid nanoparticles of carbamazepine

PubMed Central

2012-01-01

The present work aims at preparing aqueous suspension of Solid lipid Nanoparticles containing Chitosan (CT) which is a biopolymer that exhibits a number of interesting properties which include controlled drug delivery. Carbamezapine (CBZ) is a lipophilic drug which shows it antiepileptic activity by inactivating sodium channels. The solid lipid Nanoparticles (SLN) of Chitosan-CBZ were prepared by using solvent injection method using ethanol as organic solvent. The prepared SLN formulations exhibited high encapsulation efficiency, high physical stability. The drug incorporated SLNs have demonstrated that the controlled release patterns of the drug for prolonged period. The prepared SLNs were characterized for surface morphology by SEM analysis, entrapment efficiency, zeta potential, FTIR, DSC and In-vitro diffusion studies. The hydrodynamic mean diameter and zeta potential were 168.7 ±1.8 nm and −28.9 ±2.0 mV for SLN-chitosan-CBZ respectively. Therefore chitosan-SLN can be good candidates to encapsulate CBZ and to increase its therapeutic efficacy in the treatment of Epilepsy. PMID:22695222

Complexation of Statins with β-Cyclodextrin in Solutions of Small Molecular Additives and Macromolecular Colloids

NASA Astrophysics Data System (ADS)

Süle, András; Csempesz, Ferenc

The solubility of lovastatin and simvastatin (inevitable drugs in the management of cardiovascular diseases) was studied by phase-solubility measurements in multicomponent colloidal and non-colloidal media. Complexation in aqueous solutions of the highly lipophilic statins with β-cyclodextrin (β-CD) in the absence and the presence of dissolved polyvinyl pyrrolidone, its monomeric compound, tartaric acid and urea, respectively, were investigated. For the characterization of the CD-statin inclusion complexes, stability constants for the associates have been calculated.

Roles of affinity and lipophilicity in the slow kinetics of prostanoid receptor antagonists on isolated smooth muscle preparations

PubMed Central

Jones, RL; Woodward, DF; Wang, JW; Clark, RL

2011-01-01

BACKGROUND AND PURPOSE The highly lipophilic acyl-sulphonamides L-798106 and L-826266 showed surprisingly slow antagonism of the prostanoid EP3 receptor system in guinea-pig aorta. Roles of affinity and lipophilicity in the onset kinetics of these and other prostanoid ligands were investigated. EXPERIMENTAL APPROACH Antagonist selectivity was assessed using a panel of human recombinant prostanoid receptor-fluorimetric imaging plate reader assays. Potencies/affinities and onset half-times of agonists and antagonists were obtained on guinea-pig-isolated aorta and vas deferens. n-Octanol-water partition coefficients were predicted. KEY RESULTS L-798106, L-826266 and the less lipophilic congener (DG)-3ap appear to behave as selective, competitive-reversible EP3 antagonists. For ligands of low to moderate lipophilicity, potency increments for EP3 and TP (thromboxane-like) agonism on guinea-pig aorta (above pEC50 of 8.0) were associated with progressively longer onset half-times; similar trends were found for TP and histamine H1 antagonism above a pA2 limit of 8.0. In contrast, L-798106 (EP3), L-826266 (EP3, TP) and the lipophilic H1 antagonists astemizole and terfenadine exhibited very slow onset rates despite their moderate affinities; (DG)-3ap (EP3) had a faster onset. Agonism and antagonism on the vas deferens EP3 system were overall much faster, although trends were similar. CONCLUSIONS AND IMPLICATIONS High affinity and high liphophilicity may contribute to the slow onsets of prostanoid ligands in some isolated smooth muscle preparations. Both relationships are explicable by tissue disposition under the limited diffusion model. EP3 antagonists used as research tools should have moderate lipophilicity. The influence of lipophilicity on the potential clinical use of EP3 antagonists is discussed. PMID:20973775

Solid Lipid Nanoparticles as Efficient Drug and Gene Delivery Systems: Recent Breakthroughs

PubMed Central

Ezzati Nazhad Dolatabadi, Jafar; Valizadeh, Hadi; Hamishehkar, Hamed

2015-01-01

In recent years, nanomaterials have been widely applied as advanced drug and gene delivery nanosystems. Among them, solid lipid nanoparticles (SLNs) have attracted great attention as colloidal drug delivery systems for incorporating hydrophilic or lipophilic drugs and various macromolecules as well as proteins and nucleic acids. Therefore, SLNs offer great promise for controlled and site specific drug and gene delivery. This article includes general information about SLN structures and properties, production procedures, characterization. In addition, recent progress on development of drug and gene delivery systems using SLNs was reviewed. PMID:26236652

Synthesis and hypoglycemic activity of 9-O-(lipophilic group substituted) berberine derivatives.

PubMed

Zhang, Shanshan; Wang, Xiaohong; Yin, Weicheng; Liu, Zhenbao; Zhou, Mi; Xiao, Daipeng; Liu, Yanfei; Peng, Dongming

2016-10-01

A series of 9-O-(lipophilic group substituted) berberine derivatives were synthesized and evaluated for their cytotoxicity and hypoglycemic activity against HepG2 cells. All the results indicated that most of the synthesized compounds exhibited lower cytotoxicity and a certain degree of hypoglycemic activity. Especially the compounds 5g and 5h displayed dramatically increased hypoglycemic activity compared with berberine, and the cytotoxicity maintained or even lower than berberine, indicating that they are potential candidates for new anti-type 2 diabetes mellitus drugs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Physicochemical properties of valsartan and the effect of ethyl alcohol, propylene glycol and pH on its solubility.

PubMed

Mbah, C J

2005-11-01

The aqueous solubility and partition coefficient of valsartan were determined at room temperature. The effect of ethyl alcohol, propylene glycol and pH on its solubility was also investigated. It was found that both solvents increased the solubility of the drug in water. The solubilizing power of ethyl alcohol was found to be higher than that of propylene glycol. Valsartan solubility was also observed to increase at high pH values and its lipophilicity wasdemonstrated by the high positive value of the logarithm of partition coefficient.

Complete genome sequence, lifestyle, and multi-drug resistance of the human pathogen Corynebacterium resistens DSM 45100 isolated from blood samples of a leukemia patient

PubMed Central

2012-01-01

Background Corynebacterium resistens was initially recovered from human infections and recognized as a new coryneform species that is highly resistant to antimicrobial agents. Bacteremia associated with this organism in immunocompromised patients was rapidly fatal as standard minocycline therapies failed. C. resistens DSM 45100 was isolated from a blood culture of samples taken from a patient with acute myelocytic leukemia. The complete genome sequence of C. resistens DSM 45100 was determined by pyrosequencing to identify genes contributing to multi-drug resistance, virulence, and the lipophilic lifestyle of this newly described human pathogen. Results The genome of C. resistens DSM 45100 consists of a circular chromosome of 2,601,311 bp in size and the 28,312-bp plasmid pJA144188. Metabolic analysis showed that the genome of C. resistens DSM 45100 lacks genes for typical sugar uptake systems, anaplerotic functions, and a fatty acid synthase, explaining the strict lipophilic lifestyle of this species. The genome encodes a broad spectrum of enzymes ensuring the availability of exogenous fatty acids for growth, including predicted virulence factors that probably contribute to fatty acid metabolism by damaging host tissue. C. resistens DSM 45100 is able to use external L-histidine as a combined carbon and nitrogen source, presumably as a result of adaptation to the hitherto unknown habitat on the human skin. Plasmid pJA144188 harbors several genes contributing to antibiotic resistance of C. resistens DSM 45100, including a tetracycline resistance region of the Tet W type known from Lactobacillus reuteri and Streptococcus suis. The tet(W) gene of pJA144188 was cloned in Corynebacterium glutamicum and was shown to confer high levels of resistance to tetracycline, doxycycline, and minocycline in vitro. Conclusions The detected gene repertoire of C. resistens DSM 45100 provides insights into the lipophilic lifestyle and virulence functions of this newly recognized pathogen. Plasmid pJA144188 revealed a modular architecture of gene regions that contribute to the multi-drug resistance of C. resistens DSM 45100. The tet(W) gene encoding a ribosomal protection protein is reported here for the first time in corynebacteria. Cloning of the tet(W) gene mediated resistance to second generation tetracyclines in C. glutamicum, indicating that it might be responsible for the failure of minocycline therapies in patients with C. resistens bacteremia. PMID:22524407

Beyond liposomes: Recent advances on lipid based nanostructures for poorly soluble/poorly permeable drug delivery.

PubMed

Teixeira, M C; Carbone, C; Souto, E B

2017-10-01

Solid lipid nanoparticle (SLN), nanostructured lipid carriers (NLC) and hybrid nanoparticles, have gained increasing interest as drug delivery systems because of their potential to load and release drugs from the Biopharmaceutical classification system (BCS) of class II (low solubility and high permeability) and of class IV (low solubility and low permeability). Lipid properties (e.g. high solubilizing potential, biocompatibility, biotolerability, biodegradability and distinct route of absorption) contribute for the improvement of the bioavailability of these drugs for a set of administration routes. Their interest continues to grow, as translated by the number of patents being field worldwide. This paper discusses the recent advances on the use of SLN, NLC and lipid-polymer hybrid nanoparticles for the loading of lipophilic, poorly water-soluble and poorly permeable drugs, being developed for oral, topical, parenteral and ocular administration, also discussing the industrial applications of these systems. A review of the patents filled between 2014 and 2017, concerning the original inventions of lipid nanocarriers, is also provided. Copyright © 2017 Elsevier Ltd. All rights reserved.

A combination therapy for KRAS-driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin

DOE PAGES

Xia, Yifeng; Liu, Yi -Liang; Xie, Yonghua; ...

2014-11-19

Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not yet been successfully targeted. Here in this paper, we describe a combination therapy for treating these malignancies using two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of the KRAS and other small G-proteins critical for tumor growthmore » and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant NF-κB activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mTOR pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Lastly, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.« less

Modification of Salmonella Lipopolysaccharides Prevents the Outer Membrane Penetration of Novobiocin

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

Nobre, Thatyane M.; Martynowycz, Michael W.; Andreev, Konstantin

Small hydrophilic antibiotics traverse the outer membrane of Gram-negative bacteria through porin channels. Large lipophilic agents traverse the outer membrane through its bilayer, containing a majority of lipopolysaccharides in its outer leaflet. Genes controlled by the two-component regulatory system PhoPQ modify lipopolysaccharides. We isolate lipopolysaccharides from isogenic mutants of Salmonella sp., one lacking the modification, the other fully modified. These lipopolysaccharides were reconstituted asmonolayers at the air-water interface, and their properties, aswell as their interaction with a large lipophilic drug, novobiocin, was studied. X-ray reflectivity showed that the drug penetrated the monolayer of the unmodified lipopolysaccharides reaching the hydrophobic region,butwasmore » prevented fromthis penetration intothemodified lipopolysaccharides.Results correlatewith behavior of bacterial cells, which become resistant to antibiotics after PhoPQ-regulated modifications. Grazing incidence x-ray diffraction showed that novobiocin produced a striking increase in crystalline coherence length, and the size of the near-crystalline domains.« less

Bovine and Porcine Transscleral Solute Transport: Influence of Lipophilicity and the Choroid–Bruch’s Layer

PubMed Central

Cheruvu, Narayan P. S.; Kompella, Uday B.

2012-01-01

Purpose To determine the influence of the choroid–Bruch’s layer and solute lipophilicity on in vitro transscleral drug permeability in bovine and porcine eyes. Methods The in vitro permeability of two VEGF inhibitory drugs, budesonide and celecoxib, which are lipophilic and neutral at physiologic pH, and of three marker solutes, 3H-mannitol (hydrophilic, neutral), sodium fluorescein (hydrophilic, anionic), and rhodamine 6G (lipophilic, cationic), were determined across freshly excised scleras, with or without the underlying choroid–Bruch’s layer. Select studies were performed using porcine sclera with and without choroid–Bruch’s layer. Neural retina was removed by exposure of the eyecup to isotonic buffer and wherever required, the retinal pigment epithelial (RPE) layer of the preparation was disrupted and removed by exposure to hypertonic buffer. Because of the poor solubility of celecoxib and budesonide, permeability studies were conducted with 5% wt/vol of hydroxypropyl-β-cyclodextrin (HPβCD). For other solutes, permeability studies were conducted, with and without HPβCD. Partitioning of the solutes into bovine sclera and choroid–Bruch’s layer was also determined. Results The calculated log (distribution coefficient) values were −2.89, −0.68, 2.18, 3.12, and 4.02 for mannitol, sodium fluorescein, budesonide, celecoxib, and rhodamine 6G, respectively. Removal of RPE was confirmed by transmission electron microscopy and differences in the transport of mannitol. The order of the permeability coefficients (Papp) across sclera and sclera–choroid–Bruch’s layers in bovine and porcine models was 3H-mannitol > fluorescein > budesonide > celecoxib > rhodamine 6G, with HPβCD, and 3H-mannitol > fluorescein > rhodamine 6G, without HPβCD. The presence of choroid–Bruch’s layer reduced the bovine scleral permeability by 2-, 8-, 16-, 36-, and 50-fold and porcine tissue permeability by 2-, 7-, 15-, 33-, and 40-fold, respectively, for mannitol, sodium fluorescein, budesonide, celecoxib, and rhodamine 6G. The partition coefficients measured in bovine tissues correlated positively with the log (distribution coefficient) and exhibited a trend opposite that of transport. The partition coefficient ratio of bovine choroid–Bruch’s layer to sclera was ~1, 1.5, 1.7, 2, and 3.5, respectively, for the solutes, as listed earlier. Conclusions The choroid–Bruch’s layer is a more significant barrier to drug transport than is sclera. It hinders the transport of lipophilic solutes, especially a cationic solute, more than hydrophilic solutes and in a more dramatic way than does sclera. The reduction in transport across this layer directly correlates with solute binding to the tissue. Understanding the permeability properties of sclera and underlying layers would be beneficial in designing better drugs for transscleral delivery. PMID:17003447

Carbamazepine parenteral nanoemulsions prepared by spontaneous emulsification process.

PubMed

Kelmann, Regina G; Kuminek, Gislaine; Teixeira, Helder F; Koester, Letícia S

2007-09-05

Carbamazepine (CBZ), a widely used anticonvulsant drug, is a poorly soluble drug with no parenteral treatment available for patients. This study was aimed at developing a nanoemulsion for CBZ intravenous delivery. The spontaneous emulsification method was used to prepare different formulations containing 2mg/mL CBZ. Likewise, a 2(2) full factorial experimental design was applied to study the influence of two independent variables (type of oil and type of lipophilic emulsifier) on emulsion physicochemical characteristics. The nanoemulsions were evaluated concerning droplet size, zeta potential, viscosity, drug content and association to oily phase. The formulation, which presented the best characteristics required for intravenous administration was selected and refined with respect to the lipophilic emulsifier content (increase from 5% to 6% of soy lecithin). This formulation was characterized and kept its properties in a satisfactory range over the evaluated period (3 months), i.e. droplet size around 150 nm, drug content around 95% and zeta potential around -40 mV. The transmission electron microscopy revealed emulsion droplets almost spherical in shape with an amorphous core, whereas the in vitro release profile assessed by dialysis bags demonstrated a release kinetics square root time dependent, with 95% of ca. having been released within 11h.

Nonpolymeric nanoassemblies for ocular administration of acyclovir: pharmacokinetic evaluation in rabbits.

PubMed

Stella, Barbara; Arpicco, Silvia; Rocco, Flavio; Burgalassi, Susi; Nicosia, Nadia; Tampucci, Silvia; Chetoni, Patrizia; Cattel, Luigi

2012-01-01

The aim of this study was to increase bioavailability of the antiviral drug acyclovir (ACV) when administered by the ocular route. For this purpose, a new lipophilic derivative of acyclovir was synthesized, both possessing greater lipophilicity and providing the formation of a homogeneous water dispersion with higher amount of ACV than the aqueous solution of the parent drug. This was done by chemically linking acyclovir to the isoprenoid chain of squalene, obtaining 4'-trisnorsqualenoylacyclovir (SQACV), in which squalene is covalently coupled to the 4'-hydroxy group of acyclovir. This new prodrug was then formulated as nonpolymeric nanoassemblies through nanoprecipitation; the resulting particles were characterized in terms of mean diameter, zeta potential, and stability. The pharmacokinetic profile of the prodrug in the tear fluid and in the aqueous humor of rabbits was evaluated and compared to that of the parent drug. Data showed that SQACV nanoassemblies increased the amount of ACV in the aqueous humor of rabbits compared to free ACV solution. This new amphiphilic prodrug of acyclovir is a very promising tool to increase the ocular bioavailability of the parent drug. Copyright © 2011 Elsevier B.V. All rights reserved.

Effects of lipophilic components on the compatibility of lipid-based formulations with hard gelatin capsules.

PubMed

Chen, Feng-Jing; Etzler, Frank M; Ubben, Johanna; Birch, Amy; Zhong, Li; Schwabe, Robert; Dudhedia, Mayur S

2010-01-01

The present study investigated the effect of lipophilic components on the compatibility of propylene glycol (PG)-containing lipid-based drug delivery system (LBDDS) formulations with hard gelatin capsules. The presence of a lipophilic active pharmaceutical ingredient (API) (log P approximately 6.1) and an additional lipophilic excipient (Capmul MCM) significantly affected the activity of PG in the fills and the equilibrium of PG between capsule shells and fills. These changes in activity and equilibrium of PG were furthermore correlated to the mechanical and thermal properties of the liquid-filled capsules and subsequently linked to the shelf-life of the capsules on stability with respect to capsule deformation. The present study also investigated the mechanism by which lipophilic component(s) might affect the activity of PG in the fill formulations and the equilibrium of PG between capsule shells and fills. The activities of PG in two series of "binary" mixtures with Capmul MCM and with Cremophor EL were measured, respectively. The mixtures of PG containing Capmul MCM were found to be more nearly ideal than those containing Cremophor EL. The observed negative deviation from Rauolt's law indicates that the excess free energies of mixing are less then zero indicating favorable interaction between PG and the other component. It is speculated that enhanced hydrogen bonding opportunities with Cremophor EL are responsible for the decreased excess free energy of mixing. Replacement of Cremophor EL with lipophilic API also reduces the hydrogen bonding opportunities for PG in the mixtures. This hypothesis may further explain the increased activity of PG in the fills and the shifted equilibrium of PG toward the capsule shells. Activity determination utilizing headspace gas chromatography (GC) using short 30 min incubation time seems to be a time-efficient approach for assessing capsule-fill compatibility. Direct measurements of PG migration and other physical properties of the capsules took much longer time (7 weeks) for ranking the predicted capsule deformation at 40 degrees C. Asides from the time savings, activity determination can be considered to be material sparing by offering capsule-fill compatibility assessment even without the need for preparing liquid-filled capsules once appropriate positive and negative references are established. With further optimization, this approach should enable high throughput screening of LBDDS for capsule-fill compatibility in liquid-filled capsule development.

PLGA/liposome hybrid nanoparticles for short-chain ceramide delivery.

PubMed

Zou, Peng; Stern, Stephan T; Sun, Duxin

2014-03-01

Rapid premature release of lipophilic drugs from liposomal lipid bilayer to plasma proteins and biological membranes is a challenge for targeted drug delivery. The purpose of this study is to reduce premature release of lipophilic short-chain ceramides by encapsulating ceramides into liposomal aqueous interior with the aid of poly (lactic-coglycolicacid) (PLGA). BODIPY FL labeled ceramide (FL-ceramide) and BODIPY-TR labeled ceramide (TR-ceramide) were encapsulated into carboxy-terminated PLGA nanoparticles. The negatively charged PLGA nanoparticles were then encapsulated into cationic liposomes to obtain PLGA/liposome hybrids. As a control, FL-ceramide and/or TR ceramide co-loaded liposomes without PLGA were prepared. The release of ceramides from PLGA/liposome hybrids and liposomes in rat plasma, cultured MDA-MB-231 cells, and rat blood circulation was compared using fluorescence resonance energy transfer (FRET) between FL-ceramide (donor) and TR-ceramide (acceptor). FRET analysis showed that FL-ceramide and TR-ceramide in liposomal lipid bilayer were rapidly released during incubation with rat plasma. In contrast, the FL-ceramide and TR-ceramide in PLGA/liposome hybrids showed extended release. FRET images of cells revealed that ceramides in liposomal bilayer were rapidly transferred to cell membranes. In contrast, ceramides in PLGA/liposome hybrids were internalized into cells with nanoparticles simultaneously. Upon intravenous administration to rats, ceramides encapsulated in liposomal bilayer were completely released in 2 min. In contrast, ceramides encapsulated in the PLGA core were retained in PLGA/liposome hybrids for 4 h. The PLGA/liposome hybrid nanoparticles reduced in vitro and in vivo premature release of ceramides and offer a viable platform for targeted delivery of lipophilic drugs.

Amino acid conjugated antimicrobial drugs: Synthesis, lipophilicity- activity relationship, antibacterial and urease inhibition activity.

PubMed

Ullah, Atta; Iftikhar, Fatima; Arfan, Muhammad; Batool Kazmi, Syeda Tayyaba; Anjum, Muhammad Naveed; Haq, Ihsan-Ul; Ayaz, Muhammad; Farooq, Sadia; Rashid, Umer

2018-02-10

Present work describes the in vitro antibacterial evaluation of some new amino acid conjugated antimicrobial drugs. Structural modification was attempted on the three existing antimicrobial pharmaceuticals namely trimethoprim, metronidazole, isoniazid. Twenty one compounds from seven series of conjugates of these drugs were synthesized by coupling with some selected Boc-protected amino acids. The effect of structural features and lipophilicity on the antibacterial activity was investigated. The synthesized compounds were evaluated against five standard American type culture collection (ATCC) i.e. Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi strains of bacteria. Our results identified a close relationship between the lipophilicity and the activity. Triazine skeleton proved beneficial for the increase in hydrophobicity and potency. Compounds with greater hydrophobicity have shown excellent activities against Gram-negative strains of bacteria than Gram-positive. 4-amino unsubstituted trimethoprim-triazine derivative 7b have shown superior activity with MIC = 3.4 μM (2 μg/mL) for S. aureus and 1.1 μM (0.66 μg/mL) for E. coli. The synthesized compounds were also evaluated for their urease inhibition study. Microbial urease from Bacillus pasteurii was chosen for this study. Triazine derivative 7a showed excellent inhibition with IC 50  = 6.23 ± 0.09 μM. Docking studies on the crystal structure of B. pasteurii urease (PDB ID 4UBP) were carried out. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Readily prepared biodegradable nanoparticles to formulate poorly water soluble drugs improving their pharmacological properties: The example of trabectedin.

PubMed

Capasso Palmiero, Umberto; Morosi, Lavinia; Bello, Ezia; Ponzo, Marianna; Frapolli, Roberta; Matteo, Cristina; Ferrari, Mariella; Zucchetti, Massimo; Minoli, Lucia; De Maglie, Marcella; Romanelli, Pierpaolo; Morbidelli, Massimo; D'Incalci, Maurizio; Moscatelli, Davide

2018-04-28

The improvement of the pharmacological profile of lipophilic drug formulations is one of the main successes achieved using nanoparticles (NPs) in medicine. However, the complex synthesis procedure and numerous post-processing steps hamper the cost-effective use of these formulations. In this work, an approach which requires only a syringe to produce self-assembling biodegradable and biocompatible poly(caprolactone)-based NPs is developed. The effective synthesis of monodisperse NPs has been made possible by the optimization of the block-copolymer synthesized via a combination of ring opening polymerization and reversible addition-fragmentation chain transfer polymerization. These NPs can be used to formulate lipophilic drugs that are barely soluble in water, such as trabectedin, a potent anticancer therapeutic. Its biodistribution and antitumor activity have been compared with the commercially available formulation Yondelis®. The results indicate that this trabectedin NP formulation performs with the same antitumor activity as Yondelis®, but does not have the drawback of severe local vascular toxicity in the injection site. Copyright © 2018 Elsevier B.V. All rights reserved.

Squalene Synthase As a Target for Chagas Disease Therapeutics

PubMed Central

Chan, Hsiu-Chien; Li, Jikun; Zheng, Yingying; Huang, Chun-Hsiang; Ren, Feifei; Chen, Chun-Chi; Zhu, Zhen; Galizzi, Melina; Li, Zhu-Hong; Rodrigues-Poveda, Carlos A.; Gonzalez-Pacanowska, Dolores; Veiga-Santos, Phercyles; de Carvalho, Tecia Maria Ulisses; de Souza, Wanderley; Urbina, Julio A.; Wang, Andrew H.-J.; Docampo, Roberto; Li, Kai; Liu, Yi-Liang; Oldfield, Eric; Guo, Rey-Ting

2014-01-01

Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease. PMID:24789335

Synthesis of n-squalenoyl cytarabine and evaluation of its affinity with phospholipid bilayers and monolayers.

PubMed

Sarpietro, Maria Grazia; Ottimo, Sara; Giuffrida, Maria Chiara; Rocco, Flavio; Ceruti, Maurizio; Castelli, Francesco

2011-03-15

Cytarabine (1-β-D-arabinofuranosylcytosine, Ara-C), a pyrimidine nucleoside analogue, is an attractive therapeutic agent for the treatment of both acute and chronic myeloblastic leukemias. 1,1',2-tris-nor-Squalene acid (squaleneCOOH) has been conjugated to cytarabine with the formation of the squalenoyl-cytarabine prodrug, in order to improve the drug lipophilicity and, consequently, the affinity towards the environment of biological membranes, as well as of lipophilic carriers. The interaction of cytarabine and its prodrug with dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles and monolayers has been studied by the differential scanning calorimetry and the Langmuir-Blodgett techniques. The interaction has been evaluated considering the effect of the compounds on the DMPC MLV and monolayers behaviour. The aim was to have information on the interaction of the drug and the prodrug with the biological membranes and on the possibility to use liposomes as carriers for the prodrug. The results showed an improved affinity of the prodrug with MLV and monolayers with respect to the free drug. Copyright © 2011 Elsevier B.V. All rights reserved.

Development of carbon plasma-coated multiwell plates for high-throughput mass spectrometric analysis of highly lipophilic fermentation products.

PubMed

Heinig, Uwe; Scholz, Susanne; Dahm, Pia; Grabowy, Udo; Jennewein, Stefan

2010-08-01

Classical approaches to strain improvement and metabolic engineering rely on rapid qualitative and quantitative analyses of the metabolites of interest. As an analytical tool, mass spectrometry (MS) has proven to be efficient and nearly universally applicable for timely screening of metabolites. Furthermore, gas chromatography (GC)/MS- and liquid chromatography (LC)/MS-based metabolite screens can often be adapted to high-throughput formats. We recently engineered a Saccharomyces cerevisiae strain to produce taxa-4(5),11(12)-diene, the first pathway-committing biosynthetic intermediate for the anticancer drug Taxol, through the heterologous and homologous expression of several genes related to isoprenoid biosynthesis. To date, GC/MS- and LC/MS-based high-throughput methods have been inherently difficult to adapt to the screening of isoprenoid-producing microbial strains due to the need for extensive sample preparation of these often highly lipophilic compounds. In the current work, we examined different approaches to the high-throughput analysis of taxa-4(5),11(12)-diene biosynthesizing yeast strains in a 96-deep-well format. Carbon plasma coating of standard 96-deep-well polypropylene plates allowed us to circumvent the inherent solvent instability of commonly used deep-well plates. In addition, efficient adsorption of the target isoprenoid product by the coated plates allowed rapid and simple qualitative and quantitative analyses of the individual cultures. Copyright 2010 Elsevier Inc. All rights reserved.

Multiplex Liquid Chromatography-Tandem Mass Spectrometry Assay for Simultaneous Therapeutic Drug Monitoring of Ribavirin, Boceprevir, and Telaprevir

PubMed Central

Aouri, Manel; Moradpour, Darius; Cavassini, Matthias; Mercier, Thomas; Buclin, Thierry; Csajka, Chantal; Telenti, Amalio; Rauch, Andri

2013-01-01

New directly acting antivirals (DAAs) that inhibit hepatitis C virus (HCV) replication are increasingly used for the treatment of chronic hepatitis C. A marked pharmacokinetic variability and a high potential for drug-drug interactions between DAAs and numerous drug classes have been identified. In addition, ribavirin (RBV), commonly associated with hemolytic anemia, often requires dose adjustment, advocating for therapeutic drug monitoring (TDM) in patients under combined antiviral therapy. However, an assay for the simultaneous analysis of RBV and DAAs constitutes an analytical challenge because of the large differences in polarity among these drugs, ranging from hydrophilic (RBV) to highly lipophilic (telaprevir [TVR]). Moreover, TVR is characterized by erratic behavior on standard octadecyl-based reversed-phase column chromatography and must be separated from VRT-127394, its inactive C-21 epimer metabolite. We have developed a convenient assay employing simple plasma protein precipitation, followed by high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for the simultaneous determination of levels of RBV, boceprevir, and TVR, as well as its metabolite VRT-127394, in plasma. This new, simple, rapid, and robust HPLC-MS/MS assay offers an efficient method of real-time TDM aimed at maximizing efficacy while minimizing the toxicity of antiviral therapy. PMID:23629707

Optimizing Ligand Efficiency of Selective Androgen Receptor Modulators (SARMs)

PubMed Central

2015-01-01

A series of selective androgen receptor modulators (SARMs) containing the 1-(trifluoromethyl)benzyl alcohol core have been optimized for androgen receptor (AR) potency and drug-like properties. We have taken advantage of the lipophilic ligand efficiency (LLE) parameter as a guide to interpret the effect of structural changes on AR activity. Over the course of optimization efforts the LLE increased over 3 log units leading to a SARM 43 with nanomolar potency, good aqueous kinetic solubility (>700 μM), and high oral bioavailability in rats (83%). PMID:26819671

United States Air Force Summer Research Program -- 1993. Volume 7. Armstrong Laboratory

DTIC Science & Technology

1993-12-01

formulation, absorption, plasma binding affinity, biomembrane barriers, and relative extraction by the specific organ of the body concerned with...simultaneously administered or a drug may "interact" with itself. The concomitant administration of phenobarbital and warfarin results in lower plasma ... plasma protein which binds to basic lipophilic drugs including propranolol, meperidine, quinidine, and chlorpromazine. If a variation in the plasma

Rapid-gradient HPLC method for measuring drug interactions with immobilized artificial membrane: comparison with other lipophilicity measures.

PubMed

Valko, K; Du, C M; Bevan, C D; Reynolds, D P; Abraham, M H

2000-08-01

A fast-gradient high-performance liquid chromatographic (HPLC) method has been suggested to characterize the interactions of drugs with an immobilized artificial membrane (IAM). With a set of standards, the gradient retention times can be converted to Chromatographic Hydrophobicity Index values referring to IAM chromatography (CHI(IAM)) that approximates an acetonitrile concentration with which the equal distribution of compound can be achieved between the mobile phase and IAM. The CHI(IAM) values are more suitable for interlaboratory comparison and for high throughput screening of new molecular entities than the log k(IAM) values (isocratic retention factor on IAM). The fast-gradient method has been validated against the isocratic log k(IAM) values using the linear free energy relationship solvation equations based on the data from 48 compounds. The compound set was selected to provide a wide range and the least cross-correlation between the molecular descriptors in the solvation equation: (2) where SP is a solute property (e.g., logarithm of partition coefficients, reversed-phase (RP)-HPLC retention parameters, such as log k, log k(w), etc.) and the explanatory variables are solute descriptors as follows: R(2) is an excess molar refraction that can be obtained from the measured refractive index of a compound, pi(2)(H) is the solute dipolarity/polarizability, summation operatoralpha(2)(H) and summation operatorbeta(2)(0) are the solute overall or effective hydrogen-bond acidity and basicity, respectively, and V(x) is the McGowan characteristic volume (in cm(3)/100 mol) that can be calculated for any solute simply from molecular structure using a table of atomic constants. It was found that the relative constants of the solvation equation were very similar for the CHI(IAM) and for the log k(IAM). The IAM lipophilicity scale was quite similar to the octanol/water lipophilicity scale for neutral compounds. The effect of charge on the interaction with IAM was studied by varying the mobile phase pH. Copyright 2000 Wiley-Liss, Inc.

Sclera-Choroid-RPE Transport of Eight β-Blockers in Human, Bovine, Porcine, Rabbit, and Rat Models

PubMed Central

Kadam, Rajendra S.; Cheruvu, Narayan P. S.; Edelhauser, Henry F.

2011-01-01

Purpose. To determine the influence of drug lipophilicity, ocular pigmentation, and species differences on transscleral solute transport. Methods. The transport of eight β-blockers across excised sclera/sclera-choroid-RPE (SCRPE) of albino rabbit, pigmented rabbit, human, porcine, and bovine eyes was determined over 6 hours. The ex vivo transscleral β-blocker transport to the vitreous at the end of 6 hours was determined in euthanatized, pigmented Brown Norway rats. The thicknesses of the sclera and SCRPE and the melanin content in choroid-RPE (CRPE) were measured to determine whether species differences in drug transport can be explained on this basis. Results. Solute lipophilicity inversely correlated with the SCRPE cumulative percentage of transport in all species (R2 ≥ 0.80). The CRPE impeded the SCRPE transport of all β-blockers (51%–64% resistance in the rabbits; 84%–99.8% in the bovine and porcine eyes) more than the sclera, with the impedance increasing with lipophilicity. SCRPE transport followed the trend albino rabbit > pigmented rabbit > human > porcine > bovine, and a cross-species comparison showed good Spearman's rho correlation (R2 ≥ 0.85). Bovine (R2 = 0.84), porcine (R2 = 0.84), and human (R2 = 0.71) SCRPE transport was more predictive than that in the rabbit models (R2 = 0.60–0.61) of transscleral solute transport to the vitreous in rats. The CRPE concentrations were higher in pigmented rabbits than in albino rabbits. The melanin content of the CRPE exhibited the trend albino rabbit ≪ pigmented rabbit < porcine ∼ bovine < rat. Normalization to scleral thickness abolished the species differences in scleral transport. Normalization to SCRPE thickness and melanin content significantly reduced species differences in SCRPE transport. Conclusions. Owing to the presence of pigment and drug binding, choroid-RPE is the principal barrier to transscleral β-blocker transport, with the barrier being more significant for lipophilic β-blockers. Although different in magnitude between species, sclera/SCRPE transport can be correlated between species. Tissue thickness accounts for the species differences in scleral transport. Differences in tissue thickness and melanin content largely account for the species differences in SCRPE transport. PMID:21282583

Transdermal drug delivery: from micro to nano

NASA Astrophysics Data System (ADS)

Pegoraro, Carla; MacNeil, Sheila; Battaglia, Giuseppe

2012-03-01

Delivery across skin offers many advantages compared to oral or intravenous routes of drug administration. Skin however is highly impermeable to most molecules on the basis of size, hydrophilicity, lipophilicity and charge. For this reason it is often necessary to temporarily alter the barrier properties of skin for effective administration. This can be done by applying chemical enhancers, which alter the lipid structure of the top layer of skin (the stratum corneum, SC), by applying external forces such as electric currents and ultrasounds, by bypassing the stratum corneum via minimally invasive microneedles or by using nano-delivery vehicles that can cross and deliver their payload to the deeper layers of skin. Here we present a critical summary of the latest technologies used to increase transdermal delivery.

Statin intolerance: diagnosis and remedies.

PubMed

Pirillo, Angela; Catapano, Alberico Luigi

2015-05-01

Despite the efficacy of statins in reducing cardiovascular events in both primary and secondary prevention, the adherence to statin therapy is not optimal, mainly due to the occurrence of muscular adverse effects. Several risk factors may concur to the development of statin-induced myotoxicity, including patient-related factors (age, sex, and race), statin properties (dose, lipophilicity, and type of metabolism), and the concomitant administration of other drugs. Thus, the management of patients intolerant to statins, particularly those at high or very high cardiovascular risk, involves alternative therapies, including the switch to another statin or the use of intermittent dosage statin regimens, as well as nonstatin lipid lowering drugs (ezetimibe and fibrates) or new hypolipidemic drugs such as PCSK9 monoclonal antibodies, the antisense oligonucleotide against the coding region of human apolipoprotein B mRNA (mipomersen), and microsomal triglyceride transfer protein inhibitor lomitapide. Ongoing clinical trials will reveal whether the lipid-lowering effects of alternative therapies to statins can also translate into a cardiovascular benefit.

Modulated release from implantable ocular silicone oil tamponade drug reservoirs.

PubMed

Cauldbeck, Helen; Le Hellaye, Maude; McDonald, Tom O; Long, Mark; Williams, Rachel L; Rannard, Steve P; Kearns, Victoria R

2018-04-15

Complicated cases of retinal detachment can be treated with silicone oil tamponades. There is the potential for silicone oil tamponades to have adjunctive drug releasing behaviour within the eye, however the lipophilic nature of silicone oil limits the number of drugs that are suitable, and drug release from the hydrophobic reservoir is uncontrolled. Here, a radiometric technique was developed to accurately measure drug solubility in silicone oil and measure release into culture media. All-trans retinoic acid (atRA), a lipophilic drug known to act as an anti-proliferative within the eye, was used throughout this work. Chain-end modification of polydimethylsiloxane with atRA produced a polydimethylsiloxane retinoate (PDMS-atRA), which was used as an additive to silicone oil to modify the solvent environment within the silicone oil and the distribution coefficient. Blends of PDMS-atRA and silicone oil containing different concentrations of free atRA were produced. The presence of PDMS-atRA in silicone oil had a positive effect on atRA solubility and the longevity of release in vitro . The drug release period was independent of atRA starting concentration and dependent on the PDMS-atRA concentration in the blend. A clinically relevant release period of atRA over 7 weeks from a silicone oil blend with PDMS-atRA was observed. © 2018 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56 , 938-946.

Effective Drug Delivery in Diffuse Intrinsic Pontine Glioma: A Theoretical Model to Identify Potential Candidates

PubMed Central

El-Khouly, Fatma E.; van Vuurden, Dannis G.; Stroink, Thom; Hulleman, Esther; Kaspers, Gertjan J. L.; Hendrikse, N. Harry; Veldhuijzen van Zanten, Sophie E. M.

2017-01-01

Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG), patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB). We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED) may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment) of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%)—carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole—are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG. PMID:29164054

Harmony Search as a Powerful Tool for Feature Selection in QSPR Study of the Drugs Lipophilicity.

PubMed

Bahadori, Behnoosh; Atabati, Morteza

2017-01-01

Aims & Scope: Lipophilicity represents one of the most studied and most frequently used fundamental physicochemical properties. In the present work, harmony search (HS) algorithm is suggested to feature selection in quantitative structure-property relationship (QSPR) modeling to predict lipophilicity of neutral, acidic, basic and amphotheric drugs that were determined by UHPLC. Harmony search is a music-based metaheuristic optimization algorithm. It was affected by the observation that the aim of music is to search for a perfect state of harmony. Semi-empirical quantum-chemical calculations at AM1 level were used to find the optimum 3D geometry of the studied molecules and variant descriptors (1497 descriptors) were calculated by the Dragon software. The selected descriptors by harmony search algorithm (9 descriptors) were applied for model development using multiple linear regression (MLR). In comparison with other feature selection methods such as genetic algorithm and simulated annealing, harmony search algorithm has better results. The root mean square error (RMSE) with and without leave-one out cross validation (LOOCV) were obtained 0.417 and 0.302, respectively. The results were compared with those obtained from the genetic algorithm and simulated annealing methods and it showed that the HS is a helpful tool for feature selection with fine performance. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Comparative release studies on suppositories using the basket, paddle, dialysis tubing and flow-through cell methods I. Acetaminophen in a lipophilic base suppository.

PubMed

Hori, Seiichi; Kawada, Tsubasa; Kogure, Sanae; Yabu, Shinako; Mori, Kenji; Akimoto, Masayuki

2017-02-01

The release characteristics of lipophilic suppositories containing acetaminophen (AAP) were examined using four types of dissolution methods: the basket, paddle, dialysis tubing (DT) and flow-through cell (FTC) methods. The suitability of each apparatus for quality control in AAP compounded suppositories was evaluated using statistical procedures. More than 80% of the drug was released over 60 min in all the release methods studied, with the exception of the basket method. Reproducible and faster release was achieved using the paddle method at 100 and 200 rpm, whereas poor release occurred with the basket method. The mean dissolution time (MDT), maximum dissolved quantity of AAP at the end of the sampling time (Q) and dissolution efficiency (DE) were calculated by model-independent methods. The FTC method with a single chamber used in this study was also appreciable for AAP suppositories (Q of 100%, MDT of 71-91 min and DE of 75-80%). The DT apparatus is considered similar to the FTC apparatus from a quality control perspective for judging the release properties of lipophilic base suppositories containing AAP. However, even the single chamber FTC used in this study has potential as an in vitro drug release test for suppositories. The comparative dissolution method is expected to become one of the valuable tools for selecting an adequate dissolution test.

Formulation and in vitro study of antibacterial vaginal suppositories.

PubMed

Regdon, G; Gombkötö, S; Regdon, G; Selmeczi, B

1994-12-01

Vaginal suppositories frequently used in gynaecological therapy were studied. Several antibacterial pharmacons are used for the topical treatment of vaginitis of various origins. In view of the fact that the liberation of the given active substance and the subsequent therapeutic effect may be improved or inhibited by the vehicle, our aim was to find the optimal suppository base for vaginal suppositories containing sulfadimidine, chloramphenicol and gentamicin sulfate by means of in vitro experiments. On the basis of breaking hardness, disintegration time and spreading properties the French Suppocire NA product, and compositions of macrogols with lower molecular weight proved to be the best lipophilic and hydrophilic bases, respectively. Among the lipophilic bases the in vitro drug liberation of Suppocire NA was significantly better (P < 0.05) than the other lipophilic bases. This vehicle is recommended for the topical treatment of vaginitis, as these suppositories have the further advantage that they can easily be produced on a magistral, galenical or industrial scale as well.

The effect of desolvation on the binding of inhibitors to HIV-1 protease and cyclin-dependent kinases: Causes of resistance.

PubMed

Fong, Clifford W

2016-08-01

Studies of the cyclin-dependent kinase inhibitors and HIV-1 protease inhibitors have confirmed that ligand-protein binding is dependent on desolvation effects. It has been found that a four parameter linear model incorporating desolvation energy, lipophilicity, dipole moment and molecular volume of the ligands is a good model to describe the binding between ligands and kinases or proteases. The resistance shown by MDR proteases to the anti-viral drugs is multi-faceted involving varying changes in desolvation, lipophilicity and dipole moment interaction compared to the non-resistant protease. Desolvation has been shown to be the dominant factor influencing the effect of inhibitors against the cyclin-dependent kinases, but lipophilicity and dipole moment are also significant factors. The model can differentiate between the inhibitory activity of CDK2/cycE, CDK1/cycB and CDK4/cycD enzymes. Copyright © 2016 Elsevier Ltd. All rights reserved.

An Extrusion Spheronization Approach to Enable a High Drug Load Formulation of a Poorly Soluble Drug with a Low Melting Surfactant.

PubMed

Tatavarti, Aditya; Kesisoglou, Filippos

2015-11-01

Vitamin E tocopherol polyethylene glycol succinate (TPGS) is a non-ionic surface active agent, known to enhance the bioavailability of lipophilic compounds via wettability, solubility, and in some cases permeability enhancement. MK-0536 is an anti-retroviral drug with poor wettability and solubility and a high dose. Based on pharmacokinetic studies in dogs and humans, use of vitamin E TPGS in oral solid formulations of MK-0536 provides desired PK characteristics. The use of vitamin E TPGS, however, in solid dosage forms is limited because of the processing challenges resulting from its waxy nature and low melting temperature (∼37°C). The current study, for the first time, demonstrates the use of an alternative low pressure extrusion and spheronization approach to enable high loadings of the poorly soluble, poorly compactable drug and relatively high levels of vitamin E TPGS. This approach not only aided in mitigating processing challenges arising from most high energy process steps such as milling, compression, and coating, but also enabled a higher drug load formulation that provided superior bioperformance relative to a conventional high shear wet granulated formulation. An encapsulated dosage form consisting of pellets prepared by extrusion spheronization with 75% (w/w) MK-0536 and 10% (w/w) vitamin E TPGS was developed. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

The Effects of Physiological and Environmental Factors on Hepatic Perfusion and First-Pass Metabolism.

NASA Astrophysics Data System (ADS)

Modi, Marlene Woodruff

The interaction of three important parameters; hepatic blood flow (Q_{rm H} ), plasma protein binding (f), and hepatic intrinsic clearance (CL_{rm int}) determines the disposition of agents undergoing extensive first-pass metabolism. This collection of studies focuses on the interaction of these parameters in man and the rat in the presence and absence of a given physiological and environmental perturbation. Potential mechanisms implicated in the "Food Effect" phenomenon whereby concomitant food intake increases the bioavailability a basic lipophilic drug are examined. These investigations provide insight as to the physiological response of the liver in the face of nutritional, pharmacological and physiological perturbations. The measurement of hepatic blood flow is a necessary endeavor before and understanding of the hepatic circulation or hepatic clearance concepts can be realized. Preliminary studies were performed to improve our understanding of the factors affecting the interpretation of hepatic blood flow estimates. It has been postulated that this food effect is caused at least in part by a transient increase in Q _{rm H} with its associated decrease in hepatic first-pass metabolism. Posture was manipulated in such a manner as to simulate the hepatic blood flow pattern observed in postprandial subjects. Although transient changes in Q_{rm H } comparable in magnitude and duration to those encountered after food consumption were observed, the AUC _{rm oral} for propanolol was not affected. It is important to assess the free concentration being presented to the organ which is highly extracting the drug. Single macronutrient feedings of glucose and vitamin-free casein to male Sprague-Dawley rats did not produce significant changes in the serum protein binding of a model basic lipophilic drug (quinidine) in systemic or hepatic blood. It has been postulated that food intake may have a greater influence on the bioavailability of metoprolol (a high clearance drug) in extensive metabolizers of the drug. After a population of extensive and poor metabolizers of metoprolol were identified, the effect of chronic food intake on steady-state concentrations of metoprolol was examined in these two groups.

The mechanism of antimalarial action of the ruthenium(II)-chloroquine complex [RuCl(2)(CQ)] (2).

PubMed

Martínez, Alberto; Rajapakse, Chandima S K; Naoulou, Becky; Kopkalli, Yasemin; Davenport, Lesley; Sánchez-Delgado, Roberto A

2008-06-01

The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl(2)(CQ)](2) (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH(2))(3)(CQ)](2)[Cl](2), which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to beta-hematin at pH approximately 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of n-octanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH approximately 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case.

The mechanism of antimalarial action of the ruthenium (II)-chloroquine complex [RuCl2(CQ)]2

PubMed Central

Martínez, Alberto; Rajapakse, Chandima S. K.; Naoulou, Becky; Kopkalli, Yasemin; Davenport, Lesley; Sánchez-Delgado, Roberto A.

2008-01-01

The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl2(CQ)]2 (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH2)3(CQ)]2 [Cl]2, which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to β-hematin at pH ∼ 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of n-octanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH ∼ 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case. PMID:18305967

High lipophilicity of meta Mn(III) N-alkylpyridylporphyrin-based SOD mimics compensates for their lower antioxidant potency and makes them equally effective as ortho analogues in protecting SOD-deficient E. coli

PubMed Central

Kos, Ivan; Benov, Ludmil; Spasojević, Ivan; Rebouças, Júlio S.; Batinić-Haberle, Ines

2009-01-01

Lipophilicity/bioavailibility of Mn(III)N-alkylpyridylporphyrin-based SOD mimics has major impact on their in vivo ability to suppress oxidative stress. Meta isomers are less potent SOD mimics than ortho analogues, but are 10-fold more lipophilic and more planar. Enhanced lipophilicity contributes to their higher accumulation in cytosol of SOD-deficient E. coli, compensating for their lower potency; consequently both isomers exert similar-to-identical protection of SOD-deficient E. coli. Thus meta isomers may be as prospective therapeutics as are ortho porphyrins. PMID:19954250

Experimental and Conformational Analyses of Interactions between Butenafine and Lipids

PubMed Central

Mingeot-Leclercq, Marie-Paule; Gallet, Xavier; Flore, Christel; Van Bambeke, Françoise; Peuvot, Jacques; Brasseur, Robert

2001-01-01

Butenafine (N-4-tert-butylbenzyl-N-methyl-1-naphtalenemethylamine hydrochloride) is an antifungal agent of the benzylamine class that has excellent therapeutic efficacy and a remarkably long duration of action when applied topically to treat various mycoses. Given the lipophilic nature of the molecule, efficacy may be related to an interaction with cell membrane phospholipids and permeabilization of the fungal cell wall. Similarly, high lipophilicity could account for the long duration of action, since fixation to lipids in cutaneous tissues might allow them to act as local depots for slow release of the drug. We have therefore used computer-assisted conformational analysis to investigate the interaction of butenafine with lipids and extended these observations with experimental studies in vitro using liposomes. Conformational analysis of mixed monolayers of phospholipids with the neutral and protonated forms of butenafine highlighted a possible interaction with both the hydrophilic and hydrophobic domains of membrane phospholipids. Studies using liposomes demonstrated that butenafine increases membrane fluidity [assessed by fluorescence polarization of 1-(4-trimethylammonium-phenyl)-6-phenyl-1,3,5-hexatriene and 1,6-diphenylhexatriene] and membrane permeability (studied by release of calcein from liposomes). The results show, therefore, that butenafine readily interacts with lipids and is incorporated into membrane phospholipids. These findings may help explain the excellent antifungal efficacy and long duration of action of this drug when it is used as a topical antifungal agent in humans. PMID:11709307

A paradigm shift in pharmacokinetic-pharmacodynamic (PKPD) modeling: rule of thumb for estimating free drug level in tissue compared with plasma to guide drug design.

PubMed

Poulin, Patrick

2015-07-01

A basic assumption in pharmacokinetics-pharmacodynamics research is that the free drug concentration is similar in plasma and tissue, and, hence, in vitro plasma data can be used to estimate the in vivo condition in tissue. However, in a companion manuscript, it has been demonstrated that this assumption is violated for the ionized drugs. Nonetheless, these observations focus on in vitro static environments and do not challenge data with an in vivo dynamic system. Therefore, an extension from an in vitro to an in vivo system becomes the necessary next step. The objective of this study was to perform theoretical simulations of the free drug concentration in tissue and plasma by using a physiologically based pharmacokinetics (PBPK) model reproducing the in vivo conditions in human. Therefore, the effects of drug ionization, lipophilicity, and clearance have been taken into account in a dynamic system. This modeling exercise was performed as a proof of concept to demonstrate that free drug concentration in tissue and plasma may also differ in a dynamic system for passively permeable drugs that are ionized at the physiological pH. The PBPK model simulations indicated that free drug concentrations in tissue cells and plasma significantly differ for the ionized drugs because of the pH gradient effect between cells and interstitial space. Hence, a rule of thumb for potentially performing more accurate PBPK/PD modeling is suggested, which states that the free drug concentration in tissue and plasma will differ for the ionizable drugs in contrast to the neutral drugs. In addition to the pH gradient effect for the ionizable drugs, lipophilicity and clearance effects will increase or decrease the free drug concentration in tissue and plasma for each class of drugs; thus, higher will be the drug lipophilicity and clearance, lower would be the free drug concentration in plasma, and, hence, in tissue, in a dynamic in vivo system. Therefore, only considering the value of free fraction in plasma derived from a static in vitro environment might be biased to guide drug design (the old paradigm), and, hence, it is recommended to use a PBPK model to reproduce more accurately the in vivo condition in tissue (the new paradigm). This newly developed approach can be used to predict free drug concentration in diverse tissue compartments for small molecules in toxicology and pharmacology studies, which can be leveraged to optimize the pharmacokinetics drivers of tissue distribution based upon physicochemical and physiological input parameters in an attempt to optimize free drug level in tissue. Overall, this present study provides guidance on the application of plasma and tissue concentration information in PBPK/PD research in preclinical and clinical studies, which is in accordance with the recent literature. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

A Physiologically Based Pharmacokinetic Model to Predict the Pharmacokinetics of Highly Protein-Bound Drugs and Impact of Errors in Plasma Protein Binding

PubMed Central

Ye, Min; Nagar, Swati; Korzekwa, Ken

2015-01-01

Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data was often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding, and blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for terminal elimination half-life (t1/2, 100% of drugs), peak plasma concentration (Cmax, 100%), area under the plasma concentration-time curve (AUC0–t, 95.4%), clearance (CLh, 95.4%), mean retention time (MRT, 95.4%), and steady state volume (Vss, 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. PMID:26531057

PLGA/liposome hybrid nanoparticles for short-chain ceramide delivery

PubMed Central

Zou, Peng; Stern, Stephan T.; Sun, Duxin

2014-01-01

Purpose Rapid premature release of lipophilic drugs from liposomal lipid bilayer to plasma proteins and biological membranes is a challenge for targeted drug delivery. The purpose of this study is to reduce premature release of lipophilic short-chain ceramides by encapsulating ceramides into liposomal aqueous interior with the aid of poly( lactic-coglycolicacid) (PLGA). Methods BODIPY FL labeled ceramide (FL-ceramide) and BODIPY-TR labeled ceramide (TR-ceramide) were encapsulated into carboxy-terminated PLGA nanoparticles. The negatively charged PLGA nanoparticles were then encapsulated into cationic liposomes to obtain PLGA/liposome hybrids. As a control, FL-ceramide and/or TR ceramide co-loaded liposomes without PLGA were prepared. The release of ceramides from PLGA/liposome hybrids and liposomes in rat plasma, cultured MDA-MB-231 cells, and rat blood circulation was compared using fluorescence resonance energy transfer (FRET) between FL-ceramide (donor) and TR-ceramide (acceptor). Results FRET analysis showed that FL-ceramide and TR-ceramide in liposomal lipid bilayer were rapidly released during incubation with rat plasma. In contrast, the FL-ceramide and TR-ceramide in PLGA/liposome hybrids showed extended release. FRET images of cells revealed that ceramides in liposomal bilayer were rapidly transferred to cell membranes. In contrast, ceramides in PLGA/liposome hybrids were internalized into cells with nanoparticles simultaneously. Upon intravenous administration to rats, ceramides encapsulated in liposomal bilayer were completely released in 2 minutes. In contrast, ceramides encapsulated in the PLGA core were retained in PLGA/liposome hybrids for 4 hours. Conclusions The PLGA/liposome hybrid nanoparticles reduced in vitro and in vivo premature release of ceramides and offer a viable platform for targeted delivery of lipophilic drugs. PMID:24065591

Oral Delivery of Lipophilic Drugs: The Tradeoff between Solubility Increase and Permeability Decrease When Using Cyclodextrin-Based Formulations

PubMed Central

Beig, Avital; Agbaria, Riad; Dahan, Arik

2013-01-01

The purpose of this study was to investigate the impact of oral cyclodextrin-based formulation on both the apparent solubility and intestinal permeability of lipophilic drugs. The apparent solubility of the lipophilic drug dexamethasone was measured in the presence of various HPβCD levels. The drug’s permeability was measured in the absence vs. presence of HPβCD in the rat intestinal perfusion model, and across Caco-2 cell monolayers. The role of the unstirred water layer (UWL) in dexamethasone’s absorption was studied, and a simplified mass-transport analysis was developed to describe the solubility-permeability interplay. The PAMPA permeability of dexamethasone was measured in the presence of various HPβCD levels, and the correlation with the theoretical predictions was evaluated. While the solubility of dexamethasone was greatly enhanced by the presence of HPβCD (K1∶1 = 2311 M−1), all experimental models showed that the drug’s permeability was significantly reduced following the cyclodextrin complexation. The UWL was found to have no impact on the absorption of dexamethasone. A mass transport analysis was employed to describe the solubility-permeability interplay. The model enabled excellent quantitative prediction of dexamethasone’s permeability as a function of the HPβCD level. This work demonstrates that when using cyclodextrins in solubility-enabling formulations, a tradeoff exists between solubility increase and permeability decrease that must not be overlooked. This tradeoff was found to be independent of the unstirred water layer. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption. PMID:23874557

Semisolid matrix filled capsules: an approach to improve dissolution stability of phenytoin sodium formulation.

PubMed

El Massik, M A; Abdallah, O Y; Galal, S; Daabis, N A

2003-05-01

Seven semisolid fill bases were selected for the formulation of 24 capsule formulations, each containing 100 mg of phenytoin sodium. The fill materials were selected based on the water absorption capacity of their mixtures with phenytoin sodium. The fill matrices included lipophilic bases (castor oil, soya oil, and Gelucire (G) 33/01), amphiphilic bases (G 44/14 and Suppocire BP), and water-soluble bases (PEG 4000 and PEG 6000). The drug:base ratio was 1:2. Excipients such as lecithin, docusate sodium, and poloxamer 188 were added to some formulations. The dissolution rate study indicated that formulations containing lipophilic and amphiphilic bases showed the best release profiles. These are F4 (castor oil-1% docusate sodium); F10 (castor oil-3% poloxamer 188); F14 (G33/01-10% lecithin); F17 (G33/01-1% docusate sodium), and F20 (Suppocire BP). Further, the dissolution stability of the five formulations above was assessed by an accelerated stability study at 30 degrees C and 75% RH using standard Epanutin capsules for comparison. The study included the test and standard capsules either packed in the container of marketed Epanutin capsules (packed) or removed from their outer pack (unpacked). Release data indicated superior release rates of castor oil based formulations (F4 and F10) relative to standard capsules in both the unpacked and packed forms. For instance, the extent of drug release at 30 min after 1 month was 91% for F4 and F10 and 20% for standard capsules. Drug release from packed capsules after 6 months storage was 88% for both formulations F4 and F10 and 35% for standard capsules. In conclusion, the pharmaceutical quality of phenytoin sodium capsules can be improved by using a semisolid lipophilic matrix filled in hard gelatin capsules.

Development and characterization of controlled release polar lipid microparticles of candesartan cilexetil by solid dispersion

PubMed Central

Kamalakkannan, V; Puratchikody, A; Ramanathan, L

2013-01-01

Candesartan cilexetil (CC) is a newer class of angiotensin II receptor antagonist used for the treatment of hypertension. The solubility of the CC is very poor and its oral bioavailability is only 15%. The controlledrelease polar lipid microparticles of CC (formulations F1, F2, F3 and F4) were prepared using variable erodible lipophilic excipients like hydrogenated castor oil, stearic acid, cetostearyl alcohol and carnauba wax by fusion method. The particle sizes of polar lipid microparticles were less than 50 microns and they were irregular in shape. Drug content ranged between 98.96 ± 2.1 and 101.9 ± 1.6% were present in all the formulations. The formulation F3 showed better drug release throughout the study period in a controlled release manner. Moreover, the in vitro release showed that all the formulations were best fitted to Higuchi model. Accelerated stability studies indicated that there was no significant changes in the chemical and physical characteristics of the formulated drug product during initial and at the end of the study period. The FTIR and DSC studies showed that there was no interaction between the drug and lipophilic excipients and no polymorphic transitions in all formulations. The X-ray diffraction peak of solid dispersion indicated that the crystalline nature of CC disappeared and no new peaks could be observed, suggesting the absence of interaction between drug and excipients. PMID:24019822

Lipophilic extracts from banana fruit residues: a source of valuable phytosterols.

PubMed

Oliveira, Lúcia; Freire, Carmen S R; Silvestre, Armando J D; Cordeiro, Nereida

2008-10-22

The chemical composition of the lipophilic extracts of unripe pulp and peel of banana fruit 'Dwarf Cavendish' was studied by gas chromatography-mass spectrometry. Fatty acids, sterols, and steryl esters are the major families of lipophilic components present in banana tissues, followed by diacylglycerols, steryl glucosides, long chain fatty alcohols, and aromatic compounds. Fatty acids are more abundant in the banana pulp (29-90% of the total amount of lipophilic extract), with linoleic, linolenic, and oleic acids as the major compounds of this family. In banana peel, sterols represent about 49-71% of the lipophilic extract with two triterpenic ketones (31-norcyclolaudenone and cycloeucalenone) as the major components. The detection of high amounts of steryl esters (469-24405 mg/kg) and diacylglycerols (119-878 mg/kg), mainly present in the banana peel extract, explains the increase in the abundance of fatty acids and sterols after alkaline hydrolysis. Several steryl glucosides were also found in significative amounts (273-888 mg/kg), particularly in banana pulp (888 mg/kg). The high content of sterols (and their derivatives) in the 'Dwarf Cavendish' fruit can open new strategies for the valorization of the banana residues as a potential source of high-value phytochemicals with nutraceutical and functional food additive applications.

Nanocarrier for poorly water-soluble anticancer drugs--barriers of translation and solutions.

PubMed

Narvekar, Mayuri; Xue, Hui Yi; Eoh, June Young; Wong, Ho Lun

2014-08-01

Many existing chemotherapeutic drugs, repurposed drugs and newly developed small-molecule anticancer compounds have high lipophilicity and low water-solubility. Currently, these poorly water-soluble anticancer drugs (PWSAD) are generally solubilized using high concentrations of surfactants and co-solvents, which frequently lead to adverse side effects. In recent years, researchers have been actively exploring the use of nanotechnology as an alternative to the solvent-based drug solubilization approach. Several classes of nanocarrier systems (lipid-based, polymer-based and albumin-based) are widely studied for encapsulation and delivery of the existing and new PWSAD. These nanocarriers were also shown to offer several additional advantages such as enhanced tumour accumulation, reduced systemic toxicity and improved therapeutic effectiveness. In this article, the recent nanotechnological advances in PWSAD delivery will be reviewed. The barriers commonly encountered in the development of PWSAD nanoformulations (e.g. formulation issues and nanotoxicity issues) and the strategies to overcome these barriers will also be discussed. It is our goal to provide the pharmaceutical scientists and clinicians with more in-depth information about the nanodelivery approach, thus, more efficacious and safe PWSAD nanoformulations can be developed with improved translational success.

Analysis of lipophilic pigments from a phototrophic microbial mat community by high performance liquid chromatography

NASA Technical Reports Server (NTRS)

Palmisano, A. C.; Cronin, S. E.; Des Marais, D. J.

1988-01-01

As assay for lipophilic pigments in phototrophic microbial mat communities using reverse phase-high performance liquid chromatography was developed which allows the separation of 15 carotenoids and chloropigments in a single 30 min program. Lipophilic pigments in a laminated mat from a commercial salina near Laguna Guerrero Negro, Baja California Sur, Mexico reflected their source organisms. Myxoxanthophyll, echinenone, canthaxanthin, and zeaxanthin were derived from cyanobacteria; chlorophyll c, and fucoxanthin from diatoms; chlorophyll a from cyanobacteria and diatoms; bacteriochlorophylls a and c, bacteriophaeophytin a, and gamma-carotene from Chloroflexus spp.; and beta-carotene from a variety of phototrophs. Sensitivity of detection was 0.6-6.1 ng for carotenoids and 1.7-12 ng for most chloropigments. This assay represents a significant improvement over previous analyses of lipophilic pigments in microbial mats and promises to have a wider application to other types of phototrophic communities.

Dropwise additive manufacturing of pharmaceutical products for amorphous and self emulsifying drug delivery systems.

PubMed

Içten, Elçin; Purohit, Hitesh S; Wallace, Chelsey; Giridhar, Arun; Taylor, Lynne S; Nagy, Zoltan K; Reklaitis, Gintaras V

2017-05-30

The improvements in healthcare systems and the advent of the precision medicine initiative have created the need to develop more innovative manufacturing methods for the delivery and production of individualized dosing and personalized treatments. In accordance with the changes observed in healthcare systems towards more innovative therapies, this paper presents dropwise additive manufacturing of pharmaceutical products (DAMPP) for small scale, distributed manufacturing of individualized dosing as an alternative to conventional manufacturing methods A dropwise additive manufacturing process for amorphous and self-emulsifying drug delivery systems is reported, which utilizes drop-on-demand printing technology for automated and controlled deposition of melt-based formulations onto inert tablets. The advantages of drop on demand technology include reproducible production of droplets with adjustable sizing and high placement accuracy, which enable production of individualized dosing even for low dose and high potency drugs. Flexible use of different formulations, such as lipid-based formulations, allows enhancement of the solubility of poorly water soluble and highly lipophilic drugs with DAMPP. Here, DAMPP is used to produce solid oral dosage forms from melts of an active pharmaceutical ingredient and a surfactant. The dosage forms are analyzed to show the amorphous nature, self-emulsifying drug delivery system characteristics and dissolution behavior of these formulations. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug-like annotation and duplicate analysis of a 23-supplier chemical database totalling 2.7 million compounds.

PubMed

Baurin, N; Baker, R; Richardson, C; Chen, I; Foloppe, N; Potter, A; Jordan, A; Roughley, S; Parratt, M; Greaney, P; Morley, D; Hubbard, R E

2004-01-01

We have implemented five drug-like filters, based on 1D and 2D molecular descriptors, and applied them to characterize the drug-like properties of commercially available chemical compounds. In addition to previously published filters (Lipinski and Veber), we implemented a filter for medicinal chemistry tractability based on lists of chemical features drawn up by a panel of medicinal chemists. A filter based on the modeling of aqueous solubility (>1 microM) was derived in-house, as well as another based on the modeling of Caco-2 passive membrane permeability (>10 nm/s). A library of 2.7 million compounds was collated from the 23 compound suppliers and analyzed with these filters, highlighting a tendency toward highly lipophilic compounds. The library contains 1.6 M unique structures, of which 37% (607,223) passed all five drug-like filters. None of the 23 suppliers provides all the members of the drug-like subset, emphasizing the benefit of considering compounds from various compound suppliers as a source of diversity for drug discovery.

Indole-3-Carbonitriles as DYRK1A Inhibitors by Fragment-Based Drug Design.

PubMed

Meine, Rosanna; Becker, Walter; Falke, Hannes; Preu, Lutz; Loaëc, Nadège; Meijer, Laurent; Kunick, Conrad

2018-01-24

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a potential drug target because of its role in the development of Down syndrome and Alzheimer's disease. The selective DYRK1A inhibitor 10-iodo-11 H -indolo[3,2- c ]quinoline-6-carboxylic acid (KuFal194), a large, flat and lipophilic molecule, suffers from poor water solubility, limiting its use as chemical probe in cellular assays and animal models. Based on the structure of KuFal194, 7-chloro-1 H -indole-3-carbonitrile was selected as fragment template for the development of smaller and less lipophilic DYRK1A inhibitors. By modification of this fragment, a series of indole-3-carbonitriles was designed and evaluated as potential DYRK1A ligands by molecular docking studies. Synthesis and in vitro assays on DYRK1A and related protein kinases identified novel double-digit nanomolar inhibitors with submicromolar activity in cell culture assays.

Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms.

PubMed

Salas, Paloma F; Herrmann, Christoph; Cawthray, Jacqueline F; Nimphius, Corinna; Kenkel, Alexander; Chen, Jessie; de Kock, Carmen; Smith, Peter J; Patrick, Brian O; Adam, Michael J; Orvig, Chris

2013-02-28

Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ∼26.0 Å(2) give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.

Synthesis and Pharmacokinetic Evaluation of Siderophore Biosynthesis Inhibitors for Mycobacterium tuberculosis

PubMed Central

Nelson, Kathryn M.; Viswanathan, Kishore; Dawadi, Surendra; Duckworth, Benjamin P.; Boshoff, Helena I.; Barry, Clifton E.; Aldrich, Courtney C.

2015-01-01

MbtA catalyzes the first committed biosynthetic step of the mycobactins, which are important virulence factors associated with iron acquisition in Mycobacterium tuberculosis. MbtA is a validated therapeutic target for antitubercular drug development. 5′-O-[N-(salicyl)sulfamoyl]adenosine (1) is a bisubstrate inhibitor of MbtA and exhibits exceptionally potent biochemical and antitubercular activity. However, 1 suffers from sub-optimal drug disposition properties resulting in a short half-life (t1/2), low exposure (AUC), and low bioavailability (F). Four strategies were pursued to address these liabilities including the synthesis of prodrugs, increasing the pKa of the acyl-sulfonyl moiety, modulation of the lipophilicity, and strategic introduction of fluorine into 1. Complete pharmacokinetic (PK) analysis of all compounds was performed. The most successful modifications involved fluorination of the nucleoside that provided substantial improvements in t1/2 and AUC. Increasing the pKa of the acyl-sulfonyl linker yielded incremental enhancements while modulation of the lipophilicity and prodrug approaches led to substantially poorer PK parameters. PMID:26110337

PLGA-soya lecithin based micelles for enhanced delivery of methotrexate: Cellular uptake, cytotoxic and pharmacokinetic evidences.

PubMed

Singh, Anupama; Thotakura, Nagarani; Kumar, Rajendra; Singh, Bhupinder; Sharma, Gajanand; Katare, Om Prakash; Raza, Kaisar

2017-02-01

Biocompatible and biodegradable polymers like PLGA have revolutionized the drug delivery approaches. However, poor drug loading and substantially high lipophilicity, pave a path for further tailing of this promising agent. In this regard, PLGA was feathered with biocompatible phospholipid and polymeric micelles were developed for delivery of Methotrexate (MTX) to cancer cells. The nanocarriers (114.6nm±5.5nm) enhanced the cytotoxicity of MTX by 2.13 folds on MDA-MB-231 cells. Confocal laser scanning microscopy confirmed the increased intracellular delivery. The carrier decreased the protein binding potential and enhanced the bioavailable fraction of MTX. Pharmacokinetic studies vouched substantial enhancement in AUC and bioresidence time, promising an ideal carrier to effectively deliver the drug to the site of action. The developed nanocarriers offer potential to deliver the drug in the interiors of cancer cells in an effective manner for improved therapeutic action. Copyright © 2016 Elsevier B.V. All rights reserved.

Food protein-stabilized nanoemulsions as potential delivery systems for poorly water-soluble drugs: preparation, in vitro characterization, and pharmacokinetics in rats

PubMed Central

He, Wei; Tan, Yanan; Tian, Zhiqiang; Chen, Lingyun; Hu, Fuqiang; Wu, Wei

2011-01-01

Nanoemulsions stabilized by traditional emulsifiers raise toxicological concerns for long-term treatment. The present work investigates the potential of food proteins as safer stabilizers for nanoemulsions to deliver hydrophobic drugs. Nanoemulsions stabilized by food proteins (soybean protein isolate, whey protein isolate, β-lactoglobulin) were prepared by high-pressure homogenization. The toxicity of the nanoemulsions was tested in Caco-2 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide viability assay. In vivo absorption in rats was also evaluated. Food protein-stabilized nanoemulsions, with small particle size and good size distribution, exhibited better stability and biocompatibility compared with nanoemulsions stabilized by traditional emulsifiers. Moreover, β-lactoglobulin had a better emulsifying capacity and biocompatibility than the other two food proteins. The pancreatic degradation of the proteins accelerated drug release. It is concluded that an oil/water nanoemulsion system with good biocompatibility can be prepared by using food proteins as emulsifiers, allowing better and more rapid absorption of lipophilic drugs. PMID:21468355

Food protein-stabilized nanoemulsions as potential delivery systems for poorly water-soluble drugs: preparation, in vitro characterization, and pharmacokinetics in rats.

PubMed

He, Wei; Tan, Yanan; Tian, Zhiqiang; Chen, Lingyun; Hu, Fuqiang; Wu, Wei

2011-01-01

Nanoemulsions stabilized by traditional emulsifiers raise toxicological concerns for long-term treatment. The present work investigates the potential of food proteins as safer stabilizers for nanoemulsions to deliver hydrophobic drugs. Nanoemulsions stabilized by food proteins (soybean protein isolate, whey protein isolate, β-lactoglobulin) were prepared by high-pressure homogenization. The toxicity of the nanoemulsions was tested in Caco-2 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide viability assay. In vivo absorption in rats was also evaluated. Food protein-stabilized nanoemulsions, with small particle size and good size distribution, exhibited better stability and biocompatibility compared with nanoemulsions stabilized by traditional emulsifiers. Moreover, β-lactoglobulin had a better emulsifying capacity and biocompatibility than the other two food proteins. The pancreatic degradation of the proteins accelerated drug release. It is concluded that an oil/water nanoemulsion system with good biocompatibility can be prepared by using food proteins as emulsifiers, allowing better and more rapid absorption of lipophilic drugs.

Formulation, characterization and cytotoxicity studies of alendronate sodium-loaded solid lipid nanoparticles.

PubMed

Ezzati Nazhad Dolatabadi, Jafar; Hamishehkar, Hamed; Eskandani, Morteza; Valizadeh, Hadi

2014-05-01

Solid lipid nanoparticles (SLNs) are novel drug delivery system for drug targeting in various routs of administration such as parenteral, oral, ophthalmic and topical. These carriers have some advantages such as high drug payload, increased drug stability, the possibility of incorporation of lipophilic and hydrophilic drugs, and low biotoxicity. In this study, alendronate sodium was used as a hydrophilic model drug and was incorporated into SLNs. Hot homogenization method was used for preparation of alendronate sodium-loaded SLN formulations and the encapsulation efficiency of drug in SLNs was determined by ultrafiltration method using centrifugal devices. Scanning electron microscopy (SEM) was carried out to study the morphological behaviors of prepared SLNs like sphericity. Several cytotoxicity studies including MTT, DAPI staining and DNA fragmentation assays were used for biocompatibility assays. High drug encapsulation efficiency (70-85%) was achieved by drug determination through derivatization with o-phthalaldehyde. The physical stability of drug-loaded SLNs in aqueous dispersions was assessed in terms of size and drug leakage during two weeks. Scanning electron microscopy images showed spherical particles in the nanometer range confirming the obtained data from size analyzer. Several cytotoxicity studies including MTT, DAPI staining and DNA fragmentation assays as well as flow cytometry analysis confirmed the low toxicity of alendronate-loaded SLNs. The cost-efficient procedure, the avoidance of organic solvents application, acceptable reproducibility, ease of manufacturing under mild preparation conditions, high level of drug encapsulation, desirable physical stability and biocompatibility are the advantages of the proposed SLN formulations. Copyright © 2014 Elsevier B.V. All rights reserved.

Highly selective optical fluoride ion sensor with submicromolar detection limit based on aluminum(III) octaethylporphyrin in thin polymeric film.

PubMed

Badr, Ibrahim H A; Meyerhoff, Mark E

2005-04-20

A highly selective, sensitive, and reversible fluoride optical sensing film based on aluminum(III)octaethylporphyrin as a fluoride ionophore and a lipophilic pH indicator as the optical transducer is described. The fluoride optical sensing films exhibit a submicromolar detection limit and high discrimination for fluoride over several lipophilic anions such as nitrate, perchlorate, and thiocyanate.

Structure-activity relationships for amide-, carbamate-, and urea-linked analogues of the tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).

PubMed

Blaser, Adrian; Palmer, Brian D; Sutherland, Hamish S; Kmentova, Iveta; Franzblau, Scott G; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Thompson, Andrew M; Denny, William A

2012-01-12

Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH(2) linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (∼2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.

Kinetics of 11C-labeled opiates in the brain of rhesus monkeys

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

Hartvig, P.; Bergstroem, K.; Lindberg, B.

1984-07-01

The regional uptake in the brain of Rhesus monkeys of i.v. administered 11C-labeled morphine, codeine, heroin and pethidine was studied by means of positron emission tomography. The technique measures the sum of parent drug and radiolabeled metabolites. (For the sake of simplicity the drug derived radioactivity is denoted by the drug name.) Morphine had a limited uptake to discrete areas of the brain. The maximum normalized uptake, with respect to dose per kilogram body weight, was about 0.2, i.e., 20% of the calculated activity if the drug had been evenly distributed throughout the body of the monkey. Maximum radioactivity appearedmore » 30 to 45 min after injection. Morphine left the brain slowly with an estimated half-life of more than 2 hr. An area with a normalized uptake of about 1.0 was detected centrally in the lowest horizontal transsection of the skull. The origin of this area was identified as the pituitary. Codeine, heroin and pethidine were taken up to the brain to a larger extent than morphine, with maximum normalized uptakes of 2.6, 4.6 and 6.3, respectively. Maximum radioactivities of these drugs were achieved earlier and the elimination rates were faster than for morphine. Differences in the uptake of these drugs to the brain, as well as differences in time to maximal normalized uptake and rate of disappearance are considered to reflect differences in the lipophilic character between the drugs. Pethidine had the most rapid and extensive uptake followed by heroin, codeine and morphine in order of decreasing lipophilicity.« less

Using Imiquimod-Induced Psoriasis-Like Skin as a Model to Measure the Skin Penetration of Anti-Psoriatic Drugs

PubMed Central

Lin, Yin-Ku; Yang, Sien-Hung; Chen, Chin-Chuan; Kao, Hsiao-Ching; Fang, Jia-You

2015-01-01

Objective Psoriasis is a chronic inflammatory skin disease and topical therapy remains a key role for treatment. The aim of this study is to evaluate the influence of psoriasis-like lesions on the cutaneous permeation of anti-psoriatic drugs. Methods We first set up imiquimod-induced dermatitis in mice that closely resembles human psoriasis lesions. The development of the lesions is based on the IL-23/IL17A axis for phenotypical and histological characteristics. Four drugs, 5-aminolevulinic acid (ALA), tacrolimus, calcipotriol, and retinoic acid, were used to evaluate percutaneous absorption. Results The most hydrophilic molecule, ALA, revealed the greatest enhancement on skin absorption after imiquimod treatment. Imiquimod increased the skin deposition and flux of ALA by 5.6 to 14.4-fold, respectively, compared to normal skin. The follicular accumulation of ALA was also increased 3.8-fold. The extremely lipophilic drug retinoic acid showed a 1.7- and 3.8-fold increase in skin deposition and flux, respectively. Tacrolimus flux was enhanced from 2 to 21 μg/cm2/h by imiquimod intervention. However, imiquimod did not promote skin deposition of this macrolide. The lipophilicity, but not the molecular size, dominated drug permeation enhancement by psoriatic lesions. The in vivo percutaneous absorption of ALA and rhodamine B examined by confocal microscopy confirmed the deficient resistance of epidermal barrier for facilitating cutaneous delivery of drugs via psoriasis-like skin. Conclusion We established the topical delivery profiles of anti-psoriatic drugs via imiquimod-treated psoriasis-like skin. PMID:26355594

Lipophilic Fraction of Cultivated Bifurcaria bifurcata R. Ross: Detailed Composition and In Vitro Prospection of Current Challenging Bioactive Properties.

PubMed

Santos, Sónia A O; Trindade, Stephanie S; Oliveira, Catia S D; Parreira, Paula; Rosa, Daniela; Duarte, Maria F; Ferreira, Isabel; Cruz, Maria T; Rego, Andreia M; Abreu, Maria H; Rocha, Silvia M; Silvestre, Armando J D

2017-11-01

Macroalgae have been seen as an alternative source of molecules with promising bioactivities to use in the prevention and treatment of current lifestyle diseases. In this vein, the lipophilic fraction of short-term (three weeks) cultivated Bifurcaria bifurcata was characterized in detail by gas chromatography-mass spectrometry (GC-MS). B. bifurcata dichloromethane extract was composed mainly by diterpenes (1892.78 ± 133.97 mg kg -1 dry weight (DW)), followed by fatty acids, both saturated (550.35 ± 15.67 mg kg -1 DW) and unsaturated (397.06 ± 18.44 mg kg -1 DW). Considerable amounts of sterols, namely fucosterol (317.68 ± 26.11 mg kg -1 DW) were also found. In vitro tests demonstrated that the B. bifurcata lipophilic extract show antioxidant, anti-inflammatory and antibacterial activities (against both Gram-positive and Gram-negative bacteria), using low extract concentrations (in the order of µg mL -1 ). Enhancement of antibiotic activity of drug families of major clinical importance was observed by the use of B. bifurcata extract. This enhancement of antibiotic activity depends on the microbial strain and on the antibiotic. This work represents the first detailed phytochemical study of the lipophilic extract of B. bifurcata and is, therefore, an important contribution for the valorization of B. bifurcata macroalgae, with promising applications in functional foods, nutraceutical, cosmetic and biomedical fields.

Long-acting κ opioid antagonists nor-BNI, GNTI and JDTic: pharmacokinetics in mice and lipophilicity.

PubMed

Munro, Thomas A; Berry, Loren M; Van't Veer, Ashlee; Béguin, Cécile; Carroll, F Ivy; Zhao, Zhiyang; Carlezon, William A; Cohen, Bruce M

2012-05-29

Nor-BNI, GNTI and JDTic induce κ opioid antagonism that is delayed by hours and can persist for months. Other effects are transient. It has been proposed that these drugs may be slowly absorbed or distributed, and may dissolve in cell membranes, thus slowing elimination and prolonging their effects. Recent evidence suggests, instead, that they induce prolonged desensitization of the κ opioid receptor. To evaluate these hypotheses, we measured relevant physicochemical properties of nor-BNI, GNTI and JDTic, and the timecourse of brain and plasma concentrations in mice after intraperitoneal administration (using LC-MS-MS). In each case, plasma levels were maximal within 30 min and declined by >80% within four hours, correlating well with previously reported transient effects. A strong negative correlation was observed between plasma levels and the delayed, prolonged timecourse of κ antagonism. Brain levels of nor-BNI and JDTic peaked within 30 min, but while nor-BNI was largely eliminated within hours, JDTic declined gradually over a week. Brain uptake of GNTI was too low to measure accurately, and higher doses proved lethal. None of the drugs were highly lipophilic, showing high water solubility (> 45 mM) and low distribution into octanol (log D7.4 < 2). Brain homogenate binding was within the range of many shorter-acting drugs (>7% unbound). JDTic showed P-gp-mediated efflux; nor- BNI and GNTI did not, but their low unbound brain uptake suggests efflux by another mechanism. The negative plasma concentration-effect relationship we observed is difficult to reconcile with simple competitive antagonism, but is consistent with desensitization. The very slow elimination of JDTic from brain is surprising given that it undergoes active efflux, has modest affinity for homogenate, and has a shorter duration of action than nor-BNI under these conditions. We propose that this persistence may result from entrapment in cellular compartments such as lysosomes.

Highly selective Ba2+ separations with acyclic, lipophilic di-[N-(X)sulfonyl carbamoyl] polyethers.

PubMed

Elshani, Sadik; Chun, Sangki; Amiri-Eliasi, Bijan; Bartsch, Richard A

2005-01-14

New lipophilic acyclic polyethers with two N-(X)sulfonyl carbamoyl groups of "tunable" acidity exhibit remarkable selectivity for Ba2+ over other alkaline earth metal ions in competitive solvent extraction and transport across polymer inclusion membranes.

Development of a self-emulsifying formulation that reduces the food effect for torcetrapib.

PubMed

Perlman, M E; Murdande, S B; Gumkowski, M J; Shah, T S; Rodricks, C M; Thornton-Manning, J; Freel, D; Erhart, L C

2008-03-03

Torcetrapib is a highly lipophilic (Clog P=7.45) and water insoluble cholesteryl ester transfer protein (CETP) inhibitor developed for the treatment of atherosclerosis. Self-emulsifying drug delivery system (SEDDS) formulations have been developed to reduce the food effect observed in early clinical trials using medium chain triglyceride (MCT) softgels and to increase the dose per capsule. MCT/Triacetin/Polysorbate 80/Capmul MCM (20/30/20/30) (MTPC) increased fasted exposure and thus reduced the food effect from 5- to 3-fold in dogs at a dose of 90 mg. Self-emulsifying formulations also accelerated absorption and generally decreased variability. Use of the lipophilic, GRAS cosolvent triacetin allowed a 2-fold increase in the dose per capsule. For the three formulations evaluated in dogs that showed significant differences in absorption, emulsion droplet size did not appear to play a significant role. Absorption did increase with Cremophor RH40 content, and at 50% Cremophor RH40 there was no food effect (at 30 mg). High polar surfactant content also resulted in poor dose proportionality, while there was good dose proportionality for MTPC. Studies of in vitro lipolysis are being conducted to aid in understanding the in vitro/in vivo relationships for torcetrapib SEDDS absorption.

Optimised method to estimate octanol water distribution coefficient (logD) in a high throughput format.

PubMed

Low, Ying Wei Ivan; Blasco, Francesca; Vachaspati, Prakash

2016-09-20

Lipophilicity is one of the molecular properties assessed in early drug discovery. Direct measurement of the octanol-water distribution coefficient (logD) requires an analytical method with a large dynamic range or multistep dilutions, as the analyte's concentrations span across several orders of magnitude. In addition, water/buffer and octanol phases which have very different polarity could lead to matrix effects and affect the LC-MS response, leading to erroneous logD values. Most compound libraries use DMSO stocks as it greatly reduces the sample requirement but the presence of DMSO has been shown to underestimate the lipophilicity of the analyte. The present work describes the development of an optimised shake flask logD method using deepwell 96 well plate that addresses the issues related to matrix effects, DMSO concentration and incubation conditions and is also amenable to high throughput. Our results indicate that the equilibrium can be achieved within 30min by flipping the plate on its side while even 0.5% of DMSO is not tolerated in the assay. This study uses the matched matrix concept to minimise the errors in analysing the two phases namely buffer and octanol in LC-MS. Copyright © 2016 Elsevier B.V. All rights reserved.

A physiologically based pharmacokinetic model to predict the pharmacokinetics of highly protein-bound drugs and the impact of errors in plasma protein binding.

PubMed

Ye, Min; Nagar, Swati; Korzekwa, Ken

2016-04-01

Predicting the pharmacokinetics of highly protein-bound drugs is difficult. Also, since historical plasma protein binding data were often collected using unbuffered plasma, the resulting inaccurate binding data could contribute to incorrect predictions. This study uses a generic physiologically based pharmacokinetic (PBPK) model to predict human plasma concentration-time profiles for 22 highly protein-bound drugs. Tissue distribution was estimated from in vitro drug lipophilicity data, plasma protein binding and the blood: plasma ratio. Clearance was predicted with a well-stirred liver model. Underestimated hepatic clearance for acidic and neutral compounds was corrected by an empirical scaling factor. Predicted values (pharmacokinetic parameters, plasma concentration-time profile) were compared with observed data to evaluate the model accuracy. Of the 22 drugs, less than a 2-fold error was obtained for the terminal elimination half-life (t1/2 , 100% of drugs), peak plasma concentration (Cmax , 100%), area under the plasma concentration-time curve (AUC0-t , 95.4%), clearance (CLh , 95.4%), mean residence time (MRT, 95.4%) and steady state volume (Vss , 90.9%). The impact of fup errors on CLh and Vss prediction was evaluated. Errors in fup resulted in proportional errors in clearance prediction for low-clearance compounds, and in Vss prediction for high-volume neutral drugs. For high-volume basic drugs, errors in fup did not propagate to errors in Vss prediction. This is due to the cancellation of errors in the calculations for tissue partitioning of basic drugs. Overall, plasma profiles were well simulated with the present PBPK model. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Nanostructuring Biomaterials with Specific Activities towards Digestive Enzymes for Controlled Gastrointestinal Absorption of Lipophilic Bioactive Molecules.

PubMed

Joyce, Paul; Whitby, Catherine P; Prestidge, Clive A

2016-11-01

This review describes the development of novel lipid-based biomaterials that modulate fat digestion for the enhanced uptake of encapsulated lipophilic bioactive compounds (e.g. drugs and vitamins). Specific focus is directed towards analysing how key material characteristics affect the biological function of digestive lipases and manipulate lipolytic digestion. The mechanism of lipase action is a complex, interfacial process, whereby hydrolysis can be controlled by the ability for lipase to access and adsorb to the lipid-in-water interface. However, significant conjecture exists within the literature regarding parameters that influence the activities of digestive lipases. Important findings from recent investigations that strategically examined the interplay between the interfacial composition of the lipid microenvironment and lipolysis kinetics in simulated biophysical environments are presented. The correlation between lipolysis and the rate of solubilisation and absorption of lipophilic compounds in the gastrointestinal tract (GIT) is detailed. Greater insights into the mechanism of lipase action have provided a new approach for designing colloidal carriers that orally deliver poorly soluble compounds, directly impacting the pharmaceutical and food industries. Copyright © 2016 Elsevier B.V. All rights reserved.

Optimisation of cosolvent concentration for topical drug delivery III--influence of lipophilic vehicles on ibuprofen permeation.

PubMed

Watkinson, R M; Guy, R H; Oliveira, G; Hadgraft, J; Lane, M E

2011-01-01

Previously, we have reported the effects of water, ethanol, propylene glycol and various binary and ternary mixtures of these solvents on the permeation of ibuprofen in model membranes and in skin. The present study investigates the influence of lipophilic vehicles on the transport of ibuprofen in silicone membrane and in human skin. The permeation of ibuprofen was measured from mineral oil (MO), Miglyol® 812 (MG) and binary mixtures of MO and MG. The solubility of ibuprofen was 5-fold higher in MG than in MO, however, the permeation of ibuprofen from the pure vehicles and combinations of both was comparable in silicone membrane. Additionally, there were no significant differences in skin permeation for MO and MG vehicles. When the permeation of various hydrophilic and lipophilic vehicles is considered, a trend between flux values for the model membrane and skin is evident (r(2) = 0.71). The findings suggest that silicone membrane may provide information on qualitative trends in skin permeation for vehicles of diverse solubility and partition characteristics. Copyright © 2010 S. Karger AG, Basel.

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

Xia, Yifeng; Liu, Yi -Liang; Xie, Yonghua

Lung cancer is the most common human malignancy and leads to about one-third of all cancer-related deaths. Lung adenocarcinomas harboring KRAS mutations, in contrast to those with EGFR and EML4-ALK mutations, have not yet been successfully targeted. Here in this paper, we describe a combination therapy for treating these malignancies using two agents: a lipophilic bisphosphonate and rapamycin. This drug combination is much more effective than either agent acting alone in the KRAS G12D induced mouse lung model. Lipophilic bisphosphonates inhibit both farnesyl and geranylgeranyldiphosphate synthases, effectively blocking prenylation of the KRAS and other small G-proteins critical for tumor growthmore » and cell survival. Bisphosphonate treatment of cells initiated autophagy but was ultimately unsuccessful and led to p62 accumulation and concomitant NF-κB activation, resulting in dampened efficacy in vivo. However, we found that rapamycin, in addition to inhibiting the mTOR pathway, facilitated autophagy and prevented p62 accumulation-induced NF-κB activation and tumor cell proliferation. Lastly, these results suggest that using lipophilic bisphosphonates in combination with rapamycin may provide an effective strategy for targeting lung adenocarcinomas harboring KRAS mutations.« less

Synthesis and Characterization of a Novel Phenolic Lipid for Use as Potential Lipophilic Antioxidant and as a Prodrug of Butyric Acid.

PubMed

Kaki, Shiva Shanker; Kunduru, Konda Reddy; Kanjilal, Sanjit; Narayana Prasad, Rachapudi Badari

2015-01-01

Ferulic acid was modified to produce a novel phenolipid containing butyl chains. Ferulic acid was esterified with butanol to produce butyl ferulate which was further dihydroxylated followed by esterification with butyric anhydride to produce the phenolipid containing butyric acid. IR, NMR and MS techniques confirmed the structure of the synthesized structured lipophilic phenolic compound. The synthesized compound was tested for in vitro antioxidant and antimicrobial activities. The produced phenolipid showed moderate antioxidant activity in DPPH (2, 2-diphenyl-1-picrylhydrazyl) radical scavenging assay but in linoleic acid oxidation method, it exhibited good activity compared with the parent compound and the reference compounds. The prepared derivative could find applications as antioxidant in lipophilic systems and also as a potential prodrug of butyric acid. It also showed antibacterial effect against the four bacterial strains studied. The drug-likeness properties of the prepared molecule calculated were in the acceptable ranges according to Lipinski's rule of 5 and suggest that it has potential to cross the blood-brain barrier.

PEG-coumarin nanoaggregates as π-π stacking derived small molecule lipophile containing self-assemblies for anti-tumour drug delivery.

PubMed

Behl, Gautam; Kumar, Parveen; Sikka, Manisha; Fitzhenry, Laurence; Chhikara, Aruna

2018-03-01

Polymeric self-assemblies formed by non-covalent interactions such as hydrophobic interactions, hydrogen bonding, π-π stacking, host-guest and electrostatic interactions have been utilised widely and exhibit controlled release of encapsulated drug. Beside carrier-carrier interactions, small molecule amphiphiles exhibiting carrier-drug interactions have recently been an area of interest for cancer drug delivery, as most of the hydrophobic anti-tumour drugs are aromatic and exhibit π-π conjugated structure. In the present study PEG-coumarin (PC) conjugates forming self-assembled nanoaggregates were synthesised with PEG (polyethylene glycol) as hydrophilic block and coumarin as small molecule lipophilic segment. Curcumin (CUR) as model conjugated aromatic drug was loaded in to the nanoaggregates via dual hydrophobic and π-π stacking interactions. The interactions between the conjugates and CUR, drug release profile and in vitro anti-tumour efficacy were investigated in detail. CUR-loaded nanoaggregate self-assembly was driven by π-π interactions and a maximum loading level of about 18 wt.% (~60 % encapsulation efficiency) was achieved. The average hydrodynamic diameter (D av ) was in the range of 120-160 nm and a spherical morphology was observed by transmission electron microscopy (TEM). A sustained release of CUR was observed for 90 h. Cytotoxicity evaluation of CUR-loaded nanoaggregates on pancreatic cancer cell lines indicated higher efficacy, IC 50 ~11 and ~15 μM as compared to free CUR, IC 50 ~14 and ~20 μM on human pancreatic carcinoma (MIA PaCa-2) and human pancreatic duct epithelioid carcinoma (PANC-1) cell lines respectively. PC conjugates provided a new strategy of fabricating nanoparticles for drug delivery and may form the basis for the development of advanced biomaterials in near future.

Oral bioavailability assessment and intestinal lymphatic transport of Org 45697 and Org 46035, two highly lipophilic novel immunomodulator analogues.

PubMed

Caliph, Suzanne M; Faassen, W A Fried; Vogel, Gerard M; Porter, Christopher J H

2009-08-01

Org 45697 (MW 600.7, clogP 7.92, soybean oil solubility 50 mg/g) and Org 46035 (MW 601.6, clog P 8.46, soybean oil solubility 40 mg/g) are two poorly water soluble (<0.1 microg/ml), highly lipophilic drug candidates with immunomodulator activity and highly analogous chemical structures. After oral administration to conscious ambulatory rats in an aqueous-based methylcellulose/Tween 80 suspension, the bioavailability of both compounds was low (< 2% of administered dose). However, bioavailability was significantly increased (> 5 fold) after oral administration in a long chain triglyceride lipid (olive oil) formulation. Subsequent studies have explored the potential for solubilising formulations, including lipid-based formulations, to enhance the oral bioavailability of Org 45697 and Org 46035 and secondly to explore the potential contribution of intestinal lymphatic transport to intestinal absorption. The experimental data show that solubilising formulations may provide for significant increases in oral bioavailability for Org 45697 and Org 46035 and that after co-administration with lipid, 35-50% of the absorbed dose may be transported to the systemic circulation via the intestinal lymph. Interestingly, the lymphatic transport of the less lipid soluble analogue, Org 46035 was approximately 40% lower than that of Org 45697 suggesting that relatively subtle differences in lipid solubility can have significant impact on the extent of lymphatic transport.

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.

Enhanced Oral Bioavailability of Efavirenz by Solid Lipid Nanoparticles: In Vitro Drug Release and Pharmacokinetics Studies

PubMed Central

Gaur, Praveen Kumar; Mishra, Shikha; Bajpai, Meenakshi; Mishra, Anushika

2014-01-01

Solid lipid nanoparticle is an efficient lipid based drug delivery system which can enhance the bioavailability of poorly water soluble drugs. Efavirenz is a highly lipophilic drug from nonnucleoside inhibitor category for treatment of HIV. Present work illustrates development of an SLN formulation for Efavirenz with increased bioavailability. At first, suitable lipid component and surfactant were chosen. SLNs were prepared and analyzed for physical parameters, stability, and pharmacokinetic profile. Efavirenz loaded SLNs were formulated using Glyceryl monostearate as main lipid and Tween 80 as surfactant. ESLN-3 has shown mean particle size of 124.5 ± 3.2 nm with a PDI value of 0.234, negative zeta potential, and 86% drug entrapment. In vitro drug release study has shown 60.6–98.22% drug release in 24 h by various SLN formulations. Optimized SLNs have shown good stability at 40°C ± 2°C and 75 ± 5% relative humidity (RH) for 180 days. ESLN-3 exhibited 5.32-fold increase in peak plasma concentration (C max⁡) and 10.98-fold increase in AUC in comparison to Efavirenz suspension (ES). PMID:24967360

Gelucire44/14 as a novel absorption enhancer for drugs with different hydrophilicities: in vitro and in vivo improvement on transcorneal permeation.

PubMed

Liu, Rui; Liu, Zhidong; Zhang, Chengui; Zhang, Boli

2011-08-01

The objective of this study was to investigate the application of Gelucire44/14 as a novel absorption enhancer in ophthalmic drug delivery system. Six compounds, namely ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin in the order of increasing lipophilicity were selected as model drugs. The effect of Gelucire44/14 on transcorneal permeation was evaluated across excised rabbit cornea. Ocular irritation and precorneal retention time were assessed. Additionally, aqueous humor pharmacokinetic test was performed by microdialysis. The results indicated that Gelucire44/14, at a concentration of 0.05% or 0.1% (w/v), was found to maximally increase the apparent permeability coefficient by 6.47-, 4.14-, 3.50-, 3.97-, 2.92-, and 1.86-fold for ribavirin, puerarin, mangiferin, berberin hydrochloride, baicalin, and curcumin, respectively (p < 0.05). Moreover, Gelucire44/14 was nonirritant at broad concentrations of 0.025%-0.4% (w/v). Pharmacokinetic tests showed that Gelucire44/14 promoted ocular bioavailability of the compounds as indicated by 5.40-, 4.03-, 3.46-, 3.57-, 2.77-, and 1.77-fold maximal increase in the area under the curve for the drugs aforementioned, respectively (p < 0.01). Therefore, Gelucire44/14 exerted a significant improvement on the permeation of both hydrophilic and lipophilic compounds, especially hydrophilic ones. Hence, Gelucire44/14 can be considered as a safe and effective absorption enhancer for ophthalmic drug delivery system. Copyright © 2011 Wiley-Liss, Inc.

Short communication: Macrocyclic lactone residues in butter from Brazilian markets.

PubMed

Macedo, Fabio; Marsico, Eliane Teixeira; Conte-Júnior, Carlos Adam; de Almeida Furtado, Leonardo; Brasil, Taila Figueredo; Pereira Netto, Annibal Duarte

2015-06-01

Macrocyclic lactones (ML) are commonly used in drug formulations for the treatment of parasites in cattle. In Brazil, except for drugs (or formulations) with long-term (half-life) effects, ML are registered for use in bovines. Indiscriminate use of ML may result in the presence of residues in milk and dairy products due to their lipophilic properties and thermal stability. This study applied a method of liquid chromatography with fluorimetric detection, recently developed and validated for the determination of residues of abamectin, doramectin, ivermectin, and moxidectin in butter. The method was applied to 38 samples of commercial butter purchased in the metropolitan area of Rio de Janeiro, Brazil, between June and September 2013, analyzed in triplicate. Ivermectin was detected in 89.5% of the samples, with concentrations between 0.3 and 119.4 µg/kg; 76.3% of the samples contained doramectin (0.6 to 64.7 µg/kg) and 55.2% contained abamectin (0.7 to 4.5 µg/kg). Most butter samples (76.3%) contained residues of more than 1 ML; however, no residues of moxidectin were detected. The results showed a high incidence of the presence of avermectins in butter samples. Butter is not included in the Brazilian National Plan for Control of Residues and Contaminants in Animal Products. As ML residues concentrate in lipophilic compounds, butter and other fatty dairy products should be screened for the presence of ML residues. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Stable Co-crystals of Glipizide with Enhanced Dissolution Profiles: Preparation and Characterization.

PubMed

Pandey, Narendra Kumar; Sehal, Hans Raj; Garg, Varun; Gaur, Tejasvi; Kumar, Bimlesh; Singh, Sachin Kumar; Gulati, Monica; Gowthamarajan, K; Bawa, Palak; Rajesh, Sarvi Yadav; Sharma, Parth; Narang, Rakesh

2017-10-01

Present study deciphers preparation of co-crystals of lipophilic glipizide by using four different acids, oxalic, malonic, stearic, and benzoic acids, in order to achieve enhanced solubility and dissolution along with stability. All co-crystals were prepared by dissolving drug and individual acids in the ratio of 1:0.5 in acetonitrile at 60-70°C for 15 min, followed by cooling at room temperature for 24 h. FT-IR spectroscopy revealed no molecular interaction between acids and drug as the internal structure and their geometric configurations remain unchanged. Differential scanning calorimetry revealed closer melting points of raw glipizide and its co-crystals, which speculates absence of difference in crystallinity as well as intermolecular bonding of the co-crystals and drug. PXRD further revealed that all the co-crystals were having similar crystallinity as that of raw glipizide except glipizide-malonic acid co-crystals. This minor difference in the relative intensities of some of the diffraction peaks could be attributed to the crystal habit or crystal size modification. SEM revealed difference in the crystal morphology for all the co-crystals. Micromeritic, solubility, dissolution, and stability data revealed that among all the prepared co-crystals, glipizide-stearic acid co-crystals were found superior. Hence, it was concluded that glipizide-stearic acid co-crystals could offer an improved drug design strategy to overcome dissolution and bioavailability related challenges associated with lipophilic glipizide.

Central nervous system considerations in the use of beta-blockers, angiotensin-converting enzyme inhibitors, and thiazide diuretics in managing essential hypertension.

PubMed

Gengo, F M; Gabos, C

1988-07-01

The most common mild side effects occurring with use of beta-blockers, thiazide diuretics, and angiotensin-converting enzyme inhibitors for blood pressure control are central nervous system symptoms, specifically lethargy, sedation, and fatigue. These symptoms affect 5% to 10% of patients taking these drugs. The mechanism by which beta-blockers may induce central nervous system effects is uncertain. Relative lipophilicity as a factor affecting penetrance of the blood-brain barrier has not proved to be a reliable predictor of whether the drug will cause such disturbances. Comparisons of atenolol (hydrophilic) and metoprolol (lipophilic) have shown no differences between these drugs with respect to side effects of the central nervous system. The incidence of central nervous system effects with angiotensin-converting enzyme inhibitors is similar to that for most beta-blockers. The precise role of the angiotensin-converting enzyme in the central nervous system is not well defined. Most thiazide diuretics are not associated with major complications of the central nervous system, although electrolyte imbalance may occasionally lead to complaints of neurologic symptoms. Because the incidence of central nervous system effects with these three classes of drugs is so low, concern for the side effects of the central nervous system is not a prime consideration in the choice of an initial antihypertensive agent.

Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs.

PubMed

Miller, Jonathan M; Dahan, Arik; Gupta, Deepak; Varghese, Sheeba; Amidon, Gordon L

2009-07-01

The aim of this research was to gain a mechanistic understanding of ion-pair mediated membrane transport of low-permeability drugs. Quasi-equilibrium mass transport analyses were developed to describe the ion-pair mediated octanol-buffer partitioning and hydrophobic membrane permeation of the model basic drug phenformin. Three lipophilic counterions were employed: p-toluenesulfonic acid, 2-naphthalenesulfonic acid, and 1-hydroxy-2-naphthoic acid (HNAP). Association constants and intrinsic octanol-buffer partition coefficients (Log P(AB)) of the ion-pairs were obtained by fitting a transport model to double reciprocal plots of apparent octanol-buffer distribution coefficients versus counterion concentration. All three counterions enhanced the lipophilicity of phenformin, with HNAP providing the greatest increase in Log P(AB), 3.7 units over phenformin alone. HNAP also enhanced the apparent membrane permeability of phenformin, 27-fold in the PAMPA model, and 4.9-fold across Caco-2 cell monolayers. As predicted from a quasi-equilibrium analysis of ion-pair mediated membrane transport, an order of magnitude increase in phenformin flux was observed per log increase in counterion concentration, such that log-log plots of phenformin flux versus HNAP concentration gave linear relationships. These results provide increased understanding of the underlying mechanisms of ion-pair mediated membrane transport, emphasizing the potential of this approach to enable oral delivery of low-permeability drugs.

Interaction between DNA and Drugs Having Protonable Basic Groups: Characterization through Affinity Constants, Drug Release Kinetics, and Conformational Changes

PubMed Central

Alarcón, Liliana P.; Baena, Yolima; Manzo, Rubén H.

2017-01-01

This paper reports the in vitro characterization of the interaction between the phosphate groups of DNA and the protonated species of drugs with basic groups through the determination of the affinity constants, the reversibility of the interaction, and the effect on the secondary structure of the macromolecule. Affinity constants of the counterionic condensation DNA–drug were in the order of 106. The negative electrokinetic potential of DNA decreased with the increase of the proportion of loading drugs. The drugs were slowly released from the DNA–drug complexes and had release kinetics consistent with the high degree of counterionic condensation. The circular dichroism profile of DNA was not modified by complexation with atenolol, lidocaine, or timolol, but was significantly altered by the more lipophilic drugs benzydamine and propranolol, revealing modifications in the secondary structure of the DNA. The in vitro characterization of such interactions provides a physicochemical basis that would contribute to identify the effects of this kind of drugs in cellular cultures, as well as side effects observed under their clinical use. Moreover, this methodology could also be projected to the fields of intracellular DNA transfection and the use of DNA as a carrier of active drugs. PMID:28054999

Penetration studies of an extremely lipophilic active model substance from an oil-in-water emulsion: influence of the lipophilicity of the formulation in human skin - part 2.

PubMed

Naumann, S; Lange, S; Polak, G; Kalhoelfer, V; Motlagh, L; Goebel, A; Wohlrab, J; Neubert, R H H

2014-01-01

The effect of the lipophilicity of a carrier on human skin penetration of an extremely lipophilic active model substance was evaluated by using Franz type diffusion cells. Oil-in-water model emulsions containing different amounts of the oily phase were prepared, and Myritol® PC (M-PC) was selected as lipophilic marker component of the oily phase. The penetrated amounts of the lipophilic model substance salicyloyl phytosphingosine (SP) were determined by high-performance liquid chromatography with ultraviolet detection, while M-PC was detected using gas chromatography coupled with mass spectrometry. It has been ascertained that the amount of the lipid phase within the emulsion influenced the penetration profile of the active ingredient SP. The emulsion containing the lowest proportion of the lipid phase provides the best conditions for SP penetration. Surprisingly, the penetration behavior of M-PC was influenced by the oily phase in the same way. Regarding the M-PC and the SP penetration profiles from each emulsion, a solvent drag mechanism can be assumed whereby M-PC acts as penetration enhancer. In conclusion, the penetration rate of the active ingredient SP and the marker component M-PC are in reverse proportion to the oil content of the formulations. The lipophilicity of SP and M-PC, their solubility and their thermodynamic activity within the vehicle could have an effect on their penetration behavior. Additionally, M-PC has the property to enhance the penetration rates of extremely lipophilic substances even at low concentrations.

Discovery of a Potent Free Fatty Acid 1 Receptor Agonist with Low Lipophilicity, Low Polar Surface Area, and Robust in Vivo Efficacy.

PubMed

Hansen, Steffen V F; Christiansen, Elisabeth; Urban, Christian; Hudson, Brian D; Stocker, Claire J; Due-Hansen, Maria E; Wargent, Ed T; Shimpukade, Bharat; Almeida, Reinaldo; Ejsing, Christer S; Cawthorne, Michael A; Kassack, Matthias U; Milligan, Graeme; Ulven, Trond

2016-03-24

The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.

The cluster [Re6Se8I6]3- penetrates biological membranes: drug-like properties for CNS tumor treatment and diagnosis.

PubMed

Estrada, Lisbell D; Duran, Elizabeth; Cisterna, Matias; Echeverria, Cesar; Zheng, Zhiping; Borgna, Vincenzo; Arancibia-Miranda, Nicolas; Ramírez-Tagle, Rodrigo

2018-03-24

Tumorigenic cell lines are more susceptible to [Re 6 Se 8 I 6 ] 3- cluster-induced death than normal cells, becoming a novel candidate for cancer treatment. Still, the feasibility of using this type of molecules in human patients remains unclear and further pharmacokinetics analysis is needed. Using coupled plasma optical emission spectroscopy, we determined the Re-cluster tissue content in injected mice, as a biodistribution measurement. Our results show that the Re-cluster successfully reaches different tissues, accumulating mainly in heart and liver. In order to dissect the mechanism underlying cluster biodistribution, we used three different experimental approaches. First, we evaluate the degree of lipophilicity by determining the octanol/water partition coefficient. The cluster mostly remained in the octanol fraction, with a coefficient of 1.86 ± 0.02, which indicates it could potentially cross cell membranes. Then, we measured the biological membrane penetration through a parallel artificial membrane permeability assays (PAMPA) assay. The Re-cluster crosses the artificial membrane, with a coefficient of 122 nm/s that is considered highly permeable. To evaluate a potential application of the Re-cluster in central nervous system (CNS) tumors, we analyzed the cluster's brain penetration by exposing cultured blood-brain-barrier (BBB) cells to increasing concentrations of the cluster. The Re-cluster effectively penetrates the BBB, reaching nearly 30% of the brain side after 24 h. Thus, our results indicate that the Re-cluster penetrates biological membranes reaching different target organs-most probably due to its lipophilic properties-becoming a promising anti-cancer drug with high potential for CNS cancer's diagnosis and treatment.

Prospects of pharmaceuticals and biopharmaceuticals loaded microparticles prepared by double emulsion technique for controlled delivery

PubMed Central

Giri, Tapan Kumar; Choudhary, Chhatrapal; Ajazuddin; Alexander, Amit; Badwaik, Hemant; Tripathi, Dulal Krishna

2012-01-01

Several methods and techniques are potentially useful for the preparation of microparticles in the field of controlled drug delivery. The type and the size of the microparticles, the entrapment, release characteristics and stability of drug in microparticles in the formulations are dependent on the method used. One of the most common methods of preparing microparticles is the single emulsion technique. Poorly soluble, lipophilic drugs are successfully retained within the microparticles prepared by this method. However, the encapsulation of highly water soluble compounds including protein and peptides presents formidable challenges to the researchers. The successful encapsulation of such compounds requires high drug loading in the microparticles, prevention of protein and peptide degradation by the encapsulation method involved and predictable release, both rate and extent, of the drug compound from the microparticles. The above mentioned problems can be overcome by using the double emulsion technique, alternatively called as multiple emulsion technique. Aiming to achieve this various techniques have been examined to prepare stable formulations utilizing w/o/w, s/o/w, w/o/o, and s/o/o type double emulsion methods. This article reviews the current state of the art in double emulsion based technologies for the preparation of microparticles including the investigation of various classes of substances that are pharmaceutically and biopharmaceutically active. PMID:23960828

Update on antifungal therapy with terbinafine.

PubMed

Gianni, C

2010-06-01

Terbinafine, a synthetic antifungal of allylamine class, has fungicidal activity against dermatophytes, moulds and certain dimorphic fungi and fungistatic activity against Candida albicans. Following oral administration the terbinafine is absorbed rapidly (>70%) and reaches within 2 hours the peak plasma concentration. The drug is highly lipophilic and keratophilic and is highly bound to plasma protein (>90%) with a bioavailability of 70% to 80%. The drug is rapidly delivered and it is present in the stratum corneum, sebum, nails and hair for months after stopping the medication. The drug has been proven to be the choice treatment in the therapy of onychomycosis as it is very effective, well tolerated and has a relatively low potential for drug interactions. The pharmacologic and pharmacokinetic properties of terbinafine give strong support to the possibility that the pulse therapy may be equally effective in onychomycoses, possibly reducing medication costs and drug exposure. Several therapeutic patterns have been proposed: weekly intermittent terbinafine (500 mg/d for 1 week each month for 4 months), or single-dose terbinafine (1000 mg per month for 4 months). Use of topical terbinafine 1% may be practical where the tinea involvement is not extensive or chronic. Recently, the terbinafine is available in a novel topical solution (film-forming solution--FFS) effective in the treatment of tinea pedis (athlete's foot).

Fotemustine for the treatment of melanoma.

PubMed

Quéreux, Gaëlle; Dréno, Brigitte

2011-12-01

Melanoma is a rare but very aggressive form of cancer. Survival in melanoma varies widely depending on the stage of the tumor. In metastatic melanoma, prognosis is usually poor and the treatment is based on chemotherapy. So far, dacarbazine has been the drug of reference, with an average response rate of 15 - 20% when used as a monotherapy. As single drugs go, fotemustine is considered the second-best treatment, after dacarbazine. This review of the scientific literature focuses on the use of fotemustine in patients with cutaneous melanoma and discusses its clinical efficacy and safety. Fotemustine is a nitrosurea that has proved its efficacy in metastatic melanoma and particularly on cerebral metastases, given its high lipophilicity, facilitating its active penetration in all tissues including the central nervous system. However, overall response rates are low, with only few complete remissions and short response durations.

Location - Dependent Coronary Artery Diffusive and Convective Mass Transport Properties of a Lipophilic Drug Surrogate Measured Using Nonlinear Microscopy

PubMed Central

Keyes, Joseph T.; Simon, Bruce R.; Vande Geest, Jonathan P.

2013-01-01

Purpose Arterial wall mass transport properties dictate local distribution of biomolecules or locally delivered dugs. Knowing how these properties vary between coronary artery locations could provide insight into how therapy efficacy is altered between arterial locations. Methods We introduced an indocarbocyanine drug surrogate to the lumens of left anterior descending and right coronary (LADC; RC) arteries from pigs with or without a pressure gradient. Interstitial fluorescent intensity was measured on live samples with multiphoton microscopy. We also measured binding to porcine coronary SMCs in monoculture. Results Diffusive transport constants peaked in the middle sections of the LADC and RC arteries by 2.09 and 2.04 times, respectively, compared to the proximal and distal segments. There was no statistical difference between the average diffusivity value between LADC and RC arteries. The convection coefficients had an upward trend down each artery, with the RC being higher than the LADC by 3.89 times. Conclusions This study demonstrates that the convective and diffusive transport of lipophilic molecules changes between the LADC and the RC arteries as well as along their length. These results may have important implications in optimizing drug delivery for the treatment of coronary artery disease. PMID:23224981

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation.

PubMed

Sakai, Kenichi; Obata, Kouki; Yoshikawa, Mayumi; Takano, Ryusuke; Shibata, Masaki; Maeda, Hiroyuki; Mizutani, Akihiko; Terada, Katsuhide

2012-10-01

To design a high drug loading formulation of self-microemulsifying/micelle system. A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400). As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400 = 8:2 was selected, and achieved the target loading level (200 mg/mL). The formulation formed fine emulsion/micelle (49.1 nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation. The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.

Liposome-encapsulated vincristine, vinblastine and vinorelbine: a comparative study of drug loading and retention.

PubMed

Zhigaltsev, Igor V; Maurer, Norbert; Akhong, Quet-Fah; Leone, Robert; Leng, Esther; Wang, Jinfang; Semple, Sean C; Cullis, Pieter R

2005-05-05

A comparative study of the loading and retention properties of three structurally very closely related vinca alkaloids (vincristine, vinorelbine and vinblastine) in liposomal formulations has been performed. All three vinca alkaloids showed high levels of encapsulation when accumulated into egg sphingomyelin/cholesterol vesicles in response to a transmembrane pH gradient generated by the use of the ionophore A23187 and encapsulated MgSO4. However, despite the close similarities of their structures the different vinca drugs exhibited very different release behavior, with vinblastine and vinorelbine being released faster than vincristine both in vitro and in vivo. The differences in loading and retention can be related to the lipophilicity of the drugs tested, where the more hydrophobic drugs are released more rapidly. It was also found that increasing the drug-to-lipid ratio significantly enhanced the retention of vinca alkaloids when the ionophore-based method was used for drug loading. In contrast, drug retention was not dependent on the initial drug-to-lipid ratio for vinca drugs loaded into liposomes containing an acidic citrate buffer. The differences in retention can be explained on the basis of differences in the physical state of the drug inside the liposomes. The drug-to-lipid ratio dependence of retention observed for liposomes loaded with the ionophore technique may provide a way to improve the retention characteristics of liposomal formulations of vinca drugs.

Phenylpyrrolidine structural mimics of pirfenidone lacking antifibrotic activity: A new tool for mechanism of action studies.

PubMed

Haak, Andrew J; Girtman, Megan A; Ali, Mohamed F; Carmona, Eva M; Limper, Andrew H; Tschumperlin, Daniel J

2017-09-15

Pirfenidone recently received FDA approval as one of the first two drugs designed to treat idiopathic pulmonary fibrosis. While the clinical data continues to support the efficacy of pirfenidone, the specific molecular mechanism of action of this drug has not been fully defined. From a chemical perspective the comparatively simple and lipophilic structure of pirfenidone combined with its administration at high doses, both experimentally and clinically, complicates some of the basic tenants of drug action and drug design. Our objective here was to identify a commercially available structural mimic of pirfenidone which retains key aspects of its physical chemical properties but does not display any of its antifibrotic effects. We tested these molecules using lung fibroblasts derived from patients with idiopathic pulmonary fibrosis and found phenylpyrrolidine based analogs of pirfenidone that were non-toxic and lacked antifibrotic activity even when applied at millimolar concentrations. Based on our findings, these molecules represent pharmacological tools for future studies delineating pirfenidone's mechanism of action. Copyright © 2017 Elsevier B.V. All rights reserved.

Solid lipid nanoparticles for ocular drug delivery.

PubMed

Seyfoddin, Ali; Shaw, John; Al-Kassas, Raida

2010-01-01

Ocular drug delivery remains challenging because of the complex nature and structure of the eye. Conventional systems, such as eye drops and ointments, are inefficient, whereas systemic administration requires high doses resulting in significant toxicity. There is a need to develop novel drug delivery carriers capable of increasing ocular bioavailability and decreasing both local and systemic cytotoxicity. Nanotechnology is expected to revolutionize ocular drug delivery. Many nano-structured systems have been employed for ocular drug delivery and yielded some promising results. Solid lipid nanoparticles (SLNs) have been looked at as a potential drug carrier system since the 1990s. SLNs do not show biotoxicity as they are prepared from physiological lipids. SLNs are especially useful in ocular drug delivery as they can enhance the corneal absorption of drugs and improve the ocular bioavailability of both hydrophilic and lipophilic drugs. SLNs have another advantage of allowing autoclave sterilization, a necessary step towards formulation of ocular preparations. This review outlines in detail the various production, characterization, sterilization, and stabilization techniques for SLNs. In-vitro and in-vivo methods to study the drug release profile of SLNs have been explained. Special attention has been given to the nature of lipids and surfactants commonly used for SLN production. A summary of previous studies involving the use of SLNs in ocular drug delivery is provided, along with a critical evaluation of SLNs as a potential ocular delivery system.

Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents

PubMed Central

Suryadevara, Praveen Kumar; Racherla, Kishore Kumar; Olepu, Srinivas; Norcross, Neil R.; Tatipaka, Hari Babu; Arif, Jennifer A.; Planer, Joseph D.; Lepesheva, Galina; Verlinde, Christophe L. M. J.; Buckner, Frederick S.; Gelb, Michael H.

2014-01-01

New dialkylimidazole based sterol 14α-demethylase inhibitors were prepared and tested as potential anti-Trypanosoma cruzi agents. Previous studies had identified compound 2 as the most potent and selective inhibitor against parasite cultures. In addition, animal studies had demonstrated that compound 2 is highly efficacious in the acute model of the disease. However, compound 2 has a high molecular weight and high hydrophobicity, issues addressed here. Systematic modifications were carried out at four positions on the scaffold and several inhibitors were identified which are highly potent (EC50<1 nM) against T. cruzi in culture. The halogenated derivatives 36j, 36k, and 36p, display excellent activity against T.cruzi amastigotes, with reduced molecular weight and lipophilicity, and exhibit suitable physicochemical properties for an oral drug candidate. PMID:24120539

Fundamental properties of local anesthetics: half-maximal blocking concentrations for tonic block of Na+ and K+ channels in peripheral nerve.

PubMed

Bräu, M E; Vogel, W; Hempelmann, G

1998-10-01

Local anesthetics suppress excitability by interfering with ion channel function. Ensheathment of peripheral nerve fibers, however, impedes diffusion of drugs to the ion channels and may influence the evaluation of local anesthetic potencies. Investigating ion channels in excised membrane patches avoids these diffusion barriers. We investigated the effect of local anesthetics with voltage-dependent Na+ and K+ channels in enzymatically dissociated sciatic nerve fibers of Xenopus laevis using the patch clamp method. The outside-out configuration was chosen to apply drugs to the external face of the membrane. Local anesthetics reversibly blocked the transient Na+ inward current, as well as the steady-state K+ outward current. Half-maximal tonic inhibiting concentrations (IC50), as obtained from concentration-effect curves for Na+ current block were: tetracaine 0.7 microM, etidocaine 18 microM, bupivacaine 27 microM, procaine 60 microM, mepivacaine 149 microM, and lidocaine 204 microM. The values for voltage-dependent K+ current block were: bupivacaine 92 microM, etidocaine 176 microM, tetracaine 946 microM, lidocaine 1118 microM, mepivacaine 2305 microM, and procaine 6302 microM. Correlation of potencies with octanol:buffer partition coefficients (logP0) revealed that ester-bound local anesthetics were more potent in blocking Na+ channels than amide drugs. Within these groups, lipophilicity governed local anesthetic potency. We conclude that local anesthetic action on peripheral nerve ion channels is mediated via lipophilic drug-channel interactions. Half-maximal blocking concentrations of commonly used local anesthetics for Na+ and K+ channel block were determined on small membrane patches of peripheral nerve fibers. Because drugs can directly diffuse to the ion channel in this model, these data result from direct interactions of the drugs with ion channels.

Mechanism and kinetics of the loss of poorly soluble drugs from liposomal carriers studied by a novel flow field-flow fractionation-based drug release-/transfer-assay.

PubMed

Hinna, Askell Hvid; Hupfeld, Stefan; Kuntsche, Judith; Bauer-Brandl, Annette; Brandl, Martin

2016-06-28

Liposomes represent a versatile drug formulation approach e.g. for improving the water-solubility of poorly soluble drugs but also to achieve drug targeting and controlled release. For the latter applications it is essential that the drug remains associated with the liposomal carrier during transit in the vascular bed. A range of in vitro test methods has been suggested over the years for prediction of the release of drug from liposomal carriers. The majority of these fail to give a realistic prediction for poorly water-soluble drugs due to the intrinsic tendency of such compounds to remain associated with liposome bilayers even upon extensive dilution. Upon i.v. injection, in contrast, rapid drug loss often occurs due to drug transfer from the liposomal carriers to endogenous lipophilic sinks such as lipoproteins, plasma proteins or membranes of red blood cells and endothelial cells. Here we report on the application of a recently introduced in vitro predictive drug transfer assay based on incubation of the liposomal drug carrier with large multilamellar liposomes, the latter serving as a biomimetic model sink, using flow field-flow fractionation as a tool to separate the two types of liposomes. By quantifying the amount of drug remaining associated with the liposomal drug carrier as well as that transferred to the acceptor liposomes at distinct times of incubation, both the kinetics of drug transfer and release to the water phase could be established for the model drug p-THPP (5,10,15,20-tetrakis(4-hydroxyphenyl)21H,23H-porphine). p-THPP is structurally similar to temoporfin, a photosensitizer which is under clinical evaluation in a liposomal formulation. Mechanistic insights were gained by varying the donor-to-acceptor lipid mass ratio, size and lamellarity of the liposomes. Drug transfer kinetics from one liposome to another was found rate determining as compared to redistribution from the outermost to the inner concentric bilayers, such that the overall process could be adequately described by a single 1st order kinetic model. By varying the donor-to-acceptor lipid mass ratio in the range 1:1 to 1:10, a correlation was established between donor-to-acceptor-lipid mass ratio and transfer kinetics, which is regarded essential for scaling to physiological lipid mass ratios. By applying the assay to a series of structurally related model compounds of different bilayer affinity, transfer and release kinetics were established over the whole expected range of liposome bilayer associated drugs in terms of water solubility and lipophilicity. A very rapid transfer and considerable release from liposomes to the water phase was observed for the more water-soluble compounds Sudan II (clogP 5.45) and Sudan III (clogP 6.83). For the more lipophilic compounds, the rate of transfer from the donor liposomes followed the rank order Sudan IV (fastest)>Oil Red O>Sudan Black>p-THPP (slowest). For an equimolar donor-to-acceptor lipid mass ratio, half-lifes of transfer in the range of 12min (Sudan IV) up to 1.5h (p-THPP) were determined. In essence, the results presented here allow for both, mechanistic insights and predictions of drug loss from liposomal carriers upon exposure to biological sinks, which appear more realistic than the commonly employed in vitro release tests. Copyright © 2016 Elsevier B.V. All rights reserved.

Loading amorphous Asarone in mesoporous silica SBA-15 through supercritical carbon dioxide technology to enhance dissolution and bioavailability.

PubMed

Zhang, Zhengzan; Quan, Guilan; Wu, Qiaoli; Zhou, Chan; Li, Feng; Bai, Xuequn; Li, Ge; Pan, Xin; Wu, Chuanbin

2015-05-01

The aim of this study was to load amorphous hydrophobic drug into ordered mesoporous silica (SBA-15) by supercritical carbon dioxide technology in order to improve the dissolution and bioavailability of the drug. Asarone was selected as a model drug due to its lipophilic character and poor bioavailability. In vitro dissolution and in vivo bioavailability of the obtained Asarone-SBA-15 were significantly improved as compared to the micronized crystalline drug. This study offers an effective, safe, and environmentally benign means of solving the problems relating to the solubility and bioavailability of hydrophobic molecules. Copyright © 2015 Elsevier B.V. All rights reserved.

Structure/activity relationships for the enhancement by electron-affinic drugs of the anti-tumour effect of CCNU.

PubMed Central

Workman, P.; Twentyman, P. R.

1982-01-01

Using a regrowth-delay assay, we investigated structure/activity relationships for the enhancement by electron-affinic agents of the anti-tumour effect of the nitrosourea CCNU against the KHT sarcoma in C3H mice. A series of neutral 2-nitroimidazoles similar in electron affinity but varying in octanol/water partition coefficient (PC) over 4 orders of magnitude (0.016- greater than 200, Misonidazole = 0.43) were examined at a fixed dose of 2.5 mmol/kg. A parabolic (quadratic) dependence of activity on log PC was observed. Analogues more hydrophilic than misonidazole (MISO) were inactive as were those with very high PCs (greater than 20). Those with PC 0.43--20 were usually more active than MISO, some considerably so. The fairly lipophilic 5-nitroimidazoles nimorazole and metronidazole (METRO) had similar activity to MISO, despite their reduced electron affinity. Two basic 2-nitroimidazoles more efficient as radiosensitizers in vitro likewise showed activity comparable to MISO. We also investigated several agents more electron-affinic than MISO, including some non-nitro compounds. Most were inactive at maximum tolerated doses, but nitrofurazone showed reasonable activity. Sensitizer dose-response curves were obtained for MISO, METRO and two of the most effective agents, benznidazole (Ro 07-1051) and Ro 07-1902. The two latter agents were both considerably more active than MISO at low doses (0.1--0.9 mmol/kg). These studies indicate that the structural features of electron-affinic agents responsible for the enhancement of KHT tumour response to CCNU, are quite different from those affecting radiosensitization, lipophilicity being particularly important. The microsomal enzyme-inhibitor SKF 525A increased the anti-tumour effect of CCNU, suggesting inhibition of CCNU metabolism as one possible mechanism contributing to chemosensitization by lipophilic electron-affinic agents in mice. PMID:7150475

The Role of Intralipid Emulsion in the Rat Model of Digoxin Intoxication.

PubMed

Turan, Cansu Arslan; Ozturk, Tuba Cimilli; Akoglu, Ebru Unal; Ak, Rohat; Aygun, Kemal; Sahiner, Ali; Sumer, Engin; Somay, Adnan; Onur, Ozge Ecmel

2018-02-03

Although the mechanism of action is not well known, intravenous lipid emulsion (ILE) has been shown to be effective in the treatment of lipophilic drug intoxications. It is thought that, ILE probably separates the lipophilic drugs from target tissue by creating a lipid-rich compartment in the plasma. The second theory is that ILE provides energy to myocardium with high-dose free fatty acids activating the voltage-gated calcium channels in the myocytes. In this study, effects of ILE treatment on digoxin overdose were searched in an animal model in terms of cardiac side effects and survival. Forty Sprague-Dawley rats were divided into five groups. As the pre-treatment, the groups were administered saline, ILE, DigiFab and DigiFab and ILE. Following that, digoxin was infused to all groups until death except the control group. First arrhythmia and cardiac arrest observation times were recorded. According to the results, there was no statistically significant difference among the group in terms of first arrhythmia time and cardiac arrest times. However, when the saline group compared with ILE-treated group separately, significant difference was observed. DigiFab, ILE or ILE-DigiFab treatment make no significant difference in terms of the first arrhythmia and cardiac arrest duration in digoxin-intoxicated rats. However, it is not possible to say that at the given doses, ILE treatment might be successful at least as a known antidote. The fact that the statistical significance between the two groups is not observed in the subgroup analysis, the study should be repeated with larger groups.

NIR-labeled perfluoropolyether nanoemulsions for drug delivery and imaging

PubMed Central

O’Hanlon, Claire E.; Amede, Konjit G.; O’Hear, Meredith R.; Janjic, Jelena M.

2012-01-01

Theranostic nanoparticle development recently took center stage in the field of drug delivery nanoreagent design. Theranostic nanoparticles combine therapeutic delivery systems (liposomes, micelles, nanoemulsions, etc.) with imaging reagents (MRI, optical, PET, CT). This combination allows for non-invasive in vivo monitoring of therapeutic nanoparticles in diseased organs and tissues. Here, we report a novel perfluoropolyether (PFPE) nanoemulsion with a water-insoluble lipophilic drug. The formulation enables non-invasive monitoring of nanoemulsion biodistribution using two imaging modalities, 19F MRI and near-infrared (NIR) optical imaging. The nanoemulsion is composed of PFPE-tyramide as a 19F MRI tracer, hydrocarbon oil, surfactants, and a NIR dye. Preparation utilizes a combination of self-assembly and high energy emulsification methods, resulting in droplets with average diameter 180 nm and low polydispersity index (PDI less than 0.2). A model nonsteroidal anti-inflammatory drug (NSAID), celecoxib, was incorporated into the formulation at 0.2 mg/mL. The reported nanoemulsion’s properties, including small particle size, visibility under 19F NMR and NIR fluorescence spectroscopy, and the ability to carry drugs make it an attractive potential theranostic agent for cancer imaging and treatment. PMID:22675234

Lipid-drug-conjugate (LDC) solid lipid nanoparticles (SLN) for the delivery of nicotine to the oral cavity - optimization of nicotine loading efficiency.

PubMed

Ding, Yuan; Nielsen, Kent A; Nielsen, Bruno P; Bøje, Niels W; Müller, Rainer H; Pyo, Sung Min

2018-03-12

Nicotine, obtained from tobacco leaves, has been used to promote the cessation of smoking and reduce the risk of COPD and lung cancer. Incorporating the active in lipid nanoparticles is an effective tool to minimize its irritation potential and to use the particles as intermediate to produce final products. However, as a hydrophilic active, it is a challenge to prepare nicotine loaded lipid nanoparticles with high drug loading. In this study, lipid-drug-conjugates (LDC) were formed by nicotine and different fatty acids to enable the production of sufficiently loaded nicotine lipid nanoparticles. The encapsulation efficiency of nicotine in LDC-containing SLN was about 50%, which increased at least fourfold compared to the non-LDC formulations (around 10%) due to the increased lipophilicity of nicotine by strong interactions between positively charged nicotine and negatively charged fatty acids (formation of LDCs). The z-average of all formulations (150 to 350 nm) proved to be in the required submicron size range with a narrow size distribution. In summary, nicotine loaded LDC lipid nanoparticles with high drug loading were successfully developed with Kolliwax® S and stearic acid as counter-ion forming the LDC and hydrogenated sunflower oil (HSO) as lipid particle matrix. Copyright © 2018. Published by Elsevier B.V.

Poly(2-ethyl-2-oxazoline) as matrix excipient for drug formulation by hot melt extrusion and injection molding.

PubMed

Claeys, Bart; Vervaeck, Anouk; Vervaet, Chris; Remon, Jean Paul; Hoogenboom, Richard; De Geest, Bruno G

2012-10-15

Here we evaluate poly(2-ethyl-2-oxazoline)s (PEtOx) as a matrix excipient for the production of oral solid dosage forms by hot melt extrusion (HME) followed by injection molding (IM). Using metoprolol tartrate as a good water-soluble model drug we demonstrate that drug release can be delayed by HME/IM, with the release rate controlled by the molecular weight of the PEtOx. Using fenofibrate as a lipophilic model drug we demonstrate that relative to the pure drug the dissolution rate is strongly enhanced by formulation in HME/IM tablets. For both drug molecules we find that solid solutions, i.e. molecularly dissolved drug in a polymeric matrix, are obtained by HME/IM. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations

PubMed Central

DeMarco, Kevin R.; Bekker, Slava; Clancy, Colleen E.; Noskov, Sergei Y.; Vorobyov, Igor

2018-01-01

Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology, and identifies some of the challenges that lie therein. PMID:29449809

Kv11.1 (hERG)-induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv11.1 (hERG) inhibitors

PubMed Central

Yu, Z; IJzerman, A P; Heitman, L H

2015-01-01

Background and Purpose Drug-induced arrhythmia due to blockade of the Kv11.1 channel (also known as the hERG K+ channel) is a frequent side effect. Previous studies have primarily focused on equilibrium parameters, i.e. affinity or potency, of drug candidates at the channel. The aim of this study was to determine the kinetics of the interaction with the channel for a number of known Kv11.1 blockers and to explore a possible correlation with the affinity or physicochemical properties of these compounds. Experimental Approach The affinity and kinetic parameters of 15 prototypical Kv11.1 inhibitors were evaluated in a number of [3H]-dofetilide binding assays. The lipophilicity (logKW-C8) and membrane partitioning (logKW-IAM) of these compounds were determined by means of HPLC analysis. Key Results A novel [3H]-dofetilide competition association assay was set up and validated, which allowed us to determine the binding kinetics of the Kv11.1 blockers used in this study. Interestingly, the compounds' affinities (Ki values) were correlated to their association rates rather than dissociation rates. Overall lipophilicity or membrane partitioning of the compounds were not correlated to their affinity or rate constants for the channel. Conclusions and Implications A compound's affinity for the Kv11.1 channel is determined by its rate of association with the channel, while overall lipophilicity and membrane affinity are not. In more general terms, our findings provide novel insights into the mechanism of action for a compound's activity at the Kv11.1 channel. This may help to elucidate how Kv11.1-induced cardiotoxicity is governed and how it can be circumvented in the future. PMID:25296617

Endermatic, epidermatic, enepidermatic-the early history of penetration enhancers.

PubMed

Helmstädter, Axel

2011-09-15

Already at the end of the 18th century, attempts were made to administer drugs transdermally. Several techniques were applied, including rubbing drug substances into the intact or wounded skin. Penetration enhancers were investigated as well, including human and animal body fluids, in particular gastric juice and saliva. In the 19th century, lipophilic solubilizers like chloroform and ether were tried. Although the experiments were mostly done against a pre-rational background some may be worth to be judged under scientific premises. Copyright © 2011 Elsevier B.V. All rights reserved.

Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics.

PubMed

Remenar, Julius F

2014-06-02

There are now long-acting versions of six antipsychotic drugs on the U.S. market, and with them, five unique combinations of molecular form and delivery strategy long-acting-injectable-antipsychotics (LAIAs) show evidence of reduced relapses of schizophrenia, but their introduction has been slow, taking at least nine years after the approval of each oral drug. Oily solutions of lipophilic prodrugs were the first to enter the LAIA market, but they relied on esterification of a hydroxyl handle that was lost with the emergence of the atypical antipsychotics. A review of the literature and patents shows that companies tested many different approaches before reaching the currently marketed versions, including aqueous suspensions of poorly soluble salts, polymeric microspheres, and new approaches to making prodrugs. Yet, very little has been published to support faster development of safe long-acting injectables (LAIs). This review introduces some of the critical considerations in creating an LAI; then it analyzes the existing products and discusses areas where further research is needed. The available literature suggests that lipophilic prodrugs may be inherently safer than poorly soluble salts as LAIs. Other areas needing additional study include (1) the range of physical properties acceptable for LAIs and the effect of prodrug tail length in achieving them, and (2) the role of physiological responses at the injection site in the release of drug from a depot.

Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting.

PubMed

Palmer, Brian C; DeLouise, Lisa A

2016-12-15

Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

Nanoparticle enabled transdermal drug delivery systems for enhanced dose control and tissue targeting

PubMed Central

Palmer, Brian C.; DeLouise, Lisa A.

2017-01-01

Transdermal drug delivery systems have been around for decades, and current technologies (e.g. patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases. PMID:27983701

Molecular design for enhancement of ocular penetration.

PubMed

Shirasaki, Yoshihisa

2008-07-01

Over the past two decades, many oral drugs have been designed in consideration of physicochemical properties to attain optimal pharmacokinetic properties. This strategy significantly reduced attrition in drug development owing to inadequate pharmacokinetics during the last decade. On the other hand, most ophthalmic drugs are generated from reformulation of other therapeutic dosage forms. Therefore, the modification of formulations has been used mainly as the approach to improve ocular pharmacokinetics. However, to maximize ocular pharmacokinetic properties, a specific molecular design for ocular drug is preferable. Passive diffusion of drugs across the cornea membranes requires appropriate lipophilicity and aqueous solubility. Improvement of such physicochemical properties has been achieved by structure optimization or prodrug approaches. This review discusses the current knowledge about ophthalmic drugs adapted from systemic drugs and molecular design for ocular drugs. I propose the approaches for molecular design to obtain the optimal ocular penetration into anterior segment based on published studies to date.

Novel Gold(I) Thiolate Derivatives Synergistic with 5-Fluorouracil as Potential Selective Anticancer Agents in Colon Cancer.

PubMed

Atrián-Blasco, Elena; Gascón, Sonia; Rodrı Guez-Yoldi, Ma Jesus; Laguna, Mariano; Cerrada, Elena

2017-07-17

New gold(I) thiolate complexes have been synthesized and characterized, and their physicochemical properties and anticancer activity have been tested. The coordination of PTA derivatives provides optimal hydrophilicity/lipophilicity properties to the complexes, which present high solution stability. Moreover, the complexes show a high anticancer activity against Caco-2 cells, comparable to that of auranofin, and a very low cytotoxic activity against enterocyte-like differentiated cells. Their activity has been shown to produce cell death by apoptosis and arrest of the cell cycle because of interaction with the reductase enzymes and consequent reactive oxygen species production. Some of these new complexes are also able to decrease the necessary dose of 5-fluorouracil, a drug used for the treatment of colon cancer, by a synergistic mechanism.

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

Stachel, Shawn J.; Sanders, John M.; Henze, Darrell A.

We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstratedmore » efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.« less

Liposome-Based Nanomedicine Therapeutics for Rheumatoid Arthritis.

PubMed

Rahman, Mahfoozur; Beg, Sarwar; Anwar, Firoz; Kumar, Vikas; Ubale, Ruhi; Addo, Richard T; Ali, Raisuddin; Akhter, Sohail

2017-01-01

Rheumatoid arthritis (RA) is a very painful severe autoimmune disease with complex pathology characterized by progressive chronic inflammation, and devastation of the synovium, cartilage, and other joint-associated structures. Significant advances in research in the area of pathophysiology, diagnosis, drug development, and targeted delivery have led to improved RA therapy and better patient compliance. Targeted drug delivery using liposomal nanomedicines significantly alleviate the challenges with conventional anti-RA medications such as off-target effects, short biological half-life, poor bioavailability, high dose-related toxicity, etc. Liposomal nanomedicines in RA drug targeting offer the opportunity for passive targeting [based on size and polyethylene glycol (PEG)-ylation-mediated enhanced permeability and retention] and active targeting (ligation with antibody or peptides, etc.) and encapsulation of lipophilic, hydrophilic drugs, and/or combinational drugs. However, it has been found recently that such injectable nanomedicines raise the concern of an adverse immune phenomenon called complement activationrelated pseudo allergy (CARPA) and failure of therapy on multiple doses due to accelerated body clearance caused many by anti-PEG immunoglobulin M. To ensure safety and efficacy of RA therapy, these need to be considered along with the common formulation quality parameters. Here, we discuss nanotherapeutic targeting in RA therapy using liposomes. Liposomal nanoparticles are investigated for individual anti-RA drug categories. CARPA issues and pathophysiology with such nanomedicines are also discussed in detail.

Behavior of platinum(iv) complexes in models of tumor hypoxia: cytotoxicity, compound distribution and accumulation.

PubMed

Schreiber-Brynzak, Ekaterina; Pichler, Verena; Heffeter, Petra; Hanson, Buck; Theiner, Sarah; Lichtscheidl-Schultz, Irene; Kornauth, Christoph; Bamonti, Luca; Dhery, Vineet; Groza, Diana; Berry, David; Berger, Walter; Galanski, Markus; Jakupec, Michael A; Keppler, Bernhard K

2016-04-01

Hypoxia in solid tumors remains a challenge for conventional cancer therapeutics. As a source for resistance, metastasis development and drug bioprocessing, it influences treatment results and disease outcome. Bioreductive platinum(iv) prodrugs might be advantageous over conventional metal-based therapeutics, as biotransformation in a reductive milieu, such as under hypoxia, is required for drug activation. This study deals with a two-step screening of experimental platinum(iv) prodrugs with different rates of reduction and lipophilicity with the aim of identifying the most appropriate compounds for further investigations. In the first step, the cytotoxicity of all compounds was compared in hypoxic multicellular spheroids and monolayer culture using a set of cancer cell lines with different sensitivities to platinum(ii) compounds. Secondly, two selected compounds were tested in hypoxic xenografts in SCID mouse models in comparison to satraplatin, and, additionally, (LA)-ICP-MS-based accumulation and distribution studies were performed for these compounds in hypoxic spheroids and xenografts. Our findings suggest that, while cellular uptake and cytotoxicity strongly correlate with lipophilicity, cytotoxicity under hypoxia compared to non-hypoxic conditions and antitumor activity of platinum(iv) prodrugs are dependent on their rate of reduction.

Practical concept of pharmacokinetics/pharmacodynamics in the management of skin and soft tissue infections.

PubMed

Pea, Federico

2016-04-01

This article gives an overview of the practical concept of pharmacokinetic/pharmacodynamic principles useful for clinicians in the management of skin and soft tissue infections (SSTIs). Recent studies suggest that distinguishing between bacteriostatic or bactericidal activity when choosing an antimicrobial for the treatment of severe infections could probably be clinically irrelevant. Conversely, what could help clinicians in maximizing the therapeutic efficacy of the various drugs in routine practice is taking care of some pharmacokinetic/pharmacodynamic principles. Concentration-dependent agents may exhibit more rapid bacterial killing than observed with time-dependent agents. Serum concentrations may not always adequately predict tissue exposure in patients with SSTIs, and measuring concentrations at the infection site is preferable. Hydrophilic antimicrobials showed generally lower penetration rates than the lipophilic ones and might require alternative dosing approaches in the presence of severe sepsis or septic shock. Conversely, tissue penetration of lipophilic antimicrobials is often unaffected by the pathophysiological status. Real-time therapeutic drug monitoring may be a very helpful tool for optimizing therapy of severe infections. Taking care of pharmacokinetic/pharmacodynamic principles deriving from the most recent findings may help clinicians in maximizing treatment of SSTIs with antimicrobials in every situation.

Ultrasound-triggered drug delivery using acoustic droplet vaporization

NASA Astrophysics Data System (ADS)

Fabiilli, Mario Leonardo

The goal of targeted drug delivery is the spatial and temporal localization of a therapeutic agent and its associated bioeffects. One method of drug localization is acoustic droplet vaporization (ADV), whereby drug-laden perfluorocarbon (PFC) emulsions are vaporized into gas bubbles using ultrasound, thereby releasing drug locally. Transpulmonary droplets are converted into bubbles that occlude capillaries, sequestering the released drug within an organ or tumor. This research investigates the relationship between the ADV and inertial cavitation (IC) thresholds---relevant for drug delivery due to the bioffects generated by IC---and explores the delivery of lipophilic and hydrophilic compounds using PFC double emulsions. IC can positively and negatively affect ultrasound mediated drug delivery. The ADV and IC thresholds were determined for various bulk fluid, droplet, and acoustic parameters. At 3.5 MHz, the ADV threshold occurred at a lower rarefactional pressure than the IC threshold. The results suggest that ADV is a distinct phenomenon from IC, the ADV nucleus is internal to the droplet, and the IC nucleus is the bubble generated by ADV. The ADV triggered release of a lipophilic chemotherapeutic agent, chlorambucil (CHL), from a PFC-in-oil-in-water emulsion was explored using plated cells. Cells exposed to a CHL-loaded emulsion, without ADV, displayed 44% less growth inhibition than cells exposed to an equal concentration of CHL in solution. Upon ADV of the CHL-loaded emulsion, the growth inhibition increased to the same level as cells exposed to CHL in solution. A triblock copolymer was synthesized which enabled the formulation of stable water-in-PFC-in-water (W1/PFC/W2) emulsions. The encapsulation of fluorescein in the W1 phase significantly decreased the mass flux of fluorescein; ADV was shown to completely release the fluorescein from the emulsions. ADV was also shown to release thrombin, dissolved in the W1 phase, which could be used in vivo to extend synergistically the duration of ADV-generated, microbubble-based embolizations. Overall, the results suggest that PFC double emulsions can be used as an ultrasound-triggered drug delivery system. Compared to traditional drug delivery systems, ADV could be used to increase the therapeutic efficacy and decrease the systemic toxicity of drug therapy.

Layer-by-layer assembled thin films and microcapsules of nanocrystalline cellulose for hydrophobic drug delivery.

PubMed

Mohanta, Vaishakhi; Madras, Giridhar; Patil, Satish

2014-11-26

A layer-by-layer (LbL) approach has been employed for the fabrication of multilayer thin films and microcapsules having nanofibrous morphology using nanocrystalline cellulose (NCC) as one of the components of the assembly. The applicability of these nanoassemblies as drug delivery carriers has been explored by the loading of an anticancer drug, doxorubicin hydrochloride, and a water-insoluble drug, curcumin. Doxorubicin hydrochloride, having a good water solubility, is postloaded in the assembly. In the case of curcumin, which is very hydrophobic and has limited solubility in water, a stable dispersion is prepared via noncovalent interaction with NCC prior to incorporation in the LbL assembly. The interaction of various other lipophilic drugs with NCC was analyzed theoretically by molecular docking in consideration of NCC as a general carrier for hydrophobic drugs.

Dialkylimidazole inhibitors of Trypanosoma cruzi sterol 14α-demethylase as anti-Chagas disease agents.

PubMed

Suryadevara, Praveen Kumar; Racherla, Kishore Kumar; Olepu, Srinivas; Norcross, Neil R; Tatipaka, Hari Babu; Arif, Jennifer A; Planer, Joseph D; Lepesheva, Galina I; Verlinde, Christophe L M J; Buckner, Frederick S; Gelb, Michael H

2013-12-01

New dialkylimidazole based sterol 14α-demethylase inhibitors were prepared and tested as potential anti-Trypanosoma cruzi agents. Previous studies had identified compound 2 as the most potent and selective inhibitor against parasite cultures. In addition, animal studies had demonstrated that compound 2 is highly efficacious in the acute model of the disease. However, compound 2 has a high molecular weight and high hydrophobicity, issues addressed here. Systematic modifications were carried out at four positions on the scaffold and several inhibitors were identified which are highly potent (EC50 <1 nM) against T. cruzi in culture. The halogenated derivatives 36j, 36k, and 36p, display excellent activity against T. cruzi amastigotes, with reduced molecular weight and lipophilicity, and exhibit suitable physicochemical properties for an oral drug candidate. Copyright © 2013 Elsevier Ltd. All rights reserved.

2-Oxoamide inhibitors of cytosolic group IVA phospholipase A2 with reduced lipophilicity.

PubMed

Antonopoulou, Georgia; Magrioti, Victoria; Kokotou, Maroula G; Nikolaou, Aikaterini; Barbayianni, Efrosini; Mouchlis, Varnavas D; Dennis, Edward A; Kokotos, George

2016-10-01

Cytosolic GIVA phospholipase A2 (GIVA cPLA2) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA2 inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA2. Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lipophilization and MS characterization of the main anthocyanins purified from hibiscus flowers.

PubMed

Grajeda-Iglesias, Claudia; Salas, Erika; Barouh, Nathalie; Baréa, Bruno; Figueroa-Espinoza, Maria Cruz

2017-09-01

Hibiscus sabdariffa flowers represent an interesting source of anthocyanins, one of the most important plant pigments, which are responsible of the intense red color of the calyces, and have potential as natural colorants for food applications. Nevertheless, anthocyanins are highly hydrosoluble and unstable compounds. On this basis, the aim of this work was to increase the lipophilicity of the hibiscus anthocyanins by lipophilization, in order to obtain amphiphilic colorants, which could be easily incorporated in lipid-rich food matrices. Octanoyl derivatives of delphinidin-3-O-sambubioside and cyanidin-3-O-sambubioside were chemically obtained for the first time, and characterized by means of HPLC-ESI-MS data. Copyright © 2017. Published by Elsevier Ltd.

Self-assembled albumin nanoparticles as a nanocarrier for aclacinomycin A

NASA Astrophysics Data System (ADS)

Gong, Guangming; Liu, Wenya; Wang, Shudong

2016-11-01

This study aimed to reduce the cytotoxicity and improve the targeting of aclacinomycin (ACM) by covalently coupling it with amino-oxyacetic acid (AOA) to generate an active intermediate, AOA-ACM. AOA-ACM was conjugated with self-assembled human serum albumin (HSA) nanoparticles constructed using tris(2-carboxyethyl)phosphine (TCEP) as disulfide bond breaking molecules in an ‘opening stage-intermediate-closing stage’ route, in which the hydrophobic interaction, interchange of sulfhydryl and hydrogen bond may be the key factors in the assembling process. Conjugation between ACM and albumin nanoparticles was found to occur at an ACM ketone site using 1H-NMR and 13C-NMR matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass analysis indicated that the drug loading efficiency of ACM conjugated with HSA nanoparticles (NPs-ACM) was 7.4% (molar ratio = 6:1). The release of NPs-ACM was pH dependent. In vivo studies indicated that NPs-ACM exhibited fourfold higher tumor targeting capability on S180-tumor-bearing mice compared with the free ACM (p < 0.05). The cytotoxictiy and cardiotoxicity of NPs-ACM was reduced compared with the free ACM. Albumin carrier altered the blood pharmacokinetics and distribution of ACM. Hence, the NPs-ACM prodrug is ideal tumor targeting drug carriers for ACM, and the easy approach developed in this study for active intermediate and prodrug preparation can be applied to other pharmacological substances containing ketone groups. The method of preparing HSA-blank nanoparticles through TCEP reduction could be adopted to improve the water solubility of lipophilic drugs and their tumor-targeting specificity by fabricating HSA-lipophilic drug nanoparticles.

Integrating a novel SN38 prodrug into the PEGylated liposomal system as a robust platform for efficient cancer therapy in solid tumors.

PubMed

Fang, Tao; Dong, Yuehan; Zhang, Xiaomin; Xie, Ke; Lin, Li; Wang, Hangxiang

2016-10-15

Liposomal nanoassemblies have been used extensively as carriers for the delivery of both lipophilic and hydrophilic drugs. They represent a mature, versatile technology with considerable potential for improving the pharmacokinetics of drugs. However, the formulation of many chemotherapeutics into liposome systems has posed a significant challenge due to their incompatible physicochemical properties, as was the case with camptothecin-based chemotherapeutics. Here, we present a rational paradigm of potent chemotherapeutics that were reconstructed and subsequently integrated into liposomal nanoassemblies. Using SN38 (7-ethyl-10-hydroxy camptothecin) as a model drug, a lipophilic prodrug 1 (designated as LA-SN38) was constructed by tethering the linoleic acid (LA) moiety via esterification, which was further facilitated to form liposomal nanoparticles (LipoNP) through supramolecular nanoassembly. The resulting 1-loaded LipoNP exhibited sustained drug release kinetics and decreased cellular uptake by macrophage cells. Uptake by tumor cells was enhanced relative to our previous supramolecular nanoparticles (SNP 1), which were derived from the self-assembling prodrug 1. Notably, LipoNP outperformed SNP 1 in terms of pharmacokinetics and in vivo therapeutic efficacy in both human BEL-7402 hepatocellular carcinoma (HCC) and HCT-116 colorectal cancer-derived xenograft mouse models. These results were likely due to the improved systemic circulation and preferential accumulation of nanodrugs in tumors. Hence, our results suggest that the combination of liposomal delivery platforms with rational prodrug engineering may emerge as a promising approach for the effective and safe delivery of anticancer chemotherapeutics. Copyright © 2016 Elsevier B.V. All rights reserved.

Distribution of Animal Drugs between Skim Milk and Milk Fat Fractions in Spiked Whole Milk: Understanding the Potential Impact on Commercial Milk Products.

PubMed

Hakk, Heldur; Shappell, Nancy W; Lupton, Sara J; Shelver, Weilin L; Fanaselle, Wendy; Oryang, David; Yeung, Chi Yuen; Hoelzer, Karin; Ma, Yinqing; Gaalswyk, Dennis; Pouillot, Régis; Van Doren, Jane M

2016-01-13

Seven animal drugs [penicillin G (PENG), sulfadimethoxine (SDMX), oxytetracycline (OTET), erythromycin (ERY), ketoprofen (KETO), thiabendazole (THIA), and ivermectin (IVR)] were used to evaluate the drug distribution between milk fat and skim milk fractions of cow milk. More than 90% of the radioactivity was distributed into the skim milk fraction for ERY, KETO, OTET, PENG, and SDMX, approximately 80% for THIA, and 13% for IVR. The distribution of drug between milk fat and skim milk fractions was significantly correlated to the drug's lipophilicity (partition coefficient, log P, or distribution coefficient, log D, which includes ionization). Data were fit with linear mixed effects models; the best fit was obtained within this data set with log D versus observed drug distribution ratios. These candidate empirical models serve for assisting to predict the distribution and concentration of these drugs in a variety of milk and milk products.

Radiopharmaceuticals for imaging the heart

DOEpatents

Green, Mark A.; Tsang, Brenda W.

1994-01-01

Radiopharmaceuticals for imaging myocardial tissues are prepared by forming lipophilic, cationic complexes of radioactive metal ions with metal chelating ligands comprising the Schiff base adducts of triamines and tetraamines with optionally substituted salicylaldehydes. The lipophilic, cationic, radioactive complexes of the invention exhibit high uptake and retention in myocardial tissues. Preferred gallium-68(III) complexes in accordance with this invention can be used to image the heart using positron emission tomography.

Alamethicin for using in bioavailability studies? - Re-evaluation of its effect.

PubMed

Vollmer, Maren; Klingebiel, Mirko; Rohn, Sascha; Maul, Ronald

2017-03-01

A major pathway for the elimination of drugs is the biliary and renal excretion following the formation of more hydrophilic secondary metabolites such as glucuronides. For in vitro investigations of the phase II metabolism, hepatic microsomes are commonly used in the combination with the pore-forming peptide alamethicin, also to give estimates for the in vivo situation. Thus, alamethicin may represent a neglected parameter in the characterization of microsomal in vitro assays. In the present study, the influence of varying alamethicin concentrations on glucuronide formation of selected phenolic compounds was investigated systematically. A correlation between the alamethicin impact and the lipophilicity of the investigated substrates was analyzed as well. Lipophilicity was determined by the logarithm of the octanol-water partition coefficient. For every substrate, a distinct alamethicin concentration could be detected leading to a maximal glucuronidation activity. Further increase of the alamethicin application led to negative effects. The differences between the maximum depletion rates with and without alamethicin addition varied between 2.7% and 18.2% depending on the substrate. A dependence on the lipophilicity could not be confirmed. Calculation of the apparent intrinsic clearance led to a more than 2-fold increase using the most effective alamethicin concentration compared to the alamethicin free control. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mono- and Dinuclear Phosphorescent Rhenium(I) Complexes: Impact of Subcellular Localization on Anticancer Mechanisms.

PubMed

Ye, Rui-Rong; Tan, Cai-Ping; Chen, Mu-He; Hao, Liang; Ji, Liang-Nian; Mao, Zong-Wan

2016-06-01

Elucidation of relationship among chemical structure, cellular uptake, localization, and biological activity of anticancer metal complexes is important for the understanding of their mechanisms of action. Organometallic rhenium(I) tricarbonyl compounds have emerged as potential multifunctional anticancer drug candidates that can integrate therapeutic and imaging capabilities in a single molecule. Herein, two mononuclear phosphorescent rhenium(I) complexes (Re1 and Re2), along with their corresponding dinuclear complexes (Re3 and Re4), were designed and synthesized as potent anticancer agents. The subcellular accumulation of Re1-Re4 was conveniently analyzed by confocal microscopy in situ in live cells by utilizing their intrinsic phosphorescence. We found that increased lipophilicity of the bidentate ligands could enhance their cellular uptake, leading to improved anticancer efficacy. The dinuclear complexes were more potent than the mononuclear counterparts. The molecular anticancer mechanisms of action evoked by Re3 and Re4 were explored in detail. Re3 with a lower lipophilicity localizes to lysosomes and induces caspase-independent apoptosis, whereas Re4 with higher lipophilicity specially accumulates in mitochondria and induces caspase-independent paraptosis in cancer cells. Our study demonstrates that subcellular localization is crucial for the anticancer mechanisms of these phosphorescent rhenium(I) complexes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure-activity relationships of rationally designed AMACR 1A inhibitors.

PubMed

Yevglevskis, Maksims; Lee, Guat L; Nathubhai, Amit; Petrova, Yoana D; James, Tony D; Threadgill, Michael D; Woodman, Timothy J; Lloyd, Matthew D

2018-04-30

α-Methylacyl-CoA racemase (AMACR; P504S) is a promising novel drug target for prostate and other cancers. Assaying enzyme activity is difficult due to the reversibility of the 'racemisation' reaction and the difficulties in the separation of epimeric products; consequently few inhibitors have been described and no structure-activity relationship study has been performed. This paper describes the first structure-activity relationship study, in which a series of 23 known and potential rational AMACR inhibitors were evaluated. AMACR was potently inhibited (IC 50  = 400-750 nM) by ibuprofenoyl-CoA and derivatives. Potency was positively correlated with inhibitor lipophilicity. AMACR was also inhibited by straight-chain and branched-chain acyl-CoA esters, with potency positively correlating with inhibitor lipophilicity. 2-Methyldecanoyl-CoAs were ca. 3-fold more potent inhibitors than decanoyl-CoA, demonstrating the importance of the 2-methyl group for effective inhibition. Elimination substrates and compounds with modified acyl-CoA cores were also investigated, and shown to be potent inhibitors. These results are the first to demonstrate structure-activity relationships of rational AMACR inhibitors and that potency can be predicted by acyl-CoA lipophilicity. The study also demonstrates the utility of the colorimetric assay for thorough inhibitor characterisation. Copyright © 2018 Elsevier Inc. All rights reserved.

Safer staining method for acid fast bacilli.

PubMed Central

Ellis, R C; Zabrowarny, L A

1993-01-01

To develop a method for staining acid fast bacilli which excluded highly toxic phenol from the staining solution. A lipophilic agent, a liquid organic detergent, LOC High Studs, distributed by Amway, was substituted. The acid fast bacilli stained red; nuclei, cytoplasm, and cytoplasmic elements stained blue on a clear background. These results compare very favourably with acid fast bacilli stained by the traditional method. Detergents are efficient lipophilic agents and safer to handle than phenol. The method described here stains acid fast bacilli as efficiently as traditional carbol fuchsin methods. LOC High Suds is considerably cheaper than phenol. Images PMID:7687254

Safer staining method for acid fast bacilli.

PubMed

Ellis, R C; Zabrowarny, L A

1993-06-01

To develop a method for staining acid fast bacilli which excluded highly toxic phenol from the staining solution. A lipophilic agent, a liquid organic detergent, LOC High Studs, distributed by Amway, was substituted. The acid fast bacilli stained red; nuclei, cytoplasm, and cytoplasmic elements stained blue on a clear background. These results compare very favourably with acid fast bacilli stained by the traditional method. Detergents are efficient lipophilic agents and safer to handle than phenol. The method described here stains acid fast bacilli as efficiently as traditional carbol fuchsin methods. LOC High Suds is considerably cheaper than phenol.

Dermal and transdermal delivery of pharmaceutically relevant macromolecules.

PubMed

Münch, S; Wohlrab, J; Neubert, R H H

2017-10-01

The skin offers an attractive way for dermal and transdermal drug delivery that is why the drug still needs certain qualities to transcend the outermost layer of the skin, the stratum corneum. The requirements are: drugs with a maximum molecular weight of 1kDa, high lipophilicity and a certain polarity. This would restrict the use of a transdermal delivery of macromolecules, which would make the drug more effective in therapeutic administration. Various studies have shown that macromolecules without support do not penetrate the human skin. This effect can be achieved using physical and chemical methods, as well as biological peptides. The most popular physical method is the use of microneedles to create micropores in the skin and release the active agent in different sections. But also, other methods have been tested. Microjets, lasers, electroporation, sonophoresis and iontophoresis are also promising methods to successfully deliver dermal and transdermal macromolecules. Additionally, there are different penetration enhancer groups and biological peptides, which are also considered to be interesting approaches of enabling macromolecules to travel along the skin. All these methods will be described and evaluated in this review article. Copyright © 2017 Elsevier B.V. All rights reserved.

A new SOD mimic, Mn(III) ortho N-butoxyethylpyridylporphyrin combines superb potency and lipophilicity with low toxicity

PubMed Central

Rajic, Zrinka; Tovmasyan, Artak; Spasojevic, Ivan; Sheng, Huaxin; Lu, Miaomiao; Li, Alice M.; Gralla, Edith B.; Warner, David S.; Benov, Ludmil; Batinic-Haberle, Ines

2012-01-01

The Mn porphyrins of kcat(O2˙−) as high as that of a superoxide dismutase enzyme, and of optimized lipophilicity have already been synthesized. Their exceptional in vivo potency is at least in part due to their ability to mimic site and location of mitochondrial superoxide dismutase, MnSOD. MnTnHex-2-PyP5+ is the most studied among lipophilic Mn porphyrins. It is of remarkable efficacy in animal models of oxidative stress injuries and particularly in central nervous system diseases. However, when used at high single and multiple doses it becomes toxic. The toxicity of MnTnHex-2-PyP5+ has been in part attributed to its micellar properties, i.e. the presence of polar cationic nitrogens and hydrophobic alkyl chains. The replacement of a CH2 group by oxygen atom in each of the four alkyl chains was meant to disrupt the porphyrin micellar character. When such modification occurs at the end of long alkyl chains, the oxygens become heavily solvated, which leads to a significant drop in the lipophilicity of porphyrin. However, when the oxygen atoms are buried deeper within the long heptyl chains, their excessive solvation is precluded and the lipophilicity preserved. The presence of oxygens and the high lipophilicity bestow the exceptional chemical and physical properties to Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP5+. The high SOD-like activity is fully preserved and somewhat enhanced: log kcat(O2˙−) = 7.83 vs 7.48 and 7.65 for MnTnHex-2-PyP5+ and MnTnHep-2-PyP5+, respectively. MnTnBuOE-2-PyP5+ was tested in an O2˙− - specific in vivo assay – aerobic growth of SOD-deficient yeast, Saccharomyces cerevisiae, where it was fully protective in the range of 5 – 30 µM. MnTnHep-2-PyP5+ was already toxic at 5 µM, and MnTnHex-2-PyP5+ became toxic at 30 µM. In a mouse toxicity study, MnTnBuOE-2-PyP5+ was several-fold less toxic than either MnTnHex-2-PyP5+ or MnTnHep-2-PyP5+. PMID:22336516

Solutions as solutions--synthesis and use of a liquid polyester excipient to dissolve lipophilic drugs and formulate sustained-release parenterals.

PubMed

Asmus, Lutz R; Gurny, Robert; Möller, Michael

2011-11-01

Solid poly(lactides) and poly(lactide-co-glycolides) are widely used polymers for sustained-release parenterals. However, they have some unfavorable properties regarding manufacturing of the formulations and administration to the patient due to their solid aggregate state. In contrast, hexyl-substituted poly(lactic acid) (hexPLA, poly(2-hydroxyoctanoic acid)) is a viscous degradable polyester. To date, a two-step ring-opening polymerization was used for its synthesis. Here, we investigated a novel one-pot one-step melt polycondensation method to prepare hexPLA for biomedical applications by a simple green chemistry process. No catalyst or solely pharmaceutically acceptable catalysts and environmentally friendly purification methods without organic solvents were used. The resulting hexPLA polymers are stable under dry heat sterilization conditions. Low molecular weight hexPLAs with less than 5000 g/mol are less viscous than high molecular weight polymers. HexPLA can dissolve lipophilic active substances, with generally high incorporation capacities in low molecular weight polymers. The incorporation of solid compounds increases the viscosity and glass transition temperature, whereas the addition of small amounts of plasticizers or sparse warming significantly decreases the viscosity. Loratadine is soluble in hexPLA up to 28%. This highly concentrated Loratadine-hexPLA formulation released the active compound entirely over 14 days without initial burst in a zero order kinetic, matching the clinical requirements for such a sustained-release formulation. This demonstrates the potential of hexPLA as an excipient for injectable sustained-release formulations. Copyright © 2011 Elsevier B.V. All rights reserved.

Nitroimidazoles, Quinolones and Oxazolidinones as Fluorine Bearing Antitubercular Clinical Candidates.

PubMed

Patel, Rahul V; Keum, Young-Soo; Park, Se Won

2015-01-01

Tuberculosis is a leading killer of lives worldwide and the global curse of multi-drug resistant tuberculosis is attaining really dangerous levels. Synergistic interaction of HIV and TB is the twin epidemics in resource-limited countries as each potentiate progression of the other. The increasing emergence of MDR-TB and XDR-TB place an immense burden for the treatment of TB with currently available drugs. The situation urgently demands for the discovery of new drugs with novel mode of action and differs in structural features in order to overcome resistance appears in conventional TB therapeutics. The present report covers the discovery of three classes of antituberculosis drugs, Nitroimidazoles, Quinolones and Oxazolidinones, undergoing clinical development with fluorine atom in their structures. Highly electronegative fluorine atom plays a signature role in advancing medicinal innovations as it existence in the drug compounds critically influences metabolic stability and lipophilicity thereby delaying its elimination by the body which results into a long term in vivo efficiency of the drug. Presence of fluorine atom(s) in the drug structures described in this report, has been associated with the several fold increase in the overall potency of the compound as demonstrated since the early discoveries. 6 Fluorinated derivatives from these three classes as pretomanid, delamanid, moxifloxacin, gatifloxacin, linezolid and sutezolid have been discussed with their antituberculosis effects, mode of action, chemical synthetic routes and results of clinical studies.

[Studies on development of pharmaceutical preparation with the purpose of improving controlled-release and bioavailability].

PubMed

Goto, S

1995-11-01

During the past fifteen years, the experiments based on three main propositions were proceeded to carry out in our laboratory, that is, (1) Microencapsulation: The method of solvent evaporation in water or oily phases was adopted because of its comparative simplicity in the procedure and its high reproducibility. The application of pharmacokinetic consideration to in vivo evaluation of microencapsulated drugs using beagle dogs intended for obtaining controlled-release by oral administration. The pullulan acetate phthalate microcapsules containing cefadroxil were prepared by the solvent evaporation method in liquid paraffin and showed a zero-order dissolution pattern in pH 6-7.4. (2) Rectal gel preparation: The hydrogels and xerogels were prepared by Eudispert hv. These gels have excellent staying properties in the lower part of the rectum, over a fairly long period. Eudispert hv hydrogels or xerogels containing propentfylline were tested for avoidance of the first-pass metabolism. The absolute bioavailability of propentofylline from gel preparations was almost 100%. (3) Binary vehicle for transdermal delivery: The effects of glycerides, short-chain alcohols and their binary vehicles as donor components on the skin permeation of ketoprofen across the excised hairless mouse skin were evaluated with the diffusion cell. Among single vehicles, Panasate 800 as lipophilic vehicle and ethanol as hydrophilic vehicle showed the effective permeation flux of ketoprofen. The greatest enhancement was observed in an ethanol/Panasate 800 (40/60) binary vehicle. The relationship between lipophilicity and skin permeability of 16 drugs from the ethanol/Panasate 800 (40/60) binary vehicle showed a parabolic shape with a peak at a more hydrophilic range compared with other past references.

Potential Side Effect of Inadvertent Intravascular Administration of Liposomal Bupivacaine

DTIC Science & Technology

2017-06-01

treat and is potentially fatal. LAST can impair function of the central nervous system and cause cardiovascular collapse, with potentially...in the reversal of cardiovascular and central nervous system symptoms of local anesthetic and other lipophilic drug overdoses. ILE is gaining...to the sites of toxic action in the central nervous system and the heart. However, liposomal formulations of local anesthetics (EXPAREL in

Physicochemical and Pharmacological Characterization of Permanently Charged Opioids.

PubMed

Mazak, Karoly; Noszal, Bela; Hosztafi, Sandor

2017-01-01

The main aim of synthesizing permanently charged opioids is to ensure that they do not enter the central nervous system. Such drugs can provide analgesic activity with reduced sedation and other side effects on the central nervous system. We undertook a search of bibliographic databases for peer-reviewed research literature and also summarized our published results in this field. The present review focuses on the characterization of permanently charged opioids by various physicochemical methods, and in vitro as well as in vivo tests. The basicity and lipophilicity of opioid alkaloids are discussed at the microscopic, speciesspecific level. Glucuronide conjugates of opioids are also reviewed. Whereas the primary metabolite morphine-3-glucuronide does not bind to opioid receptors with high affinity, morphine-6-glucuronide is a potent analgesic, at least, partly due to its unexpectedly high lipophilicity. We discuss the quaternary ammonium opioid derivatives of a permanent positive charge, detailing their antinociceptive activity and effects on gastrointestinal motility in various in vivo animal tests and in vitro studies. Compounds with antagonistic activity are also reviewed. The last part of our study concentrates on sulfate conjugates of morphine derivatives that display unique pharmacological properties because they carry a negative charge at any pH value in the human body. In conclusion, the findings of this review confirm the importance of permanently charged opioids in the investigated fields of pharmacology. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Synthesis and structure-activity relationships for extended side chain analogues of the antitubercular drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824).

PubMed

Palmer, Brian D; Sutherland, Hamish S; Blaser, Adrian; Kmentova, Iveta; Franzblau, Scott G; Wan, Baojie; Wang, Yuehong; Ma, Zhenkun; Denny, William A; Thompson, Andrew M

2015-04-09

Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.

Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy Greyhound dogs

PubMed Central

KuKanich, Butch; Allen, Philip

2014-01-01

The purpose of this study was to compare the pharmacokinetics of two highly protein bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy Greyhound dogs (3 males and 3 females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL/min/kg) was faster than buprenorphine (10.3 mL/min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including: octanol:water partition coefficient and pKa the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. PMID:24684621

Radiopharmaceuticals for imaging the heart

DOEpatents

Green, M.A.; Tsang, B.W.

1994-06-28

Radiopharmaceuticals for imaging myocardial tissues are prepared by forming lipophilic, cationic complexes of radioactive metal ions with metal chelating ligands comprising the Schiff base adducts of triamines and tetraamines with optionally substituted salicylaldehydes. The lipophilic, cationic, radioactive complexes of the invention exhibit high uptake and retention in myocardial tissues. Preferred gallium-68(III) complexes in accordance with this invention can be used to image the heart using positron emission tomography. 6 figures.

The multiple roles of computational chemistry in fragment-based drug design

NASA Astrophysics Data System (ADS)

Law, Richard; Barker, Oliver; Barker, John J.; Hesterkamp, Thomas; Godemann, Robert; Andersen, Ole; Fryatt, Tara; Courtney, Steve; Hallett, Dave; Whittaker, Mark

2009-08-01

Fragment-based drug discovery (FBDD) represents a change in strategy from the screening of molecules with higher molecular weights and physical properties more akin to fully drug-like compounds, to the screening of smaller, less complex molecules. This is because it has been recognised that fragment hit molecules can be efficiently grown and optimised into leads, particularly after the binding mode to the target protein has been first determined by 3D structural elucidation, e.g. by NMR or X-ray crystallography. Several studies have shown that medicinal chemistry optimisation of an already drug-like hit or lead compound can result in a final compound with too high molecular weight and lipophilicity. The evolution of a lower molecular weight fragment hit therefore represents an attractive alternative approach to optimisation as it allows better control of compound properties. Computational chemistry can play an important role both prior to a fragment screen, in producing a target focussed fragment library, and post-screening in the evolution of a drug-like molecule from a fragment hit, both with and without the available fragment-target co-complex structure. We will review many of the current developments in the area and illustrate with some recent examples from successful FBDD discovery projects that we have conducted.

Non steady-state descriptions of drug permeation through stratum corneum. I. The biphasic brick-and-mortar model.

PubMed

Heisig, M; Lieckfeldt, R; Wittum, G; Mazurkevich, G; Lee, G

1996-03-01

The diffusion equation should be solved for the non-steady-state problem of drug diffusion within a two-dimensional, biphasic stratum corneum membrane having homogeneous lipid and corneocyte phases. A numerical method was developed for a brick-and-mortar SC-geometry, enabling an explicit solution for time-dependent drug concentration within both phases. The lag time and permeability were calculated. It is shown how the barrier property of this model membrane depends on relative phase permeability, corneocyte alignment, and corneocyte-lipid partition coefficient. Additionally, the time-dependent drug concentration profiles within the membrane can be observed during the lag and steady-state phases. The model SC-membrane predicts, from purely morphological principles, lag times and permeabilities that are in good agreement with experimental values. The long lag times and very small permeabilities reported for human SC can only be predicted for a highly-staggered corneocyte geometry and corneocytes that are 1000 times less permeable than the lipid phase. Although the former conclusion is reasonable, the latter is questionable. The elongated, flattened corneocyte shape renders lag time and permeability insensitive to large changes in their alignment within the SC. Corneocyte/lipid partitioning is found to be fundamentally different to SC/donor partitioning, since increasing drug lipophilicity always reduces both lag time and permeability.

Solid lipid nanoparticles as insulin inhalation carriers for enhanced pulmonary delivery.

PubMed

Bi, Ru; Shao, Wei; Wang, Qun; Zhang, Na

2009-02-01

Growing attentions have been paid to the pulmonary route for systemic delivery of peptide and protein drugs, such as insulin. Advantages of this non-injective route include rapid drug deposition in the target organ, fewer systemic side effects and avoiding first pass metabolism. However, sustained release formulations for pulmonary delivery have not been fully exploited till now. In our study, a novel dry powder inhalation (DPI) system of insulin loaded solid lipid nanoparticles (Ins-SLNs) was investigated for prolonged drug release, improved stability and effective inhalation. Firstly, the drug was incorporated into the lipid carriers for a maximum entrapment efficiency as high as 69.47 +/- 3.27% (n = 3). Secondly, DPI formulation was prepared by spray freeze drying of Ins-SLNs suspension, with optimized lyoprotectant and technique parameters in this procedure. The properties of DPI particles were characterized for their pulmonary delivery potency. Thirdly, the in vivo study of intratracheal instillation of Ins-SLNs to diabetic rats showed prolonged hypoglycemic effect and a relative pharmacological bioavailability of 44.40% could be achieved in the group of 8 IU/kg dosage. These results indicated that SLNs have shown increasing potential as an efficient and non-toxic lipophilic colloidal drug carrier for enhanced pulmonary delivery of insulin.

Predicting Error Bars for QSAR Models

NASA Astrophysics Data System (ADS)

Schroeter, Timon; Schwaighofer, Anton; Mika, Sebastian; Ter Laak, Antonius; Suelzle, Detlev; Ganzer, Ursula; Heinrich, Nikolaus; Müller, Klaus-Robert

2007-09-01

Unfavorable physicochemical properties often cause drug failures. It is therefore important to take lipophilicity and water solubility into account early on in lead discovery. This study presents log D7 models built using Gaussian Process regression, Support Vector Machines, decision trees and ridge regression algorithms based on 14556 drug discovery compounds of Bayer Schering Pharma. A blind test was conducted using 7013 new measurements from the last months. We also present independent evaluations using public data. Apart from accuracy, we discuss the quality of error bars that can be computed by Gaussian Process models, and ensemble and distance based techniques for the other modelling approaches.

The acid/base profile of agrochemicals.

PubMed

Manallack, D T

2017-08-01

Drug-likeness has long been studied in the pursuit of finding new medicines. Similarly, in the agrochemical field there is value in exploring the properties of the chemicals involved. Patterns that emerge can potentially influence future discovery campaigns to improve the probability of commercial success. In this study we investigate the acid/base properties and physicochemical characteristics of three classes of compounds: fungicides, herbicides and insecticides. In comparison with FDA-approved drugs, it was noted that the pesticides were generally smaller, possessed a neutral charge state and were more lipophilic. The results are discussed in the light of their intended targets.

Removal of methadone by extended dialysis using a high cut-off dialyzer: implications for the treatment of overdose and for pain management in patients undergoing light chain removal.

PubMed

Arelin, Viktor; Schmidt, Julius J; Kayser, Nathalie; Kühn-Velten, W Nikolaus; Suhling, Hendrik; Eden, Gabriele; Kielstein, Jan T

2016-06-01

The synthetic opioid methadone hydrochloride has a low molecular weight of 346 D, a high volume of distribution (4 - 7 L/kg), and is lipophilic. It is used as an analgesic and for the maintenance treatment of opiate dependence. In drug addicts, methadone is frequently involved in mixed intoxications that can lead to death. Here we present the case of a drug addict in whom a high cut-off dialysis membrane together with extended dialysis was used in the setting of suspected overdose and acute kidney injury. Although the observed dialyzer plasma clearance (31.5 mL/min) and reduction ratio (38%) were higher than previously reported for standard hemodialysis, the total amount of methadone in the spent dialysate after 1 extended dialysis session was quite low. Hence, even extended dialysis with a high cut-off membrane does not seem to offer a clinically relevant benefit in the setting of overdose for enhanced methadone removal. On the other hand, in patients undergoing high cut-off dialysis for the removal of light chains, methadone could still be used as an analgesic without an additional dose after high cut-off hemodialysis.

Modulation of drug release from nanocarriers loaded with a poorly water soluble drug (flurbiprofen) comprising natural waxes.

PubMed

Baviskar, D T; Amritkar, A S; Chaudhari, H S; Jain, D K

2012-08-01

In this study, flurbiprofen (FLB) Solid Lipid Nanoparticles (SLN) composed from a mixture of beeswax and carnauba wax, Tween 80 and egg lecithin as emulsifiers have been prepared. FLB was incorporated as model lipophilic drug to assess the influence of matrix composition in the drug release profile. SLN were produced by microemulsion technique. In vitro studies were performed in Phosphate Buffered Saline (PBS). The FLB loaded SLN showed a mean particle size of 75 +/- 4 nm, a polydispersity index approximately 0.2 +/- 0.02 and an entrapment efficiency (EE) of more than 95%. Suspensions were stable, with zeta potential values in the range of -15 to -17 mV. DSC thermograms and UV analysis indicated the stability of nanoparticles with negligible drug leakage. Nanoparticles with higher beeswax content in their core exhibited faster drug release than those containing more carnauba wax.

Novel strategies for the formulation and processing of poorly water-soluble drugs.

PubMed

Göke, Katrin; Lorenz, Thomas; Repanas, Alexandros; Schneider, Frederic; Steiner, Denise; Baumann, Knut; Bunjes, Heike; Dietzel, Andreas; Finke, Jan H; Glasmacher, Birgit; Kwade, Arno

2018-05-01

Low aqueous solubility of active pharmaceutical ingredients presents a serious challenge in the development process of new drug products. This article provides an overview on some of the current approaches for the formulation of poorly water-soluble drugs with a special focus on strategies pursued at the Center of Pharmaceutical Engineering of the TU Braunschweig. These comprise formulation in lipid-based colloidal drug delivery systems and experimental as well as computational approaches towards the efficient identification of the most suitable carrier systems. For less lipophilic substances the preparation of drug nanoparticles by milling and precipitation is investigated for instance by means of microsystem-based manufacturing techniques and with special regard to the preparation of individualized dosage forms. Another option to overcome issues with poor drug solubility is the incorporation into nanospun fibers. Copyright © 2017 Elsevier B.V. All rights reserved.

Solid lipid microparticles containing loratadine prepared using a Micromixer.

PubMed

Milak, Spomenka; Medlicott, Natalie; Tucker, Ian G

2006-12-01

Solid lipid microparticles were investigated as a taste-masking approach for a lipophilic weak base in a suspension. The idea was that the drug concentration in the aqueous phase of a suspension might be reduced by its partitioning into the solid lipid particles. Loratadine, as a model drug, was used to prepare Precirol ATO 5 microparticles by a Micromixer. The effects of three process variables: drug loading, PVA concentration and water/lipid ratio on the microparticle size, encapsulation efficiency, surface appearance, in-vitro release and drug partitioning in a suspension were studied. Loratadine release was slow in simulated saliva and very fast at the pH of stomach. In suspension of loratadine lipid microparticles, drug was released into the aqueous phase to the same concentration as in a drug suspension. Therefore, the usefulness of these microparticles for taste-masking in liquids is limited. However, they might be useful for taste-masking in solid dosage forms.

Medicinal Chemical Properties of Successful Central Nervous System Drugs

PubMed Central

Pajouhesh, Hassan; Lenz, George R.

2005-01-01

Summary: Fundamental physiochemical features of CNS drugs are related to their ability to penetrate the blood-brain barrier affinity and exhibit CNS activity. Factors relevant to the success of CNS drugs are reviewed. CNS drugs show values of molecular weight, lipophilicity, and hydrogen bond donor and acceptor that in general have a smaller range than general therapeutics. Pharmacokinetic properties can be manipulated by the medicinal chemist to a significant extent. The solubility, permeability, metabolic stability, protein binding, and human ether-ago-go-related gene inhibition of CNS compounds need to be optimized simultaneously with potency, selectivity, and other biological parameters. The balance between optimizing the physiochemical and pharmacokinetic properties to make the best compromises in properties is critical for designing new drugs likely to penetrate the blood brain barrier and affect relevant biological systems. This review is intended as a guide to designing CNS therapeutic agents with better drug-like properties. PMID:16489364

Biodistribution of biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging.

PubMed

Asem, Heba; Zhao, Ying; Ye, Fei; Barrefelt, Åsa; Abedi-Valugerdi, Manuchehr; El-Sayed, Ramy; El-Serafi, Ibrahim; Abu-Salah, Khalid M; Hamm, Jörg; Muhammed, Mamoun; Hassan, Moustapha

2016-12-19

Multifunctional nanocarriers for controlled drug delivery, imaging of disease development and follow-up of treatment efficacy are promising novel tools for disease diagnosis and treatment. In the current investigation, we present a multifunctional theranostic nanocarrier system for anticancer drug delivery and molecular imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) as an MRI contrast agent and busulphan as a model for lipophilic antineoplastic drugs were encapsulated into poly (ethylene glycol)-co-poly (caprolactone) (PEG-PCL) micelles via the emulsion-evaporation method, and PEG-PCL was labelled with VivoTag 680XL fluorochrome for in vivo fluorescence imaging. Busulphan entrapment efficiency was 83% while the drug release showed a sustained pattern over 10 h. SPION loaded-PEG-PCL micelles showed contrast enhancement in T 2 *-weighted MRI with high r 2 * relaxivity. In vitro cellular uptake of PEG-PCL micelles labeled with fluorescein in J774A cells was found to be time-dependent. The maximum uptake was observed after 24 h of incubation. The biodistribution of PEG-PCL micelles functionalized with VivoTag 680XL was investigated in Balb/c mice over 48 h using in vivo fluorescence imaging. The results of real-time live imaging were then confirmed by ex vivo organ imaging and histological examination. Generally, PEG-PCL micelles were highly distributed into the lungs during the first 4 h post intravenous administration, then redistributed and accumulated in liver and spleen until 48 h post administration. No pathological impairment was found in the major organs studied. Thus, with loaded contrast agent and conjugated fluorochrome, PEG-PCL micelles as biodegradable and biocompatible nanocarriers are efficient multimodal imaging agents, offering high drug loading capacity, and sustained drug release. These might offer high treatment efficacy and real-time tracking of the drug delivery system in vivo, which is crucial for designing of an efficient drug delivery system.

A testing strategy to predict risk for drug-induced liver injury in humans using high-content screen assays and the 'rule-of-two' model.

PubMed

Chen, Minjun; Tung, Chun-Wei; Shi, Qiang; Guo, Lei; Shi, Leming; Fang, Hong; Borlak, Jürgen; Tong, Weida

2014-07-01

Drug-induced liver injury (DILI) is a major cause of drug failures in both the preclinical and clinical phase. Consequently, improving prediction of DILI at an early stage of drug discovery will reduce the potential failures in the subsequent drug development program. In this regard, high-content screening (HCS) assays are considered as a promising strategy for the study of DILI; however, the predictive performance of HCS assays is frequently insufficient. In the present study, a new testing strategy was developed to improve DILI prediction by employing in vitro assays that was combined with the RO2 model (i.e., 'rule-of-two' defined by daily dose ≥100 mg/day & logP ≥3). The RO2 model was derived from the observation that high daily doses and lipophilicity of an oral medication were associated with significant DILI risk in humans. In the developed testing strategy, the RO2 model was used for the rational selection of candidates for HCS assays, and only the negatives predicted by the RO2 model were further investigated by HCS. Subsequently, the effects of drug treatment on cell loss, nuclear size, DNA damage/fragmentation, apoptosis, lysosomal mass, mitochondrial membrane potential, and steatosis were studied in cultures of primary rat hepatocytes. Using a set of 70 drugs with clear evidence of clinically relevant DILI, the testing strategy improved the accuracies by 10 % and reduced the number of drugs requiring experimental assessment by approximately 20 %, as compared to the HCS assay alone. Moreover, the testing strategy was further validated by including published data (Cosgrove et al. in Toxicol Appl Pharmacol 237:317-330, 2009) on drug-cytokine-induced hepatotoxicity, which improved the accuracies by 7 %. Taken collectively, the proposed testing strategy can significantly improve the prediction of in vitro assays for detecting DILI liability in an early drug discovery phase.

PAMAM dendrimer hydrogel film—biocompatible material to an efficient dermal delivery of drugs

NASA Astrophysics Data System (ADS)

Magalhães, Thamiris Machado; Guerra, Rodrigo Cinti; San Gil, Rosane Aguiar da Silva; Valente, Ana Paula; Simão, Renata Antoun; Soares, Bluma Guenther; Mendes, Thamara de Carvalho; Pyrrho, Alexandre dos Santos; Sousa, Valeria Pereira de; Rodrigues-Furtado, Vanessa Lúcia

2017-08-01

We report the preparation, characterization, and drug release kinetics of a pH-responsive hydrogel film from a dendrimer megamer. The megamer (GP32) is a three-dimensional reticulated structure with a mean diameter of 71.16 nm (PDI 0.150) and was prepared by the reaction between Poly(amidoamine) generation4 (PAMAM G4) dendrimer and glutaraldehyde (G:P molar ratio 32). The crosslinking units in the megamer are provided mainly by the bicyclic dimer 2-hydroxy-3,4,4a,7,8,8a-hexahydro-2 H-chromene-6-carbaldehyde as determined by high-resolution (800 MHz) 1H NMR and FTIR. The hydrogel film (F[GP32]) is formed upon evaporation of a methanolic solution of the megamer and has a high degree of organization and homogeneity. Further crosslinking with glutaraldehyde (CLF[GP32]) enhanced the mechanical properties of the hydrogel film. The chemical constitution and unique megamer architecture enable the hydrogel film to carry both lipophilic and hydrophilic substances. The film did not cause any dermal irritation or clinical signs of toxicity in tests on rabbits, allowed for a sustained release of ketoprofen and played an important role in the process of drug delivery into the receptor medium. This performance taken together with the absence of toxicity makes this hydrogel film a good choice for dermal sustained drug release. [Figure not available: see fulltext.

Fully glutathione degradable waterborne polyurethane nanocarriers: Preparation, redox-sensitivity, and triggered intracellular drug release.

PubMed

Omrani, Ismail; Babanejad, Niloofar; Shendi, Hasan Kashef; Nabid, Mohammad Reza

2017-01-01

Polyurethanes are important class of biomaterials that are extensively used in medical devices. In spite of their easy synthesis, polyurethanes that are fully degradable in response to the intracellular reducing environment are less explored for controlled drug delivery. Herein, a novel glutathione degradable waterborne polyurethane (WPU) nanocarrier for redox triggered intracellular delivery of a model lipophilic anticancer drug, doxorubicin (DOX) is reported. The WPU was prepared from polyaddition reaction of isophorone diisocyanate (IPDI) and a novel linear polyester polyol involving disulfide linkage, disulfide labeled chain extender, dimethylolpropionic acid (DMPA) using dibutyltin dilaurate (DBTDL) as a catalyst. The resulting polyurethane self-assembles into nanocarrier in water. The dynamic light scattering (DLS) measurements and scanning electron microscope (SEM) revealed fast swelling and disruption of nanocarriers under an intracellular reduction-mimicking environment. The in vitro release studies showed that DOX was released in a controlled and redox-dependent manner. MTT assays showed that DOX-loaded WPU had a high in vitro antitumor activity in both HDF noncancer cells and MCF- 7 cancer cells. In addition, it is found that the blank WPU nanocarriers are nontoxic to HDF and MCF-7 cells even at a high concentration of 2mg/mL. Hence, nanocarriers based on disulfide labeled WPU have appeared as a new class of biocompatible and redox-degradable nanovehicle for efficient intracellular drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Formulation Studies of InhA inhibitors and Combination therapy to improve efficacy against Mycobacterium tuberculosis

PubMed Central

Knudson, Susan E.; Cummings, Jason E.; Bommineni, Gopal R.; Pan, Pan; Tonge, Peter J.; Slayden, Richard A.

2016-01-01

Summary Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery. Lead diphenyl ethers were formulated in co-solvent and Self-Dispersing Lipid Formulations (SDLFs) and evaluated in a rapid murine Mtb infection model that assesses dissemination to and bacterial burden in the spleen. In vitro synergy studies were performed with the lead diphenyl ether compounds, SB-PT070 and SB-PT091, and rifampin (RIF), which demonstrated an additive effect, and that guided the in vivo studies. Combinatorial therapy in vivo studies with these compounds delivered in our Self-Micro Emulsifying Drug Delivery System (SMEDDS) resulted in an additional 1.4 log10 CFU reduction in the spleen of animals co-treated with SB-PT091 and RIF and an additional 1.7 log10 reduction in the spleen with animals treated with both SB-PT070 and RIF. PMID:27865404

Assessment of the chromatographic lipophilicity of eight cephalosporins on different stationary phases.

PubMed

Dąbrowska, Monika; Starek, Małgorzata; Komsta, Łukasz; Szafrański, Przemysław; Stasiewicz-Urban, Anna; Opoka, Włodzimierz

2017-04-01

The retention behaviors were investigated for a series of eight cephalosporins in thin-layer chromatography (TLC) using stationary phases of RP-2, RP-8, RP-18, NH 2 , DIOL, and CN chemically bonded silica gel. Additionally, various binary mobile phases (water/methanol and water/acetone) were used in different volume proportions. The retention behavior of the analyzed molecules was defined by R M0 constant. In addition, reversed phase high performance liquid chromatography (RP-HPLC) was performed in lipophilicity studies by using immobilized artificial membrane (IAM) stationary phase. Obtained chromatographic data (R M0 and logk' IAM ) were correlated with the lipophilicity, expressed as values of the log calculated (logP calc ) and experimental (logP exp(shake-flask) ) partition coefficient. Principal component analysis (PCA) was applied in order to obtain an overview of similarity or dissimilarity among the analyzed compounds. Hierarchical cluster analysis (HCA) was performed to compare the separation characteristics of the applied stationary phases. This study was undertaken to identify the best chromatographic system and chromatographic data processing method to enable the prediction of logP values. A comprehensive chromatographic investigation into the retention of the analyzed cephalosporins revealed a similar behavior on RP-18, RP-8 and CN stationary phases. The weak correlations obtained between experimental and certain computed lipophilicity indices revealed that R M0 and PC1/RM are relevant lipophilicity parameters and the RP-8, CN and RP-18 plates are appropriate stationary phases for lipophilicity investigation, whereas computational approaches still cannot fully replace experimentation. Copyright © 2017 Elsevier B.V. All rights reserved.

Multilayered silica-biopolymer nanocapsules with a hydrophobic core and a hydrophilic tunable shell thickness

NASA Astrophysics Data System (ADS)

Vecchione, Raffaele; Luciani, Giuseppina; Calcagno, Vincenzo; Jakhmola, Anshuman; Silvestri, Brigida; Guarnieri, Daniela; Belli, Valentina; Costantini, Aniello; Netti, Paolo A.

2016-04-01

Stable, biocompatible, multifunctional and multicompartment nanocarriers are much needed in the field of nanomedicine. Here, we report a simple, novel strategy to design an engineered nanocarrier system featuring an oil-core/hybrid polymer/silica-shell. Silica shells with a tunable thickness were grown in situ, directly around a highly mono-disperse and stable oil-in-water emulsion system, stabilized by a double bio-functional polyelectrolyte heparin/chitosan layer. Such silica showed a complete degradation in a physiological medium (SBF) in a time frame of three days. Moreover, the outer silica shell was coated with polyethyleneglycol (PEG) in order to confer antifouling properties to the final nanocapsule. The outer silica layer combined its properties (it is an optimal bio-interface for bio-conjugations and for the embedding of hydrophilic drugs in the porous structure) with the capability to stabilize the oil core for the confinement of high payloads of lipophilic tracers (e.g. CdSe quantum dots, Nile Red) and drugs. In addition, polymer layers - besides conferring stability to the emulsion while building the silica shell - can be independently exploited if suitably functionalized, as demonstrated by conjugating chitosan with fluorescein isothiocyanate. Such numerous features in a single nanocarrier system make it very intriguing as a multifunctional platform for smart diagnosis and therapy.Stable, biocompatible, multifunctional and multicompartment nanocarriers are much needed in the field of nanomedicine. Here, we report a simple, novel strategy to design an engineered nanocarrier system featuring an oil-core/hybrid polymer/silica-shell. Silica shells with a tunable thickness were grown in situ, directly around a highly mono-disperse and stable oil-in-water emulsion system, stabilized by a double bio-functional polyelectrolyte heparin/chitosan layer. Such silica showed a complete degradation in a physiological medium (SBF) in a time frame of three days. Moreover, the outer silica shell was coated with polyethyleneglycol (PEG) in order to confer antifouling properties to the final nanocapsule. The outer silica layer combined its properties (it is an optimal bio-interface for bio-conjugations and for the embedding of hydrophilic drugs in the porous structure) with the capability to stabilize the oil core for the confinement of high payloads of lipophilic tracers (e.g. CdSe quantum dots, Nile Red) and drugs. In addition, polymer layers - besides conferring stability to the emulsion while building the silica shell - can be independently exploited if suitably functionalized, as demonstrated by conjugating chitosan with fluorescein isothiocyanate. Such numerous features in a single nanocarrier system make it very intriguing as a multifunctional platform for smart diagnosis and therapy. Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nr01192f

Food matrix and processing influence on carotenoid bioaccessibility and lipophilic antioxidant activity of fruit juice-based beverages.

PubMed

Rodríguez-Roque, María Janeth; de Ancos, Begoña; Sánchez-Vega, Rogelio; Sánchez-Moreno, Concepción; Cano, M Pilar; Elez-Martínez, Pedro; Martín-Belloso, Olga

2016-01-01

The biological activity of carotenoids depends on their bioaccessibility and solubilization in the gastrointestinal tract. These compounds are poorly dispersed in the aqueous media of the digestive tract due to their lipophilic nature. Thus, it is important to analyze the extent to which some factors, such as the food matrix and food processing, may improve their bioaccessibility. Beverages formulated with a blend of fruit juices and water (WB), milk (MB) or soymilk (SB) were treated by high-intensity pulsed electric fields (HIPEF) (35 kV cm(-1) with 4 μs bipolar pulses at 200 Hz for 1800 μs), high-pressure processing (HPP) (400 MPa at 40 °C for 5 min) or thermal treatment (TT) (90 °C for 1 min) in order to evaluate the influence of food matrix and processing on the bioaccessibility of carotenoids and on the lipophilic antioxidant activity (LAA). The bioaccessibility of these compounds diminished after applying any treatment (HIPEF, HPP and TT), with the exception of cis-violaxanthin + neoxanthin, which increased by 79% in HIPEF and HPP beverages. The lowest carotenoid bioaccessibility was always obtained in TT beverages (losses up to 63%). MB was the best food matrix for improving the bioaccessibility of carotenoids, as well as the LAA. The results demonstrate that treatment and food matrix modulated the bioaccessibility of carotenoids as well as the lipophilic antioxidant potential of beverages. Additionally, HIPEF and HPP could be considered as promising technologies to obtain highly nutritional and functional beverages.

Factors determining accumulation of bisphenol A and alkylphenols at a low trophic level as exemplified by mussels Mytilus trossulus.

PubMed

Staniszewska, Marta; Graca, Bożena; Sokołowski, Adam; Nehring, Iga; Wasik, Andrzej; Jendzul, Anna

2017-01-01

The aim of the study was to investigate abiotic and biotic factors influencing the accumulation of endocrine disrupting compounds (EDCs) such as bisphenol A (BPA), 4-tert-octylphenol (OP) and 4-nonylphenol (NP) in mussels Mytilus trossulus from the Gulf of Gdansk (Southern Baltic). The key abiotic factor influencing BPA, OP and NP accumulation in mussels is their hydrophilicity/lipophilicity, which affects their main assimilation routes - by digestive tract for the more lipophilic OP and NP, and additionally by the gills for the less lipophilic BPA. As a result, high condition index (i.e. higher soft tissue weight) is more often correlated with high concentrations of OP and NP in mussels than with BPA. Furthermore, alkylphenols have 6-8 times greater accumulative potential than BPA. Concentration of the studied compounds was lower in females than in males following spawning, and the effect lasted longer for BPA than for alkylphenols. The influence of season and hydrological conditions on BPA, OP, NP in the mussel was more pronounced than the proximity of external sources of these compounds. An increase in water temperature in summer probably stimulated the solubility of BPA, the least lipophilic of the studied compounds, and led to increased assimilation of this compound from water (through gills). On the other hand, high OP and NP concentrations in mussels occurred in spring, which was caused by increased surface run-off and sediments resuspension. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Clinico-pathologic correlation of dementia produced by thinner and cocaine].

PubMed

Barroso Moguel, R; Méndez Armenta, M; Villeda Hernández, J

1993-01-01

Industrial solvents mixed from thinner, used in paints, leathers, rubber, varnishes, have neurotoxic action. By laboral inhalation or spontaneously these are absorbed from the lungs, transported by blood and because of this high lipophilic section are retained within the lipid rich nervous system. Euphoric effects appear accompanied with visual and additive halucinations. In chronic abusers it produce schizophrenic-paranoid consequences with encephalic and peripheral neuronal and nervous fibers destruction, accompanied of blindness and paralysis. Cocaine is another neurotoxic drug. At first it produces euphoria, arterial hypertension and symptoms suggestive of underlying psychiatric diseases. The cocaine addicts often suffer depression, paranoia, hallucinations, seizures and suicidal ideation. The morphological base of the symptomatology is the encephalic and peripheral neuronal and nerve fibers destruction.

Interactions between Human Liver Fatty Acid Binding Protein and Peroxisome Proliferator Activated Receptor Selective Drugs

PubMed Central

Velkov, Tony

2013-01-01

Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs). PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L-) FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD) of PPARα. This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPARαLBD. The role of L-FABP in the delivery of ligands directly to PPARα via this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed. PMID:23476633

Drug release control and system understanding of sucrose esters matrix tablets by artificial neural networks.

PubMed

Chansanroj, Krisanin; Petrović, Jelena; Ibrić, Svetlana; Betz, Gabriele

2011-10-09

Artificial neural networks (ANNs) were applied for system understanding and prediction of drug release properties from direct compacted matrix tablets using sucrose esters (SEs) as matrix-forming agents for controlled release of a highly water soluble drug, metoprolol tartrate. Complexity of the system was presented through the effects of SE concentration and tablet porosity at various hydrophilic-lipophilic balance (HLB) values of SEs ranging from 0 to 16. Both effects contributed to release behaviors especially in the system containing hydrophilic SEs where swelling phenomena occurred. A self-organizing map neural network (SOM) was applied for visualizing interrelation among the variables and multilayer perceptron neural networks (MLPs) were employed to generalize the system and predict the drug release properties based on HLB value and concentration of SEs and tablet properties, i.e., tablet porosity, volume and tensile strength. Accurate prediction was obtained after systematically optimizing network performance based on learning algorithm of MLP. Drug release was mainly attributed to the effects of SEs, tablet volume and tensile strength in multi-dimensional interrelation whereas tablet porosity gave a small impact. Ability of system generalization and accurate prediction of the drug release properties proves the validity of SOM and MLPs for the formulation modeling of direct compacted matrix tablets containing controlled release agents of different material properties. Copyright © 2011 Elsevier B.V. All rights reserved.

[Do pharmaceutical waste and drug residue pose a risk to public health?].

PubMed

Haguenoer, Jean-Marie

2010-01-01

Recently, awareness has developed of the environmental consequences of drug waste and disposal. These residues are identified as coming from either diffuse sources, the most significant of which is via the discharge of these residues in urine and feces, and thus the sewage system and water contains these drug remnants and their metabolites, or from point sources, sometimes with very high levels of concentration in waste from chemical and pharmaceutical industries, health care settings, but also from intensive livestock farming and aquaculture. Depending on their physical chemistry properties, these substances are more or less naturally biodegradable and easily treated in sewage purification plants. The effectiveness of these treatment processes is highly random and unpredictable, but is overall around 60%, nevertheless with variations of 2-99% according to the molecules. The silt from these treatment plants, sometimes very rich in lipophilic substances is on occasion reused for agricultural application as fertilizer, paving the way for a possible contamination of crops. Furthermore, the use of veterinary drugs in animals can lead to soil contamination either directly or through manure and slurry. The contamination can equally reach and affect surface water, groundwater and sometimes the water intended for human consumption. The National academy of Pharmacy has established some general recommendations on the proper use of drugs, environmental monitoring and surveillance, risk assessment for humans and the environment, prevention and the need for prevention. Several categories of drugs are more worrying: cancer treatments, antibiotics as well as transfers of anti-bio-resistance, and hormonal derivatives which has been previously demonstrated to contribute, along with other molecules, to detrimental effects on endocrines.

Overcoming hERG affinity in the discovery of maraviroc; a CCR5 antagonist for the treatment of HIV.

PubMed

Price, David A; Armour, Duncan; de Groot, Marcel; Leishman, Derek; Napier, Carolyn; Perros, Manos; Stammen, Blanda L; Wood, Anthony

2008-01-01

Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.

Influence of some DNA-alkylating drugs on thermal stability, acid and osmotic resistance of the membrane of whole human erythrocytes and their ghosts.

PubMed

Ivanov, I T; Gadjeva, V

2000-09-01

Human erythrocytes and their resealed ghosts were alkylated under identical conditions using three groups of alkylating antitumor agents: mustards, triazenes and chloroethyl nitrosoureas. Osmotic fragility, acid resistance and thermal stability of membranes were changed only in alkylated ghosts in proportion to the concentration of the alkylating agent. All the alkylating agents decreased acid resistance in ghosts. The clinically used drugs sarcolysine, dacarbazine and lomustine all decreased osmotic fragility and thermal stability of ghost membranes depending on their lipophilicity. DM-COOH did not decrease osmotic fragility and thermal stability of ghost membranes, while NEM increased thermal stability of membranes. The preliminary but not subsequent treatment of ghosts with DM-COOH fully abolished the alkylation-induced thermal labilization of ghost membrane proteins while NEM had a partial effect only. The present study gives direct evidence that alkylating agents, having a high therapeutic activity against malignant growth, bind covalently to proteins of cellular membranes.

Profiling of lipophilic and phenolic phytochemicals of four cultivars from cherimoya (Annona cherimola Mill.).

PubMed

Santos, Sónia A O; Vilela, Carla; Camacho, João F; Cordeiro, Nereida; Gouveia, Manuela; Freire, Carmen S R; Silvestre, Armando J D

2016-11-15

The lipophilic and phenolic extractives of the ripe mesocarp of four cherimoya cultivars ('Perry Vidal', 'Mateus I', 'Mateus III' and 'Funchal') from Madeira Island, were studied for the first time. The predominant lipophilic compounds are kaurene diterpenes (42.2-59.6%), fatty acids (18.0-35.6%) and sterols (9.6-23.7%). Kaur-16-en-19-oic acid is the major lipophilic component of all cultivars accounting between 554 and 1350mgkg(-1) of dry material. The studied fruits also contain a high variety of flavan-3-ols, including galloylated and non-galloylated compounds. Five phenolic compounds were identified for the first time: catechin, (epi)catechin-(epi)gallocatechin, (epi)gallocatechin, (epi)afzelechin-(epi)catechin and procyanidin tetramer. 'Mateus I' and 'Mateus III' cultivars present the highest content of phenolic compounds (6299 and 9603mgkg(-1) of dry weight, respectively). These results support the use of this fruit as a rich source of health-promoting components, with the capacity to prevent or delay the progress of oxidative-stress related disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Novel Substrate-Based Inhibitors of Human Glutamate Carboxypeptidase II with Enhanced Lipophilicity

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

Plechanovová, Anna; Byun, Youngjoo; Alquicer, Glenda

2012-10-09

Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance ofmore » nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.« less

Product development studies of amino acid conjugate of Aceclofenac.

PubMed

Singh, Ajay Pal; Ramadan, Wafa Mossa; Dahiya, Rajiv; Sarpal, A S; Pathak, Kamla

2009-04-01

The prodrugs designed by classical approach increase lipophilicity of the drug, which decreases the water solubility thus decreasing the concentration gradient, which controls drug absorption. To overcome the limitations of traditional prodrug approach, water soluble prodrugs can be designed by adding selected amino acid to the drug moiety that are the substrates for the enzyme located at the intestinal brush border thus overcoming pharmaceutical problem without compromising bioavailability. ACaa (Amino acid conjugate of Aceclofenac) was synthesized by conjugation with l-phenylalanine by conventional coupling method using N, N-dicyclohexylcarbodiimide and ACaa was characterized by melting point, TLC, photomicrograph, UV, FT-IR, FT-NMR, MS-FAB, XRD and DSC. As a part of product development study ACaa was subjected to studies like In-vivo in albino rats and in-vitro like ACaa reversion to AC (Aceclofenac) in aqueous buffers of pH 1.21, 2.38. 3.10, 6.22 and 7.41, at a constant concentration (0.05M), ionic strength (micro = 0.5) and at a temperature of 37 degrees C +/- 0.5 degrees C, ACaa showed negligible reversion (2.15 %) up to 24 hrs study at acidic pH thus suggesting stability in acidic environment of stomach, the rate of reversion increased as pH of medium increased. pH- partition profile, pH- solubility profile and micromeritic studies were also carried out in comparison to pure drug. The solubility and lipophilicity of ACaa exhibited higher values at all pH range when compared to AC. The micromeritic properties also evaluated in terms of particle shape and size, IQCS and kurtosis. Resulting IQCS value approached zero thus suggesting reducing in the degree of skewness.

Self-assembled albumin nanoparticles as a nanocarrier for aclacinomycin A.

PubMed

Gong, Guangming; Liu, Wenya; Wang, Shudong

2016-11-18

This study aimed to reduce the cytotoxicity and improve the targeting of aclacinomycin (ACM) by covalently coupling it with amino-oxyacetic acid (AOA) to generate an active intermediate, AOA-ACM. AOA-ACM was conjugated with self-assembled human serum albumin (HSA) nanoparticles constructed using tris(2-carboxyethyl)phosphine (TCEP) as disulfide bond breaking molecules in an 'opening stage-intermediate-closing stage' route, in which the hydrophobic interaction, interchange of sulfhydryl and hydrogen bond may be the key factors in the assembling process. Conjugation between ACM and albumin nanoparticles was found to occur at an ACM ketone site using 1 H-NMR and 13 C-NMR matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass analysis indicated that the drug loading efficiency of ACM conjugated with HSA nanoparticles (NPs-ACM) was 7.4% (molar ratio = 6:1). The release of NPs-ACM was pH dependent. In vivo studies indicated that NPs-ACM exhibited fourfold higher tumor targeting capability on S180-tumor-bearing mice compared with the free ACM (p < 0.05). The cytotoxictiy and cardiotoxicity of NPs-ACM was reduced compared with the free ACM. Albumin carrier altered the blood pharmacokinetics and distribution of ACM. Hence, the NPs-ACM prodrug is ideal tumor targeting drug carriers for ACM, and the easy approach developed in this study for active intermediate and prodrug preparation can be applied to other pharmacological substances containing ketone groups. The method of preparing HSA-blank nanoparticles through TCEP reduction could be adopted to improve the water solubility of lipophilic drugs and their tumor-targeting specificity by fabricating HSA-lipophilic drug nanoparticles.

Preclinical characterization of anticancer gallium(III) complexes: solubility, stability, lipophilicity and binding to serum proteins.

PubMed

Rudnev, Alexander V; Foteeva, Lidia S; Kowol, Christian; Berger, Roland; Jakupec, Michael A; Arion, Vladimir B; Timerbaev, Andrei R; Keppler, Bernhard K

2006-11-01

The discovery and development of gallium(III) complexes capable of inhibiting tumor growth is an emerging area of anticancer drug research. A range of novel gallium coordination compounds with established cytotoxic efficacy have been characterized in terms of desirable chemical and biochemical properties and compared with tris(8-quinolinolato)gallium(III) (KP46), a lead anticancer gallium-based candidate that successfully finished phase I clinical trials (under the name FFC11), showing activity against renal cell cancer. In view of probable oral administration, drug-like parameters, such as solubility in water, saline and 0.5% dimethyl sulfoxide, stability against hydrolysis, measured as the rate constant of hydrolytic degradation in water or physiological buffer using a capillary zone electrophoresis (CZE) assay, and the octanol-water partition coefficient (logP) providing a rational estimate of a drug's lipophilicity, have been evaluated and compared. The differences in bioavailability characteristics between different complexes were discussed within the formalism of structure-activity relationships. The reactivity toward major serum transport proteins, albumin and transferrin, was also assayed in order to elucidate the drug's distribution pathway after intestinal absorption. According to the values of apparent binding rate constants determined by CZE, both KP46 and bis(2-acetylpyridine-4,4-dimethyl-3-thiosemicarbazonato-N,N,S)gallium(III) tetrachlorogallate(III) (KP1089) bind to transferrin faster than to albumin. This implies that transferrin would rather mediate the accumulation of gallium antineoplastic agents in solid tumors. A tendency of being faster converted into the protein-bound form found for KP1089 (due possibly to non-covalent binding) seems complementary to its greater in vitro antiproliferative activity.

Hydrogel-based ultra-moisturizing cream formulation for skin hydration and enhanced dermal drug delivery.

PubMed

Lee, Sang Gon; Kim, Sung Rae; Cho, Hye In; Kang, Mean Hyung; Yeom, Dong Woo; Lee, Seo Hyun; Lee, Sangkil; Choi, Young Wook

2014-01-01

To develop an external vehicle for skin hydration and enhanced dermal drug delivery, a hydrogel-based ultra-moisturizing cream (HUMC) was successfully formulated with carbopol 934P, urea, Tinocare GL, grape seed oil, and other excipients. The HUMC showed plastic flow behavior due to a gel structure with a cream base. Different types of drug-free vehicles such as a hydrogel, conventional cream (CC), and three HUMCs were prepared and subjected to an in vivo skin hydration test on a hairless mouse using a corneometer. Hydration effect (∆AU) was in the order of HUMC2>HUMC1 ≥ CC>HUMC3>hydrogel. Using nile red (NR) and 5-carboxyfluorescein (5-CF) as lipophilic and hydrophilic fluorescent probes, respectively, in vitro skin permeation and accumulation studies were conducted using Franz diffusion cells. The values of steady-state flux (Jss, ng/h/cm(2)) were obtained: 74.8 (CC), 145.6 (HUMC1), and 161.9 (HUMC2) for NR delivery; 6.8 (CC), 8.3 (HUMC1), and 10.9 (HUMC2) for 5-CF delivery. The amounts retained in the skin at 12 h (Qr, ng/cm(2)) were determined: 86.4 (CC) and 102.0 (HUMC2) for NR; and 70.1 (CC) and 195.6 (HUMC2) for 5-CF. Confocal microscopy was used to visualize the distribution of the fluorescent probes. NR tended to be localized into the deeper part of the skin with adipose tissue whereas 5-CF localized in the upper layer of the skin. Thus we propose that HUMC2 is an efficacious vehicle for skin hydration and enhances dermal delivery of lipophilic and hydrophilic drugs.

Design, synthesis and biological evaluation of (S)-valine thiazole-derived cyclic and non-cyclic peptidomimetic oligomers as modulators of human P-glycoprotein (ABCB1)

PubMed Central

Singh, Satyakam; Prasad, Nagarajan Rajendra; Kapoor, Khyati; Chufan, Eduardo E.; Patel, Bhargav A.; Ambudkar, Suresh V.; Talele, Tanaji T.

2014-01-01

Multidrug resistance (MDR) caused by ATP-binding cassette (ABC) transporter P-glycoprotein (P-gp) through extrusion of anticancer drugs from the cells is a major cause of failure to cancer chemotherapy. Previously, selenazole containing cyclic peptides were reported as P-gp inhibitors and these were also used for co-crystallization with mouse P-gp, which has 87% homology to human P-gp. It has been reported that human P-gp, can simultaneously accommodate 2-3 moderate size molecules at the drug binding pocket. Our in-silico analysis based on the homology model of human P-gp spurred our efforts to investigate the optimal size of (S)-valine-derived thiazole units that can be accommodated at drug-binding pocket. Towards this goal, we synthesized varying lengths of linear and cyclic derivatives of (S)-valine-derived thiazole units to investigate the optimal size, lipophilicity and the structural form (linear and cyclic) of valine-derived thiazole peptides that can accommodate well in the P-gp binding pocket and affects its activity, previously an unexplored concept. Among these oligomers, lipophilic linear- (13) and cyclic-trimer (17) derivatives of QZ59S-SSS were found to be the most and equally potent inhibitors of human P-gp (IC50 = 1.5 μM). Cyclic trimer and linear trimer being equipotent, future studies can be focused on non-cyclic counterparts of cyclic peptides maintaining linear trimer length. Binding model of the linear trimer (13) within the drug-binding site on the homology model of human P-gp represents an opportunity for future optimization, specifically replacing valine and thiazole groups in the non-cyclic form. PMID:24288265

Design, synthesis, and biological evaluation of (S)-valine thiazole-derived cyclic and noncyclic peptidomimetic oligomers as modulators of human P-glycoprotein (ABCB1).

PubMed

Singh, Satyakam; Prasad, Nagarajan Rajendra; Kapoor, Khyati; Chufan, Eduardo E; Patel, Bhargav A; Ambudkar, Suresh V; Talele, Tanaji T

2014-01-03

Multidrug resistance caused by ATP binding cassette transporter P-glycoprotein (P-gp) through extrusion of anticancer drugs from the cells is a major cause of failure in cancer chemotherapy. Previously, selenazole-containing cyclic peptides were reported as P-gp inhibitors and were also used for co-crystallization with mouse P-gp, which has 87 % homology to human P-gp. It has been reported that human P-gp can simultaneously accommodate two to three moderately sized molecules at the drug binding pocket. Our in silico analysis, based on the homology model of human P-gp, spurred our efforts to investigate the optimal size of (S)-valine-derived thiazole units that can be accommodated at the drug binding pocket. Towards this goal, we synthesized varying lengths of linear and cyclic derivatives of (S)-valine-derived thiazole units to investigate the optimal size, lipophilicity, and structural form (linear or cyclic) of valine-derived thiazole peptides that can be accommodated in the P-gp binding pocket and affects its activity, previously an unexplored concept. Among these oligomers, lipophilic linear (13) and cyclic trimer (17) derivatives of QZ59S-SSS were found to be the most and equally potent inhibitors of human P-gp (IC50 =1.5 μM). As the cyclic trimer and linear trimer compounds are equipotent, future studies should focus on noncyclic counterparts of cyclic peptides maintaining linear trimer length. A binding model of the linear trimer 13 within the drug binding site on the homology model of human P-gp represents an opportunity for future optimization, specifically replacing valine and thiazole groups in the noncyclic form. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Design of a serotonin 4 receptor radiotracer with decreased lipophilicity for single photon emission computed tomography.

PubMed

Fresneau, Nathalie; Dumas, Noé; Tournier, Benjamin B; Fossey, Christine; Ballandonne, Céline; Lesnard, Aurélien; Millet, Philippe; Charnay, Yves; Cailly, Thomas; Bouillon, Jean-Philippe; Fabis, Frédéric

2015-04-13

With the aim to develop a suitable radiotracer for the brain imaging of the serotonin 4 receptor subtype (5-HT4R) using single photon emission computed tomography (SPECT), we synthesized and evaluated a library of di- and triazaphenanthridines with lipophilicity values which were in the range expected to favour brain penetration, and which demonstrated specific binding to the target of interest. Adding additional nitrogen atoms to previously described phenanthridine ligands exhibiting a high unspecific binding, we were able to design a radioiodinated compound [(125)I]14. This compound exhibited a binding affinity value of 0.094 nM toward human 5-HT4R and a high selectivity over other serotonin receptor subtypes (5-HTR). In vivo SPECT imaging studies and competition experiments demonstrated that the decreased lipophilicity (in comparison with our previously reported compounds 4 and 5) allowed a more specific labelling of the 5-HT4R brain-containing regions. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

HPTLC and magnetochromatography of new complexes of carboxylates with transition metals or rare earth elements and their ligands - study of lipophilicity.

PubMed

Malinowska, Irena; Wronka, Agnieszka; Ferenc, Wiesława

2017-05-01

Nineteen new complexes of carboxylates with transition and rare elements as central ions and their ligands were characterized by chromatographic analyses. The parameter of relative lipophilicity (R M0 ) of the tested compounds was determined experimentally by the reversed-phase high-performance thin layer chromatography method with mixtures of various organic modifiers (acetonitrile, acetone, dioxane) and water as a mobile phase. The extrapolated R M0 values were compared with the logP values calculated from the molecular structures of tested solutes. Similarities between the lipophilicity indices were analysed by principal component analysis and linear regression. Thin-layer chromatography combined with a magnetic field has been proposed as a complementary method for determination of lipophilicity of the investigated compounds. The chromatograms in the field and outside it were developed simultaneously in two identical chromatographic chambers. One of them was placed in the external magnetic field of 0.4 T inductivity. We proved that chelation causes a drastic change in compound lipophilicity, but all complexes did not exhibit enhanced activity as compared with the parent ligand. Also in the magnetic field the retention of some complexes changed, which means that the presence of the field influences the physicochemical properties of the compounds and their interactions with the stationary phase. Copyright © 2016 John Wiley & Sons, Ltd.

Antiglycation activity of lipophilized epigallocatechin gallate (EGCG) derivatives.

PubMed

Wang, Mingfu; Zhang, Xinchen; Zhong, Ying Joy; Perera, Nishani; Shahidi, Fereidoon

2016-01-01

Lipophilized EGCG derivatives were synthesized by esterification of EGCG with aliphatic fatty acids and demonstrated to possess many advantages, such as higher lipophilicity and apparent health benefits over the parent EGCG. This study used a total of seven lipophilized EGCG derivatives with fatty acids of different chain lengths attached and examined the impact of lipophilization on EGCG's antiglycation activity in vitro. The length of fatty acid chain was found to be an important factor, which positively correlated with ABTS radical scavenging capacity but long chain bulky substitutes prevented methylglyoxal (MGO) trapping. Except docosahexaenoic acid (DHA), lipophilization generally showed no interference with EGCG's in vitro inhibitory activity of advanced glycation endproducts (AGEs) formation. Therefore, the lipophilized EGCG derivatives are promising candidates worthy of further exploration for preventing AGEs accumulation in vivo and hence treating AGEs-associated diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dodecyltriphenylphosphonium inhibits multiple drug resistance in the yeast Saccharomyces cerevisiae.

PubMed

Knorre, Dmitry A; Markova, Olga V; Smirnova, Ekaterina A; Karavaeva, Iuliia E; Sokolov, Svyatoslav S; Severin, Fedor F

2014-08-08

Multiple drug resistance pumps are potential drug targets. Here we asked whether the lipophilic cation dodecyltriphenylphosphonium (C12TPP) can interfere with their functioning. First, we found that suppression of ABC transporter gene PDR5 increases the toxicity of C12TPP in yeast. Second, C12TPP appeared to prevent the efflux of rhodamine 6G - a fluorescent substrate of Pdr5p. Moreover, C12TPP increased the cytostatic effects of some other known Pdr5p substrates. The chemical nature of C12TPP suggests that after Pdr5p-driven extrusion the molecules return to the plasma membrane and then into the cytosol, thus effectively competing with other substrates of the pump. Copyright © 2014 Elsevier Inc. All rights reserved.

Computer-aided molecular modeling techniques for predicting the stability of drug cyclodextrin inclusion complexes in aqueous solutions

NASA Astrophysics Data System (ADS)

Faucci, Maria Teresa; Melani, Fabrizio; Mura, Paola

2002-06-01

Molecular modeling was used to investigate factors influencing complex formation between cyclodextrins and guest molecules and predict their stability through a theoretical model based on the search for a correlation between experimental stability constants ( Ks) and some theoretical parameters describing complexation (docking energy, host-guest contact surfaces, intermolecular interaction fields) calculated from complex structures at a minimum conformational energy, obtained through stochastic methods based on molecular dynamic simulations. Naproxen, ibuprofen, ketoprofen and ibuproxam were used as model drug molecules. Multiple Regression Analysis allowed identification of the significant factors for the complex stability. A mathematical model ( r=0.897) related log Ks with complex docking energy and lipophilic molecular fields of cyclodextrin and drug.

Influence of Permeant Lipophilicity on Permeation Across Human Sclera

PubMed Central

Wen, He; Li, S. Kevin

2010-01-01

Purpose The objectives of this study were to determine the effects of permeant lipophilicity on permeant uptake into and transport across human sclera for transscleral delivery. Methods Model permeants with a wide range of lipophilicities were selected and studied with human sclera. Uptake experiments were carried out to measure permeant partitioning into the sclera. Transport experiments were performed in side-by-side diffusion cells, and the permeability coefficients and transport lag times of the permeants across the sclera were evaluated. Results Permeants with higher lipophilicity showed higher partition coefficients to human sclera, and the apparent transport lag time also increased significantly as the permeant lipophilicity increased. No correlation between the permeability coefficients and lipophilicity of the model permeants was observed in this study with human sclera. A hypothesis on the different findings between the present and previous studies was proposed. Conclusions Permeants with higher lipophilicity exhibited stronger binding to human sclera and would therefore lead to larger permeant partitioning to the sclera and longer transport lag time. The steady-state permeability coefficients of the permeants were not significantly affected by permeant lipophilicity. PMID:20734114

The Effect of Capsaicin Derivatives on Tight-Junction Integrity and Permeability of Madin-Darby Canine Kidney Cells.

PubMed

Kaiser, Mathias; Chalapala, Sudharani; Gorzelanny, Christian; Perali, Ramu Sridhar; Goycoolea, Francisco Martin

2016-02-01

Capsaicin is known to interfere with tight junctions (TJs) of epithelial cells and therefore to enhance paracellular permeability of poorly absorbable drugs. However, due to its low water solubility, pungency, and cytotoxicity, its pharmacologic use is limited. In this study, we investigated the effect of capsaicin derivatives of synthetic (e.g., 10-hydroxy-N-(4-hydroxy-3-methoxybenzyl)decanamide, etc.) and natural (olvanil and dihydrocapsaicin) origin on Madin-Darby Canine Kidney-C7 cells. Impedance spectroscopy was used to determine the transepithelial electrical resistance and the capacitance. Permeability assays with fluorescein isothiocyanate-dextran were carried out to evaluate the impact on cell permeability. The results show that lipophilicity could play an important role for the interference with TJ and that the mechanism is independent from the ion channel TRPV-1 and hence on the flux of calcium into the cells. In summary, we synthesized 4 derivatives of capsaicin of lower lipophilicity and compared their properties with other well-known vanilloids. We show that these compounds are able to enhance the permeability of a hydrophilic macromolecule, by opening the TJ for a shorter time than capsaicin. This behavior is dependent on the lipophilicity of the molecule. Understanding of these phenomena may lead to better control of administration of therapeutic molecules. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Inclusion Complexes of a New Family of Non-Ionic Amphiphilic Dendrocalix[4]arene and Poorly Water-Soluble Drugs Naproxen and Ibuprofen.

PubMed

Khan, Khalid; Badshah, Syed Lal; Ahmad, Nasir; Rashid, Haroon Ur; Mabkhot, Yahia

2017-05-11

The inclusion complexes of a new family of nonionic amphiphilic calix[4]arenes with the anti-inflammatory hydrophobic drugs naproxen (NAP) and ibuprofen (IBP) were investigated. The effects of the alkyl chain's length and the inner core of calix[4]arenes on the interaction of the two drugs with the calix[4]arenes were explored. The inclusion complexes of Amphiphiles 1a - c with NAP and IBP increased the solubility of these drugs in aqueous media. The interaction of 1a - c with the drugs in aqueous media was investigated through fluorescence, molecular modeling, and ¹H-NMR analysis. TEM studies further supported the formation of inclusion complexes. The length of lipophilic alkyl chains and the intrinsic cyclic nature of cailx[4]arene derivatives 1a - c were found to have a significant impact on the solubility of NAP and IBP in pure water.

Statin Prescriptions and Breast Cancer Recurrence Risk: A Danish Nationwide Prospective Cohort Study

PubMed Central

Pedersen, Lars; Tarp, Maja; Cronin-Fenton, Deirdre P.; Garne, Jens Peter; Silliman, Rebecca A.; Sørensen, Henrik Toft; Lash, Timothy L.

2011-01-01

Background Accumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied. Methods We conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I–III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18 769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre-diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. All statistical tests were two-sided. Results Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10-year risk difference = −0.10, 95% confidence interval = −0.11 to −0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = −0.01 to 0.11). Conclusions Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I–III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed. PMID:21813413

Comparison Study of Two Differently Clicked 18F-Folates—Lipophilicity Plays a Key Role

PubMed Central

Kettenbach, Kathrin; Reffert, Laura M.; Schieferstein, Hanno; Pektor, Stefanie; Eckert, Raphael; Miederer, Matthias; Rösch, Frank

2018-01-01

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable 18F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel 18F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the 18F-folates was investigated. 18F-Ala-folate and 18F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked 18F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with 18F-DBCO-folate, 18F-Ala-folate (logD = −1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, 18F-Ala-folate is expected to be a promising candidate for FR-PET imaging. PMID:29562610

New approaches for the reliable in vitro assessment of binding affinity based on high-resolution real-time data acquisition of radioligand-receptor binding kinetics.

PubMed

Zeilinger, Markus; Pichler, Florian; Nics, Lukas; Wadsak, Wolfgang; Spreitzer, Helmut; Hacker, Marcus; Mitterhauser, Markus

2017-12-01

Resolving the kinetic mechanisms of biomolecular interactions have become increasingly important in early-phase drug development. Since traditional in vitro methods belong to dose-dependent assessments, binding kinetics is usually overlooked. The present study aimed at the establishment of two novel experimental approaches for the assessment of binding affinity of both, radiolabelled and non-labelled compounds targeting the A 3 R, based on high-resolution real-time data acquisition of radioligand-receptor binding kinetics. A novel time-resolved competition assay was developed and applied to determine the K i of eight different A 3 R antagonists, using CHO-K1 cells stably expressing the hA 3 R. In addition, a new kinetic real-time cell-binding approach was established to quantify the rate constants k on and k off , as well as the dedicated K d of the A 3 R agonist [ 125 I]-AB-MECA. Furthermore, lipophilicity measurements were conducted to control influences due to physicochemical properties of the used compounds. Two novel real-time cell-binding approaches were successfully developed and established. Both experimental procedures were found to visualize the kinetic binding characteristics with high spatial and temporal resolution, resulting in reliable affinity values, which are in good agreement with values previously reported with traditional methods. Taking into account the lipophilicity of the A 3 R antagonists, no influences on the experimental performance and the resulting affinity were investigated. Both kinetic binding approaches comprise tracer administration and subsequent binding to living cells, expressing the dedicated target protein. Therefore, the experiments resemble better the true in vivo physiological conditions and provide important markers of cellular feedback and biological response.

Design of Potent and Selective Inhibitors to Overcome Clinical Anaplastic Lymphoma Kinase Mutations Resistant to Crizotinib

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

Huang, Qinhua; Johnson, Ted W.; Bailey, Simon

2014-02-27

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

Predicting Error Bars for QSAR Models

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

Schroeter, Timon; Technische Universitaet Berlin, Department of Computer Science, Franklinstrasse 28/29, 10587 Berlin; Schwaighofer, Anton

2007-09-18

Unfavorable physicochemical properties often cause drug failures. It is therefore important to take lipophilicity and water solubility into account early on in lead discovery. This study presents log D{sub 7} models built using Gaussian Process regression, Support Vector Machines, decision trees and ridge regression algorithms based on 14556 drug discovery compounds of Bayer Schering Pharma. A blind test was conducted using 7013 new measurements from the last months. We also present independent evaluations using public data. Apart from accuracy, we discuss the quality of error bars that can be computed by Gaussian Process models, and ensemble and distance based techniquesmore » for the other modelling approaches.« less

Distribution of Animal Drugs among Curd, Whey, and Milk Protein Fractions in Spiked Skim Milk and Whey.

PubMed

Shappell, Nancy W; Shelver, Weilin L; Lupton, Sara J; Fanaselle, Wendy; Van Doren, Jane M; Hakk, Heldur

2017-02-01

It is important to understand the partitioning of drugs in processed milk and milk products, when drugs are present in raw milk, in order to estimate the potential consumer exposure. Radioisotopically labeled erythromycin, ivermectin, ketoprofen, oxytetracycline, penicillin G, sulfadimethoxine, and thiabendazole were used to evaluate the distribution of animal drugs among rennet curd, whey, and protein fractions from skim cow milk. Our previous work reported the distribution of these same drugs between skim and fat fractions of milk. Drug distribution between curd and whey was significantly correlated (R 2 = 0.70) to the drug's lipophilicity (log P), with improved correlation using log D (R 2 = 0.95). Distribution of drugs was concentration independent over the range tested (20-2000 nM). With the exception of thiabendazole and ivermectin, more drug was associated with whey protein than casein on a nmol/g protein basis (oxytetracycline experiment not performed). These results provide insights into the distribution of animal drug residues, if present in cow milk, among milk fractions, with possible extrapolation to milk products.

Using pharmacokinetics to predict the effects of pregnancy and maternal-infant transfer of drugs during lactation.

PubMed

Anderson, Gail D

2006-12-01

Knowledge of pharmacokinetics and the use of a mechanistic-based approach can improve our ability to predict the effects of pregnancy for medications when data are limited. Despite the many physiological changes that occur during pregnancy that could theoretically affect absorption, bioavailability does not appear to be altered. Decreased albumin and alpha(1)-acid glycoprotein concentrations during pregnancy will result in decreased protein binding for highly bound drugs. For drugs metabolised by the liver, this can result in misinterpretation of total plasma concentrations of low extraction ratio drugs and overdosing of high extraction ratio drugs administered by non-oral routes. Renal clearance and the activity of the CYP isozymes, CYP3A4, 2D6 and 2C9, and uridine 5'-diphosphate glucuronosyltransferase are increased during pregnancy. In contrast, CYP1A2 and 2C19 activity is decreased. The dose of a drug an infant receives during breastfeeding is dependent on the amount excreted into the breast milk, the daily volume of milk ingested and the average plasma concentration of the mother. The lipophilicity, protein binding and ionisation properties of a drug will determine how much is excreted into the breast milk. The milk to plasma concentration ratio has large inter- and intrasubject variability and is often not known. In contrast, protein binding is usually known. An extensive literature review was done to identify case reports including infant concentrations from breast-fed infants exposed to maternal drugs. For drugs that were at least 85% protein bound, measurable concentrations of drug in the infant did not occur if there was no placental exposure immediately prior to or during delivery. Knowledge of the protein binding properties of a drug can provide a quick and easy tool to estimate exposure of an infant to medication from breastfeeding.

Combined effects of the drug distribution and mucus diffusion properties of self-microemulsifying drug delivery systems on the oral absorption of fenofibrate.

PubMed

Sunazuka, Yushi; Ueda, Keisuke; Higashi, Kenjirou; Tanaka, Yusuke; Moribe, Kunikazu

2018-05-24

We present the absorption improvement mechanism of fenofibrate (FFB), a Biopharmaceutics Classification System (BCS) class II drug, from self-microemulsifying drug delivery systems (SMEDDS), centered on improving the diffusion of FFB through the unstirred water layer (UWL). Four SMEDDS formulations containing Labrafac™ lipophile WL 1349 (WL1349) or Labrafil ® M 1944CS (M1944) oils and NIKKOL HCO-40 (HCO40) or NIKKOL HCO-60 (HCO60) surfactants were prepared. Every SMEDDS formulation formed microemulsion droplets of approximately 30 nm. In vitro tests showed that the microemulsion droplets containing M1944 had relatively small FFB solubilization capacities, causing larger amounts of FFB to be dissolved in the bulk water phase, compared to the droplets containing WL1349. The diffusivity of the microemulsion droplets through the mucin solution layer was enhanced when using HCO40 compared to HCO60. The oral absorption in rats was the highest when using the SMEDDS formulation containing M1944 and HCO40. High FFB distribution in the bulk water phase and fast diffusion of microemulsion droplets through the mucus layer contributed to the efficient delivery of FFB molecules through the UWL to the epithelial cells, leading to enhanced FFB absorption. Copyright © 2018 Elsevier B.V. All rights reserved.

Development and characterization of a novel lipohydrogel nanocarrier: repaglinide as a lipophilic model drug.

PubMed

Ebrahimi, Hossein Ali; Javadzadeh, Yousef; Hamidi, Mehrdad; Barzegar Jalali, Mohammad

2016-04-01

Solid lipid nanoparticles (SLNs) are highly susceptible to phagocytosis by reticuloendothelial system (RES). To overcome this problem, a novel hydrogel-coated SLNs structure was developed and evaluated in this study. Solid lipid nanoparticles surface was coated with chitosan, via electrostatic attraction with the negatively charged SLNs surface. The resulting polymer-coated SLNs then hosted an inorganic poly-anionic agent, tripolyphosphate, to form the final lipohydrogel structure. Compared with the bare SLNs, lipohydrogel nanoparticles (LHNs) showed a significant increase in size and zeta potential. The release profile showed lower burst release and lower release rate for LHNs compared with SLNs. LHNs nanoparticles released the model antidiabetic drug, repaglinide, in a more sustained manner with lower burst effect compared with the corresponding SLN structure. Cytotoxicity studies via cell culture and MTT assay revealed no bio-toxicity of the SLNs and LHNs. In addition, intravenous administration of repaglinide-loaded SLNs and LHNs in rats showed longer drug residence time in circulation for LHNs, a trend also evident for the blood glucose level-time profile. The particle size, zeta potential, FTIR and microscopy data demonstrated the formation of the supposed lipohydrogel nanoparticles. All these benefits of LHNs propose it as a promising candidate for controlled release of the drugs. © 2016 Royal Pharmaceutical Society, Journal of Pharmacy and Pharmacology.

Suppressive effects of diltiazem and verapamil on delayed rectifier K(+)-channel currents in murine thymocytes.

PubMed

Baba, Asuka; Tachi, Masahiro; Maruyama, Yoshio; Kazama, Itsuro

2015-10-01

Lymphocytes predominantly express delayed rectifier K(+)-channels (Kv1.3) in their plasma membranes, and these channels play crucial roles in the lymphocyte activation and proliferation. Since diltiazem and verapamil, which are highly lipophilic Ca(2+) channel blockers (CCBs), exert relatively stronger immunomodulatory effects than the other types of CCBs, they would affect the Kv1.3-channel currents in lymphocytes. Employing the standard patch-clamp whole-cell recording technique in murine thymocytes, we examined the effects of these drugs on the channel currents and the membrane capacitance. Both diltiazem and verapamil significantly suppressed the peak and the pulse-end currents of the channels, although the effects of verapamil were more marked than those of diltiazem. Both drugs significantly lowered the membrane capacitance, indicating the interactions between the drugs and the plasma membranes. This study demonstrated for the first time that CCBs, such as diltiazem and verapamil, exert inhibitory effects on Kv1.3-channels expressed in lymphocytes. The effects of these drugs may be associated with the mechanisms of immunomodulation by which they decrease the production of inflammatory cytokines. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Catalytic asymmetric trifluoromethylthiolation via enantioselective [2,3]-sigmatropic rearrangement of sulfonium ylides

NASA Astrophysics Data System (ADS)

Zhang, Zhikun; Sheng, Zhe; Yu, Weizhi; Wu, Guojiao; Zhang, Rui; Chu, Wen-Dao; Zhang, Yan; Wang, Jianbo

2017-10-01

The trifluoromethylthio (SCF3) functional group has been of increasing importance in drug design and development as a consequence of its unique electronic properties and high stability coupled with its high lipophilicity. As a result, methods to introduce this highly electronegative functional group have attracted considerable attention in recent years. Although significant progress has been made in the introduction of SCF3 functionality into a variety of molecules, there remain significant challenges regarding the enantioselective synthesis of SCF3-containing compounds. Here, an asymmetric trifluoromethylthiolation that proceeds through the enantioselective [2,3]-sigmatropic rearrangement of a sulfonium ylide generated from a metal carbene and sulfide (Doyle-Kirmse reaction) has been developed using chiral Rh(II) and Cu(I) catalysts. This transformation features mild reaction conditions and excellent enantioselectivities (up to 98% yield and 98% e.e.), thus providing a unique, highly efficient and enantioselective method for the construction of C(sp3)-SCF3 bonds bearing chiral centres.

Utilizing food effects to overcome challenges in delivery of lipophilic bioactives: structural design of medical and functional foods.

PubMed

McClements, David Julian

2013-12-01

The oral bioavailability of many lipophilic bioactives, such as pharmaceuticals and nutraceuticals, is relatively low due to their poor solubility, permeability and/or chemical stability within the human gastrointestinal tract (GIT). The oral bioavailability of lipophilic bioactives can be improved by designing food matrices that control their release, solubilization, transport and absorption within the GIT. This article discusses the challenges associated with delivering lipophilic bioactive components, the impact of food composition and structure on oral bioavailability and the design of functional and medical foods for improving the oral bioavailability of lipophilic bioactives. Food-based delivery systems can be used to improve the oral bioavailability of lipophilic bioactives. There are a number of potential advantages to delivering lipophilic bioactives using functional or medical foods: greater compliance than conventional delivery forms; increased bioavailability and efficacy; and reduced variability in biological effects. However, food matrices are structurally complex multicomponent materials and research is still needed to identify optimum structures and compositions for particular bioactives.

Treatment of Gram-negative bacterial infections by potentiation of antibiotics.

PubMed

Zabawa, Thomas P; Pucci, Michael J; Parr, Thomas R; Lister, Troy

2016-10-01

Infections caused by antibiotic-resistant pathogens, particularly Gram-negative bacteria, represent significant treatment challenges for physicians resulting in high rates of morbidity and mortality. The outer membrane of Gram-negative bacteria acts as a permeability barrier to many compounds that would otherwise be effective antibacterial agents, including those effective against Gram-positive pathogens. Potentiator molecules disrupt this barrier allowing entry of otherwise impermeant molecules, thus providing a strategy to render multi-drug resistant pathogens susceptible to a broader range of antibiotics. Potentiator molecules are cationic and the mechanism of disruption involves interaction with the negatively charged outer membrane. This physical attribute, along with an often high degree of lipophilicity typically endears these molecules with unacceptable toxicity. Presented herein are examples of advanced potentiator molecules being evaluated for use in combination therapy for the treatment of resistant Gram-negative infections. Copyright © 2016 Elsevier Ltd. All rights reserved.

Diabetes and hypertension increase the placental and transcellular permeation of the lipophilic drug diazepam in pregnant women

PubMed Central

2013-01-01

Background Previous studies carried out in our laboratories have demonstrated impaired drug permeation in diabetic animals. In this study the permeation of diazepam (after a single dose of 5 mg/day, administered intramuscularly) will be investigated in diabetic and hypertensive pregnant women. Methods A total 75 pregnant women were divided into three groups: group 1 (healthy control, n = 31), group 2 (diabetic, n = 14) and group 3 (hypertensive, n = 30). Two sets of diazepam plasma concentrations were collected and measured (after the administration of the same dose of diazepam), before, during and after delivery. The first set of blood samples was taken from the mother (maternal venous plasma). The second set of samples was taken from the fetus (fetal umbilical venous and arterial plasma). In order to assess the effect of diabetes and hypertension on diazepam placental-permeation, the ratios of fetal to maternal blood concentrations were determined. Differences were considered statistically significant if p ≤ 0.05. Results The diabetes and hypertension groups have 2-fold increase in the fetal umbilical-venous concentrations, compared to the maternal venous concentrations. Feto: maternal plasma-concentrations ratios were higher in diabetes (2.01 ± 1.10) and hypertension (2.26 ± 1.23) groups compared with control (1.30 ± 0.48) while, there was no difference in ratios between the diabetes and hypertension groups. Umbilical-cord arterial: venous ratios (within each group) were similar among all groups (control: 0.97 ± 0.32; hypertension: 1.08 ± 0.60 and diabetes: 1.02 ± 0.77). Conclusions On line with our previous findings which demonstrate disturbed transcellular trafficking of lipophilic drugs in diabetes, this study shows significant increase in diazepam placental-permeation in diabetic and hypertensive pregnant women suggesting poor transcellular control of drug permeation and flux, and bigger exposure of the fetus to drug-placental transport. PMID:24134697

One-Pot Isomerization–Cross Metathesis–Reduction (ICMR) Synthesis of Lipophilic Tetrapeptides

PubMed Central

2015-01-01

An efficient, versatile and rapid method toward homologue series of lipophilic tetrapeptide derivatives (herein, the opioid peptides H-TIPP-OH and H-DIPP-OH) is reported. High atom economy and a minimal number of synthetic steps resulted from a one-pot tandem isomerization-cross metathesis-reduction sequence (ICMR), applicable both in solution and solid phase methodology. The broadly applicable synthesis proceeds with short reaction times and simple work-up, as illustrated in this work for alkylated opioid tetrapeptides. PMID:24906051

A Fast Chromatographic Method for Estimating Lipophilicity and Ionization in Nonpolar Membrane-Like Environment.

PubMed

Caron, Giulia; Vallaro, Maura; Ermondi, Giuseppe; Goetz, Gilles H; Abramov, Yuriy A; Philippe, Laurence; Shalaeva, Marina

2016-03-07

This study describes the design and implementation of a new chromatographic descriptor called log k'80 PLRP-S that provides information about the lipophilicity of drug molecules in the nonpolar environment, both in their neutral and ionized form. The log k'80 PLRP-S obtained on a polymeric column with acetonitrile/water mobile phase is shown to closely relate to log Ptoluene (toluene dielectric constant ε ∼ 2). The main intermolecular interactions governing log k'80 PLRP-S were deconvoluted using the Block Relevance (BR) analysis. The information provided by this descriptor was compared to ElogD and calclog Ptol, and the differences are highlighted. The "charge-flush" concept is introduced to describe the sensitivity of log k'80 PLRP-S to the ionization state of compounds in the pH range 2 to 12. The ability of log k'80 PLRP-S to indicate the propensity of neutral molecules and monoanions to form Intramolecular Hydrogen Bonds (IMHBs) is proven through a number of examples.

Nanosized self-emulsifying lipid vesicles of diacylglycerol-PEG lipid conjugates: Biophysical characterization and inclusion of lipophilic dietary supplements

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

Koynova, Rumiana; Tihova, Mariana; Biopharma)

Hydrated diacylglycerol-PEG lipid conjugates, glyceryl dioleate-PEG12 (GDO-PEG12) and glyceryl dipalmitate-PEG23 (GDP-PEG23), spontaneously form uni- or oligolamellar liposomes in their liquid crystalline phase, in distinct difference from the PEGylated phospholipids which form micelles. GDP-PEG23 exhibits peculiar hysteretic phase behavior and can arrange into a long-living hexagonal phase at ambient and physiological temperatures. Liposomes of GDO-PEG12 and its mixture with soy lecithin exchange lipids with the membranes much more actively than common lecithin liposomes; such an active lipid exchange might facilitate the discharging of the liposome cargo upon uptake and internalization, and can thus be important in drug delivery applications. Diacylglycerol-PEG lipidmore » liposome formulations can encapsulate up to 20-30 wt.% lipophilic dietary supplements such as fish oil, coenzyme Q10, and vitamins D and E. The encapsulation is feasible by way of dry mixing, avoiding the use of organic solvent.« less

Noninvasive Fluorescence Resonance Energy Transfer Imaging of in vivo Premature Drug Release from Polymeric Nanoparticles

PubMed Central

Zou, Peng; Chen, Hongwei; Paholak, Hayley J.; Sun, Duxin

2013-01-01

Understanding in vivo drug release kinetics is critical for the development of nanoparticle-based delivery systems. In this study, we developed a fluorescence resonance energy transfer (FRET) imaging approach to noninvasively monitor in vitro and in vivo cargo release from polymeric nanoparticles. The FRET donor dye (DiO or DiD) and acceptor dye (DiI or DiR) were individually encapsulated into poly(ethylene oxide)-b-polystyrene (PEO-PS) nanoparticles. When DiO (donor) nanoparticles and DiI (acceptor) nanoparticles were co-incubated with cancer cells for 2 h, increased FRET signals were observed from cell membranes, suggesting rapid release of DiO and DiI to cell membranes. Similarly, increased FRET ratios were detected in nude mice after intravenous co-administration of DiD (donor) nanoparticles and DiR (acceptor) nanoparticles. In contrast, another group of nude mice i.v. administrated with DiD/DiR co-loaded nanoparticles showed decreased FRET ratios. Based on the difference in FRET ratios between the two groups, in vivo DiD/DiR release half-life from PEO-PS nanoparticles was determined to be 9.2 min. In addition, it was observed that the presence of cell membranes facilitated burst release of lipophilic cargos while incorporation of oleic acid-coated iron oxide into PEO-PS nanoparticles slowed the release of DiD/DiR to cell membranes. The developed in vitro and in vivo FRET imaging techniques can be used to screening stable nano-formulations for lipophilic drug delivery. PMID:24033270

The use of intravenous lipid emulsion as an antidote in veterinary toxicology.

PubMed

Fernandez, Alberto L; Lee, Justine A; Rahilly, Louisa; Hovda, Lynn; Brutlag, Ahna G; Engebretsen, Kristin

2011-08-01

To review the use of IV lipid emulsion (ILE) for the treatment of toxicities related to fat-soluble agents; evaluate current human and veterinary literature; and to provide proposed guidelines for the use of this emerging therapy in veterinary medicine and toxicology. Human and veterinary medical literature. Human data are composed mostly of case reports describing the response to treatment with ILE as variant from mild improvement to complete resolution of clinical signs, which is suspected to be due to the variability of lipid solubility of the drugs. The use of ILE therapy has been advocated as an antidote in cases of local anesthetic and other lipophilic drug toxicoses, particularly in the face of cardiopulmonary arrest and unsuccessful cardiopulmonary cerebral resuscitation. The use of ILE therapy in veterinary medicine has recently been advocated by animal poison control centers for toxicoses associated with fat-soluble agents, but there are only few clinical reports documenting successful use of this therapy. Evidence for the use of ILE in both human and veterinary medicine is composed primarily from experimental animal data. The use of ILE appears to be a safe therapy for the poisoned animal patient, but is warranted only with certain toxicoses. Adverse events associated with ILE in veterinary medicine are rare and anecdotal. Standard resuscitation protocols should be exhausted before considering this therapy and the potential side effects should be evaluated before administration of ILE as a potential antidote in cases of lipophilic drug toxicoses. Further research is waranted. © Veterinary Emergency and Critical Care Society 2011.

Lipophilicity affects the pharmacokinetics and toxicity of local anaesthetic agents administered by caudal block.

PubMed

Nava-Ocampo, Alejandro A; Bello-Ramírez, Angélica M

2004-01-01

1. Drugs administered into the epidural space by caudal block are cleared by means of a process potentially affected by the lipophilic character of the compounds. 2. In the present study, we examined the relationship between the octanol-water partition coefficient (log Poct) and the time to reach the maximum plasma drug concentration (tmax) of lignocaine, bupivacaine and ropivacaine administered by caudal block in paediatric patients. We also examined the relationship between log Poct and the toxicity of these local anaesthetic agents in experimental models. The tmax and toxicity data were obtained from the literature. 3. Ropivacaine, with a log Poct of 2.9, exhibited a tmax of 61.6 min. The tmax of lignocaine, with a log Poct of 2.4, and bupivacaine, with a log Poct of with 3.4, were approximately 50% shorter than ropivacaine. At log Poct of approximately 3.0, the toxicity of these local anaesthetic agents was substantially increased. The relationship between log Poct and the convulsive effect in dogs was similar to the relationship between log Poct and the lethal dose in sheep. 4. With local anaesthetic agents, it appears that the relationship between log Poct and drug transfer from the epidural space to the blood stream is parabolic, being the slowest rate of transference at log Poct 3.0. Toxicity, due to plasma availability of these local anaesthetic agents, seems to be increased at log Poct equal or higher than 3.0 secondary to the highest transfer from plasma into the central nervous system.

Use of rivastigmine transdermal patch in the treatment of Alzheimer's disease.

PubMed

Winblad, Bengt; Machado, João Carlos

2008-12-01

Cholinesterase inhibitors such as rivastigmine and donepezil exhibit a dose-response relationship, with higher doses of the drugs demonstrating greater efficacy. Transdermal patches provide smooth continuous drug delivery, with the potential to offer efficacious levels of drug exposure while avoiding the peaks and troughs associated with side effects. As a small, lipophilic and hydrophilic molecule, rivastigmine (C14H22N2O2) is chemically well-suited to transdermal delivery. The technology underlying the rivastigmine patch allows it to be discreetly small and thin. The target dose 9.5 mg/24 h rivastigmine patch has a diameter of just 3.5 cm and a surface area of 10 cm2. A large randomized controlled trial has demonstrated that the target dose 9.5 mg/24 h rivastigmine patch provided similar efficacy to the highest rivastigmine capsule doses, yet with three times fewer reports of nausea and vomiting. Thus, the rivastigmine patch enables quick and easy access to high dose efficacy. The skin tolerability profile is good, and the patch has demonstrated excellent adhesion. The apparent success of rivastigmine patch, in terms of clinical utility and patient acceptability, suggests that it may mark the next generation of dementia treatment.

Optimization of diclofenac sodium profile from halloysite nanotubules.

PubMed

Krejčová, Kateřina; Deasy, Patrick B; Rabišková, Miloslava

2013-04-01

Halloysite, aluminosilicate clay with the particle shape of multilayered hollow nanotubes, used in various non-medical applications, e.g. in ceramic industry, was discovered for pharmaceutical purposes in recent years. Several drugs of hydrophilic and lipophilic nature have been successfully encapsulated into halloysite tubules in order to modify their dissolution profile. The main goal of this experiment was to optimize the dissolution profile of diclofenac sodium - a drug with problematic solubility - from halloysite tubules using various polymers. Loading of the drug together with povidone or Eudragit® RS did not lead to drug burst effect reduction and its slower dissolution. In the case of povidone, drug improved wettability and solubilization rather than viscosity increasing expectations were observed. Eudragit® RS formed a solid dispersion with diclofenac sodium and thus the solvent/drug solution penetration through the polymer and not the drug solubility was the dissolution rate limiting factor. Reduction of the burst effect and further prolongation of drug release was achieved by coating the drug-loaded halloysite with chitosan. This formulation exhibited a diffusion-controlled prolonged release following Higuchi kinetic model.

Synthesis of β-cyclodextrin hydrogel nanoparticles for improving the solubility of dexibuprofen: characterization and toxicity evaluation.

PubMed

Khalid, Qandeel; Ahmad, Mahmood; Minhas, Muhammad Usman

2017-11-01

This study was aimed to enhance aqueous solubility of dexibuprofen through designing β-cyclodextrin (βCD) hydrogel nanoparticles and to evaluate toxicological potential through acute toxicity studies in rats. Dexibuprofen is a non-steroidal analgesic and anti-inflammatory drug that is one of safest over the counter medications. However, its clinical effectiveness is hampered due to poor aqueous solubility. βCD hydrogel nanoparticles were prepared and characterized by percent yield, drug loading, solubilization efficiency, FTIR, XRD, DSC, FESEM and in-vitro dissolution studies. Acute oral toxicity study was conducted to assess safety of oral administration of prepared βCD hydrogel nanoparticles. βCD hydrogel nanoparticles dramatically enhanced the drug loading and solubilization efficiency of dexibuprofen in aqueous media. FTIR, TGA and DSC studies confirmed the formation of new and a stable nano-polymeric network and interactions of dexibuprofen with these nanoparticles. Resulting nanoparticles were highly porous with 287 nm in size. XRD analysis revealed pronounced reduction in crystalline nature of dexibuprofen within nanoparticles. Release of dexibuprofen in βCD hydrogel nanoparticles was significantly higher compared with dexibuprofen tablet at pH 1.2 and 6.8. In acute toxicity studies, no significant changes in behavioral, physiological, biochemical or histopathologic parameters of animals were observed. The efficient preparation, high solubility, excellent physicochemical characteristics, improved dissolution and non-toxic βCD hydrogel nanoparticles may be a promising approach for oral delivery of lipophilic drugs.

Formulation studies of InhA inhibitors and combination therapy to improve efficacy against Mycobacterium tuberculosis.

PubMed

Knudson, Susan E; Cummings, Jason E; Bommineni, Gopal R; Pan, Pan; Tonge, Peter J; Slayden, Richard A

2016-12-01

Previously, structure-based drug design was used to develop substituted diphenyl ethers with potency against the Mycobacterium tuberculosis (Mtb) enoyl-ACP reductase (InhA), however, the highly lipophilic centroid compound, SB-PT004, lacked sufficient efficacy in the acute murine Mtb infection model. A next generation series of compounds were designed with improved specificity, potency against InhA, and reduced cytotoxicity in vitro, but these compounds also had limited solubility. Accordingly, solubility and pharmacokinetics studies were performed to develop formulations for this class and other experimental drug candidates with high logP values often encountered in drug discovery. Lead diphenyl ethers were formulated in co-solvent and Self-Dispersing Lipid Formulations (SDLFs) and evaluated in a rapid murine Mtb infection model that assesses dissemination to and bacterial burden in the spleen. In vitro synergy studies were performed with the lead diphenyl ether compounds, SB-PT070 and SB-PT091, and rifampin (RIF), which demonstrated an additive effect, and that guided the in vivo studies. Combinatorial therapy in vivo studies with these compounds delivered in our Self-Micro Emulsifying Drug Delivery System (SMEDDS) resulted in an additional 1.4 log 10  CFU reduction in the spleen of animals co-treated with SB-PT091 and RIF and an additional 1.7 log 10 reduction in the spleen with animals treated with both SB-PT070 and RIF. Copyright © 2016 Elsevier Ltd. All rights reserved.

Temperature Dependence of Nonelectrolyte Permeation across Red Cell Membranes

PubMed Central

Galey, W. R.; Owen, J. D.; Solomon, A. K.

1973-01-01

The temperature dependence of permeation across human red cell membranes has been determined for a series of hydrophilic and lipophilic solutes, including urea and two methyl substituted derivatives, all the straight-chain amides from formamide through valeramide and the two isomers, isobutyramide and isovaleramide. The temperature coefficient for permeation by all the hydrophilic solutes is 12 kcal mol-1 or less, whereas that for all the lipophilic solutes is 19 kcal mol-1 or greater. This difference is consonant with the view that hydrophilic molecules cross the membrane by a path different from that taken by the lipophilic ones. The thermodynamic parameters associated with lipophile permeation have been studied in detail. ΔG is negative for adsorption of lipophilic amides onto an oil-water interface, whereas it is positive for transfer of the polar head from the aqueous medium to bulk lipid solvent. Application of absolute reaction rate theory makes it possible to make a clear distinction between diffusion across the water-red cell membrane interface and diffusion within the membrane. Diffusion coefficients and apparent activation enthalpies and entropies have been computed for each process. Transfer of the polar head from the solvent into the interface is characterized by ΔG ‡ = 0 kcal mol-1 and ΔS ‡ negative, whereas both of these parameters have large positive values for diffusion within the membrane. Diffusion within the membrane is similar to what is expected for diffusion through a highly associated viscous fluid. PMID:4708405

Chromatographic and computational assessment of lipophilicity using sum of ranking differences and generalized pair-correlation.

PubMed

Andrić, Filip; Héberger, Károly

2015-02-06

Lipophilicity (logP) represents one of the most studied and most frequently used fundamental physicochemical properties. At present there are several possibilities for its quantitative expression and many of them stems from chromatographic experiments. Numerous attempts have been made to compare different computational methods, chromatographic methods vs. computational approaches, as well as chromatographic methods and direct shake-flask procedure without definite results or these findings are not accepted generally. In the present work numerous chromatographically derived lipophilicity measures in combination with diverse computational methods were ranked and clustered using the novel variable discrimination and ranking approaches based on the sum of ranking differences and the generalized pair correlation method. Available literature logP data measured on HILIC, and classical reversed-phase combining different classes of compounds have been compared with most frequently used multivariate data analysis techniques (principal component and hierarchical cluster analysis) as well as with the conclusions in the original sources. Chromatographic lipophilicity measures obtained under typical reversed-phase conditions outperform the majority of computationally estimated logPs. Oppositely, in the case of HILIC none of the many proposed chromatographic indices overcomes any of the computationally assessed logPs. Only two of them (logkmin and kmin) may be selected as recommended chromatographic lipophilicity measures. Both ranking approaches, sum of ranking differences and generalized pair correlation method, although based on different backgrounds, provides highly similar variable ordering and grouping leading to the same conclusions. Copyright © 2015. Published by Elsevier B.V.

Fast log P determination by ultra-high-pressure liquid chromatography coupled with UV and mass spectrometry detections.

PubMed

Henchoz, Yveline; Guillarme, Davy; Martel, Sophie; Rudaz, Serge; Veuthey, Jean-Luc; Carrupt, Pierre-Alain

2009-08-01

Ultra-high-pressure liquid chromatography (UHPLC) systems able to work with columns packed with sub-2 microm particles offer very fast methods to determine the lipophilicity of new chemical entities. The careful development of the most suitable experimental conditions presented here will help medicinal chemists for high-throughput screening (HTS) log P(oct) measurements. The approach was optimized using a well-balanced set of 38 model compounds and a series of 28 basic compounds such as beta-blockers, local anesthetics, piperazines, clonidine, and derivatives. Different organic modifiers and hybrid stationary phases packed with 1.7-microm particles were evaluated in isocratic as well as gradient modes, and the advantages and limitations of tested conditions pointed out. The UHPLC approach offered a significant enhancement over the classical HPLC methods, by a factor 50 in the lipophilicity determination throughput. The hyphenation of UHPLC with MS detection allowed a further increase in the throughput. Data and results reported herein prove that the UHPLC-MS method can represent a progress in the HTS-measurement of lipophilicity due to its speed (at least a factor of 500 with respect to HPLC approaches) and to an extended field of application.

Exploiting the Phenomenon of Liquid-Liquid Phase Separation for Enhanced and Sustained Membrane Transport of a Poorly Water-Soluble Drug.

PubMed

Indulkar, Anura S; Gao, Yi; Raina, Shweta A; Zhang, Geoff G Z; Taylor, Lynne S

2016-06-06

Recent studies on aqueous supersaturated lipophilic drug solutions prepared by methods including antisolvent addition, pH swing, or dissolution of amorphous solid dispersions (ASDs) have demonstrated that when crystallization is slow, these systems undergo liquid-liquid phase separation (LLPS) when the concentration of the drug in the medium exceeds its amorphous solubility. Following LLPS, a metastable equilibrium is formed where the concentration of drug in the continuous phase corresponds to the amorphous solubility while the dispersed phase is composed of a nanosized drug-rich phase. It has been reasoned that the drug-rich phase may act as a reservoir, enabling the rate of passive transport of the drug across a membrane to be maintained at the maximum value for an extended period of time. Herein, using clotrimazole as a model drug, and a flow-through diffusion cell, the reservoir effect is demonstrated. Supersaturated clotrimazole solutions at concentrations below the amorphous solubility show a linear relationship between the maximum flux and the initial concentration. Once the concentration exceeds the amorphous solubility, the maximum flux achieved reaches a plateau. However, the duration for which the high flux persists was found to be highly dependent on the number of drug-rich nanodroplets present in the donor compartment. Macroscopic amorphous particles of clotrimazole did not lead to the same reservoir effect observed with the nanodroplets formed through the process of LLPS. A first-principles mathematical model was developed which was able to fit the experimental receiver concentration-time profiles for concentration regimes both below and above amorphous solubility, providing support for the contention that the nanodroplet phase does not directly diffuse across the membrane but, instead, rapidly replenishes the drug in the aqueous phase that has been removed by transport across the membrane. This study provides important insight into the properties of supersaturated solutions and how these might in turn impact oral absorption through effects on passive membrane transport rates.

Autonomous Rhythmic Drug Delivery Systems Based on Chemical and Biochemomechanical Oscillators

NASA Astrophysics Data System (ADS)

Siegel, Ronald A.

While many drug delivery systems target constant, or zero-order drug release, certain drugs and hormones must be delivered in rhythmic pulses in order to achieve their optimal effect. Here we describe studies with two model autonomous rhythmic delivery systems. The first system is driven by a pH oscillator that modulates the ionization state of a model drug, benzoic acid, which can permeate through a lipophilic membrane when the drug is uncharged. The second system is based on a nonlinear negative feedback instability that arises from coupling of swelling of a hydrogel membrane to an enzymatic reaction, with the hydrogel controlling access of substrate to the enzyme, and the enzyme's product controlling the hydrogel's swelling state. The latter system, whose autonomous oscillations are driven by glucose at constant external activity, is shown to deliver gonadotropin releasing hormone (GnRH) in rhythmic pulses, with periodicity of the same order as observed in sexually mature adult humans. Relevant experimental results and some mathematical models are reviewed.

The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships.

PubMed

Shaghafi, Michael B; Barrett, David G; Willard, Francis S; Overman, Larry E

2014-02-15

We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Novel 1,2-dihydroquinazolin-2-ones: Design, synthesis, and biological evaluation against Trypanosoma brucei.

PubMed

Pham, ThanhTruc; Walden, Madeline; Butler, Christopher; Diaz-Gonzalez, Rosario; Pérez-Moreno, Guiomar; Ceballos-Pérez, Gloria; Gomez-Pérez, Veronica; García-Hernández, Raquel; Zecca, Henry; Krakoff, Emma; Kopec, Brian; Ichire, Ogar; Mackenzie, Caden; Pitot, Marika; Ruiz, Luis Miguel; Gamarro, Francisco; González-Pacanowska, Dolores; Navarro, Miguel; Dounay, Amy B

2017-08-15

In 2014, a published report of the high-throughput screen of>42,000 kinase inhibitors from GlaxoSmithKline against T. brucei identified 797 potent and selective hits. From this rich data set, we selected NEU-0001101 (1) for hit-to-lead optimization. Through our preliminary compound synthesis and SAR studies, we have confirmed the previously reported activity of 1 in a T. brucei cell proliferation assay and have identified alternative groups to replace the pyridyl ring in 1. Pyrazole 24 achieves improvements in both potency and lipophilicity relative to 1, while also showing good in vitro metabolic stability. The SAR developed on 24 provides new directions for further optimization of this novel scaffold for anti-trypanosomal drug discovery. Copyright © 2017 Elsevier Ltd. All rights reserved.

Vane's blood-bathed organ technique adapted to examine the endothelial effects of cardiovascular drugs in vivo.

PubMed

Gryglewski, Ryszard J; Mackiewicz, Zygmunt

2010-01-01

This study describes a modification of Vane's blood-bathed organ technique (BBOT). This new technique consisted of replacing the cascade of contractile smooth muscle organs within the traditional BBOT by a single collagen strip cut from a rabbit's hind leg tendon. Utilizing the extracorporeal circulation of an anesthetized heparinized mongrel cat or Wistar rat, arterial blood was dripped (1-3 ml min(-1)) over a collagen strip. This resulted in a gain in weight of the strip, which was due to the deposition of platelet aggregates and a few blood cells trapped over the strip. Arterial blood that had been used for the superfusion was pumped back into the animal's venous system. However, when this technique is adapted to human volunteers, the superfusing blood should be discarded. In animal experiments, intravenous injections of a variety of classic fibrinolytic agents (e.g., streptokinase) promoted the formation of platelet thrombi. Nitric oxide donors (e.g., SIN-1) at non-hypotensive doses hardly affected the mass of platelet thrombi deposited over the collagen strip, whereas endogenous prostacyclin (e.g., released from vascular endothelium by bradykinin) or exogenous prostacyclin and its stable analogues (e.g., iloprost) dissipated platelet thrombi as measured by a loss in the weight of the blood superfused collagen strip. This model allowed us to assay numerous drugs for their releasing properties of endogenous prostacyclin from vascular endothelium. These drugs included lipophilic angiotensin converting enzyme inhibitors (ACE-Is), which act in vivo as bradykinin potentiating factors (BPF). Other PGI(2)-releasers included statins (e.g., atorvastatin and simvastatin), thienopyridines (e.g., ticlopidine and clopidogrel), a number of thromboxane synthase inhibitors, flavonoids, bradykinin itself, cholinergic M receptor agonists and nicotinic acid derivatives. The thrombolytic actions of lipophilic ACE-Is (e.g., quinapril and perindopril) were prevented by pretreatment with either bradykinin B(2) receptor antagonists (e.g., icatibant) or with endothelial COX-2 inhibitors (e.g., rofecoxib, celecoxib and high dose aspirin). The inhibition of endothelial nitric oxide synthetase (eNOS) by L-NAME hardly blunted the thrombolytic response to ACE-Is. Hence, it can be concluded that many recognized cardiovascular drugs apart from their known basic mechanisms of action, may also behave as releasers of endogenous endothelial prostacyclin. Furthermore, in many instances, this effect may be the primary mechanism of their therapeutic efficacy.

Correlations between chromatographic parameters and bioactivity predictors of potential herbicides.

PubMed

Janicka, Małgorzata

2014-08-01

Different liquid chromatography techniques, including reversed-phase liquid chromatography on Purosphere RP-18e, IAM.PC.DD2 and Cosmosil Cholester columns and micellar liqud chromatography with a Purosphere RP-8e column and using buffered sodium dodecyl sulfate-acetonitrile as the mobile phase, were applied to study the lipophilic properties of 15 newly synthesized phenoxyacetic and carbamic acid derivatives, which are potential herbicides. Chromatographic lipophilicity descriptors were used to extrapolate log k parameters (log kw and log km) and log k values. Partitioning lipophilicity descriptors, i.e., log P coefficients in an n-octanol-water system, were computed from the molecular structures of the tested compounds. Bioactivity descriptors, including partition coefficients in a water-plant cuticle system and water-human serum albumin and coefficients for human skin partition and permeation were calculated in silico by ACD/ADME software using the linear solvation energy relationship of Abraham. Principal component analysis was applied to describe similarities between various chromatographic and partitioning lipophilicities. Highly significant, predictive linear relationships were found between chromatographic parameters and bioactivity descriptors. © The Author [2013]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Lipophilicity indices derived from the liquid chromatographic behavior observed under bimodal retention conditions (reversed phase/hydrophilic interaction): application to a representative set of pyridinium oximes.

PubMed

Voicu, Victor; Sârbu, Costel; Tache, Florentin; Micăle, Florina; Rădulescu, Ştefan Flavian; Sakurada, Koichi; Ohta, Hikoto; Medvedovici, Andrei

2014-05-01

The liquid chromatographic behavior observed under bimodal retention conditions (reversed phase and hydrophilic interaction) offers a new basis for the determination of some derived lipophilicity indices. The experiments were carried out on a representative group (30 compounds) of pyridinium oximes, therapeutically tested in acetylcholinesterase reactivation, covering a large range of lipophilic character. The chromatographic behavior was observed on a mixed mode acting stationary phase, resulting from covalent functionalization of high purity spherical silica with long chain alkyl groups terminated by a polar environment created through the vicinal diol substitution at the lasting carbon atoms (Acclaim Mixed Mode HILIC 1 column). Elution was achieved by combining different proportions of 5 mM ammonium formiate solutions in water and acetonitrile. The derived lipophilicity indices were compared with logP values resulting from different computational algorithms. The correlations between experimental and computed data sets are significant. To obtain a better insight on the transition from reversed phase to hydrophilic interaction retention mechanisms, the variation of the thermodynamic parameters determined through the van׳t Hoff approach was also discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

Comparative pharmacokinetics of intravenous fentanyl and buprenorphine in healthy greyhound dogs.

PubMed

KuKanich, B; Allen, P

2014-12-01

The purpose of this study was to compare the pharmacokinetics of two highly protein-bound, lipophilic opioid drugs. Fentanyl (10 μg/kg) and buprenorphine (20 μg/kg) were administered intravenously (IV) to six healthy greyhound dogs (three males and three females). The doses were based on clinically administered doses for dogs. Plasma drug concentrations were determined using liquid chromatography with mass spectrometry, and noncompartmental pharmacokinetics were estimated with computer software. The volume of distribution (area) was larger for fentanyl (7.42 L/kg) compared to buprenorphine (3.54 L/kg). The plasma clearance of fentanyl (38.6 mL·min/kg) was faster than buprenorphine (10.3 mL·min/kg). The terminal half-life of fentanyl (2.22 h) was shorter than buprenorphine (3.96 h). Despite similar physicochemical properties including octanol-water partition coefficient and pKa, the pharmacokinetics of fentanyl and buprenorphine were not similar. Both fentanyl (84%) and buprenorphine (95-98%) are considered highly protein bound, but the differences in protein binding may contribute to the lack of similarity of pharmacokinetics in healthy dogs. © 2014 John Wiley & Sons Ltd.

Facile route to versatile nanoplatforms for drug delivery by one-pot self-assembly.

PubMed

Zhou, Xing; Che, Ling; Wei, Yanling; Dou, Yin; Chen, Sha; He, Hongmei; Gong, Hao; Li, Xiaohui; Zhang, Jianxiang

2014-06-01

There is still unmet demand for developing powerful approaches to produce polymeric nanoplatforms with versatile functions and broad applications, which are essential for the successful bench-to-bedside translation of polymeric nanotherapeutics developed in the laboratory. We have discovered a facile, convenient, cost-effective and easily scalable one-pot strategy to assemble various lipophilic therapeutics bearing carboxyl groups into nanomedicines, through which highly effective cargo loading and nanoparticle formation can be achieved simultaneously. Besides dramatically improving water solubility, the assembled nanopharmaceuticals showed significantly higher bioavailability and much better therapeutic activity. These one-pot assemblies may also serve as nanocontainers to effectively accommodate other highly hydrophobic drugs such as paclitaxel (PTX). PTX nanomedicines thus formulated display strikingly enhanced in vitro antitumor activity and can reverse the multidrug resistance of tumor cells to PTX therapy. The special surface chemistry offers these assembled entities the additional capability of efficiently packaging and efficaciously transfecting plasmid DNA, with a transfection efficiency markedly higher than that of commonly used positive controls. Consequently, this one-pot assembly approach provides a facile route to multifunctional nanoplatforms for simultaneous delivery of multiple therapeutics with improved therapeutic significance. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Lipids, tocopherols, and carotenoids in leaves of amaranth and quinoa cultivars and a new approach to overall evaluation of nutritional quality traits.

PubMed

Tang, Yao; Li, Xihong; Chen, Peter X; Zhang, Bing; Hernandez, Marta; Zhang, Hua; Marcone, Massimo F; Liu, Ronghua; Tsao, Rong

2014-12-31

Composition of lipophilic phytochemicals including fatty acids, tocopherols, and carotenoids in leaves of 6 quinoa and 14 amaranth cultivars was analyzed. The oil yields in quinoa and amaranth leaves were only 2.72-4.18%, which contained mainly essential fatty acids and had a highly favorable ω-3/ω-6 ratio (2.28-3.89). Pro-vitamin A carotenoids, mainly α- and β-carotenes, and xanthophylls, predominantly lutein and violaxanthin, were found in all samples. The primary tocopherol isomers present in both quinoa and amaranth leaves were α- and β-tocopherols. Added to the discussion on the lipophilic nutrients was the normalization of ω-3/ω-6 ratio, α-tocopherol equivalents, and carotenoids, in an attempt to establish a novel system for evaluation of the overall quality attributes of lipophilic nutrients (NQ value). The NQ value, but not the individual components, was highly correlated with all the antioxidant activities, supporting the ranking order of the potential nutritional quality of quinoa and amaranth leaves based on this new method.

Root Uptake Of Lipophilic Zinc-Rhamnolipid Complexes

EPA Science Inventory

This study investigated the formation and plant uptake of lipophilic metal-rhamnolipid complexes. Monorhamnosyl and dirhamnosyl rhamnolipids formed lipophilic complexes with copper (Cu), manganese (Mn), and zinc (Zn). Rhamnolipids significantly increased Zn absorption by Bra...