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Sample records for drug-drug interaction study

  1. Can drug-drug interactions be predicted from in vitro studies?

    PubMed

    Kremers, Pierre

    2002-03-19

    Potential drug-drug interactions as well as drug-xenobiotic interactions are a major source of clinical problems, sometimes with dramatic consequences. Investigation of drug-drug interactions during drug development is a major concern for the drug companies while developing new drugs. Our knowledge of the drug-metabolising enzymes, their mechanism of action, and their regulation has made considerable progress during the last decades. Various efficient in vitro approaches have been developed during recent years and powerful computer-based data handling is becoming widely available. All these tools allow us to initiate, early in the development of new chemical entities, large-scale studies on the interactions of drugs with selective cytochrome P-450 (CYP) isozymes, drug receptors, and other cellular entities. Standardisation and validation of these methodological approaches significantly improve the quality of the data generated and the reliability of their interpretation. The simplicity and the low costs associated with the use of in vitro techniques have made them a method of choice to investigate drug-drug interactions. Promising successes have been achieved in the extrapolation of in vitro data to the in vivo situation and in the prediction of drug-drug interaction. Nevertheless, linking in vitro and in vivo studies still remains fraught with difficulties and should be made with great caution. PMID:12806001

  2. Impact of Participatory Design for Drug-Drug Interaction Alerts. A Comparison Study Between Two Interfaces.

    PubMed

    Luna, Daniel; Otero, Carlos; Risk, Marcelo; Stanziola, Enrique; González Bernaldo de Quirós, Fernán

    2016-01-01

    Decision support systems for alert drug-drug interactions have been shown as valid strategy to reduce medical error. Even so the use of these systems has not been as expected, probably due to the lack of a suitable design. This study compares two interfaces, one of them developed using participatory design techniques (based on user centered design processes). This work showed that the use of these techniques improves satisfaction, effectiveness and efficiency in an alert system for drug-drug interactions, a fact that was evident in specific situations such as the decrease of errors to meet the specified task, the time, the workload optimization and users overall satisfaction with the system. PMID:27577343

  3. A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.

    PubMed

    Floyd, J S; Kaspera, R; Marciante, K D; Weiss, N S; Heckbert, S R; Lumley, T; Wiggins, K L; Tamraz, B; Kwok, P-Y; Totah, R A; Psaty, B M

    2012-05-01

    An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8. PMID:22419147

  4. Using Nonexperts for Annotating Pharmacokinetic Drug-Drug Interaction Mentions in Product Labeling: A Feasibility Study

    PubMed Central

    Ning, Yifan; Hernandez, Andres; Horn, John R; Jacobson, Rebecca; Boyce, Richard D

    2016-01-01

    Background Because vital details of potential pharmacokinetic drug-drug interactions are often described in free-text structured product labels, manual curation is a necessary but expensive step in the development of electronic drug-drug interaction information resources. The use of nonexperts to annotate potential drug-drug interaction (PDDI) mentions in drug product label annotation may be a means of lessening the burden of manual curation. Objective Our goal was to explore the practicality of using nonexpert participants to annotate drug-drug interaction descriptions from structured product labels. By presenting annotation tasks to both pharmacy experts and relatively naïve participants, we hoped to demonstrate the feasibility of using nonexpert annotators for drug-drug information annotation. We were also interested in exploring whether and to what extent natural language processing (NLP) preannotation helped improve task completion time, accuracy, and subjective satisfaction. Methods Two experts and 4 nonexperts were asked to annotate 208 structured product label sections under 4 conditions completed sequentially: (1) no NLP assistance, (2) preannotation of drug mentions, (3) preannotation of drug mentions and PDDIs, and (4) a repeat of the no-annotation condition. Results were evaluated within the 2 groups and relative to an existing gold standard. Participants were asked to provide reports on the time required to complete tasks and their perceptions of task difficulty. Results One of the experts and 3 of the nonexperts completed all tasks. Annotation results from the nonexpert group were relatively strong in every scenario and better than the performance of the NLP pipeline. The expert and 2 of the nonexperts were able to complete most tasks in less than 3 hours. Usability perceptions were generally positive (3.67 for expert, mean of 3.33 for nonexperts). Conclusions The results suggest that nonexpert annotation might be a feasible option for comprehensive

  5. Clinical Weighting of Drug-Drug Interactions in Hospitalized Elderly.

    PubMed

    Juárez-Cedillo, Teresa; Martinez-Hernández, Cynthia; Hernández-Constantino, Angel; Garcia-Cruz, Juan Carlos; Avalos-Mejia, Annia M; Sánchez-Hurtado, Luis A; Islas Perez, Valentin; Hansten, Philip D

    2016-04-01

    Adverse drug reactions impact on patient health, effectiveness of pharmacological therapy and increased health care costs. This investigation intended to detect the most critical drug-drug interactions in hospitalized elderly patients, weighting clinical risk. We conducted a cross-sectional study between January and April 2014; all patients 70 years or older, hospitalized for >24 hr and prescribed at least one medication were included in the study. Drug-drug interactions were estimated by combining Stockley's, Hansten and Tatro drug interactions. Drug-drug interactions were weighted using a risk-analysis method based on failure modes, effects and criticality analysis. We calculated a criticality index for each drug involved in the drug-drug interactions based on the severity of the interaction mechanism, the frequency the drug was involved in drug-drug interactions and the risk of drug-drug interactions in patients with impaired renal function. The average number of drugs consumed in the hospital was 6 ± 2.69, involving 160 active ingredients. The most frequent were as follows: Furosemide, followed by Enalapril. Of drug-drug interactions, 2% were classified as contraindicated, 14% advised against and 83% advised caution during the hospital stay. Thirty-four drug-drug interactions were assessed, of which 23 were pharmacodynamic drug-drug interactions and 12 were pharmacokinetic drug-drug interactions (1 was both). The clinical risk calculated for each drug-drug interaction included heparins + non-steroidal anti-inflammatory drugs (NSAIDs) or Digoxin + Calcium Gluconate, cases which are pharmacodynamic drug-drug interactions with agonist effect and clinical risk of bleeding, one of the most common clinical risks in the hospital. An index of clinical risk for drug-drug interactions can be calculated based on severity by the interaction mechanism, the frequency that the drug is involved in drug-drug interactions and the risk of drug-drug interactions in an

  6. Using improved serial blood sampling method of mice to study pharmacokinetics and drug-drug interaction.

    PubMed

    Watanabe, Ayahisa; Watari, Ryosuke; Ogawa, Keiko; Shimizu, Ryosuke; Tanaka, Yukari; Takai, Nozomi; Nezasa, Ken-ichi; Yamaguchi, Yoshitaka

    2015-03-01

    In pharmacokinetic evaluation of mice, using serial sampling methods rather than a terminal blood sampling method could reduce the number of animals needed and lead to more reliable data by excluding individual differences. In addition, using serial sampling methods can be valuable for evaluation of the drug-drug interaction (DDI) potential of drug candidates. In this study, we established an improved method for serially sampling the blood from one mouse by only one incision of the lateral tail vein, and investigated whether our method could be adapted to pharmacokinetic and DDI studies. After intravenous and oral administration of ibuprofen and fexofenadine (BCS class II and III), the plasma concentration and pharmacokinetic parameters were evaluated by our method and a terminal blood sampling method, with the result that both methods gave comparable results (ibuprofen: 63.8 ± 4.0% and 64.4%, fexofenadine: 6.5 ± 0.7% and 7.9%, respectively, in bioavailability). In addition, our method could be adapted to DDI study for cytochrome P450 and organic anion transporting polypeptide inhibition. These results demonstrate that our method can be useful for pharmacokinetic evaluation from the perspective of reliable data acquisition as well as easy handling and low stress to mice and improve the quality of pharmacokinetic and DDI studies. PMID:25452230

  7. Drug-drug interaction studies on first-line anti-tuberculosis drugs.

    PubMed

    Bhutani, Hemant; Singh, Saranjit; Jindal, K C

    2005-01-01

    The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40 degrees C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%-5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%-95% and 70%-75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner. PMID:16370181

  8. Adverse drug reactions caused by drug-drug interactions reported to Croatian Agency for Medicinal Products and Medical Devices: a retrospective observational study

    PubMed Central

    Mirošević Skvrce, Nikica; Macolić Šarinić, Viola; Mucalo, Iva; Krnić, Darko; Božina, Nada; Tomić, Siniša

    2011-01-01

    Aim To analyze potential and actual drug-drug interactions reported to the Spontaneous Reporting Database of the Croatian Agency for Medicinal Products and Medical Devices (HALMED) and determine their incidence. Methods In this retrospective observational study performed from March 2005 to December 2008, we detected potential and actual drug-drug interactions using interaction programs and analyzed them. Results HALMED received 1209 reports involving at least two drugs. There were 468 (38.7%) reports on potential drug-drug interactions, 94 of which (7.8% of total reports) were actual drug-drug interactions. Among actual drug-drug interaction reports, the proportion of serious adverse drug reactions (53 out of 94) and the number of drugs (n = 4) was significantly higher (P < 0.001) than among the remaining reports (580 out of 1982; n = 2, respectively). Actual drug-drug interactions most frequently involved nervous system agents (34.0%), and interactions caused by antiplatelet, anticoagulant, and non-steroidal anti-inflammatory drugs were in most cases serious. In only 12 out of 94 reports, actual drug-drug interactions were recognized by the reporter. Conclusion The study confirmed that the Spontaneous Reporting Database was a valuable resource for detecting actual drug-drug interactions. Also, it identified drugs leading to serious adverse drug reactions and deaths, thus indicating the areas which should be in the focus of health care education. PMID:21990078

  9. Aprepitant: drug-drug interactions in perspective.

    PubMed

    Aapro, M S; Walko, C M

    2010-12-01

    The implications of chemotherapeutic drug-drug interactions can be serious and thus need to be addressed. This review concerns the potential interactions of the antiemetic aprepitant, a neurokinin-1 receptor antagonist indicated for use (in Europe) in highly emetogenic chemotherapy and moderately emetogenic chemotherapy (MEC) in combination with a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist and corticosteroids and (in the United States) in combination with other antiemetic agents, for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy including high-dose cisplatin. When considering use of aprepitant for prevention of chemotherapy-induced nausea and vomiting, its potential drug-drug interaction profile as a moderate inhibitor of cytochrome P-450 isoenzyme 3A4 (CYP3A4) has been a source of concern for some physicians and other health care professionals. We explore in this paper how real those concerns are. Our conclusion is that either no interaction or no clinically relevant interaction exists with chemotherapeutic agents (intravenous cyclophosphamide, docetaxel, intravenous vinorelbine) or 5-HT3 antagonists (granisetron, ondansetron, palonosetron). For relevant interactions, appropriate measures, such as corticosteroid dose modifications and extended International Normalized Ratio monitoring of patients on warfarin therapy, can be taken to effectively manage them. Therefore, the concern of negative interactions remains largely theoretical but needs to be verified with new agents extensively metabolized through the 3A4 pathway. PMID:20488873

  10. A Study on Polypharmacy and Potential Drug-Drug Interactions among Elderly Patients Admitted in Department of Medicine of a Tertiary Care Hospital in Puducherry

    PubMed Central

    Kalyansundaram, Dharani; Bahurupi, Yogesh

    2016-01-01

    Introduction The proportion of elderly population has been constantly increasing over last few years. Polypharmacy is unavoidable in the elderly as they often suffer from multiple co-morbidities. Potential drug-drug interaction due to polypharmacy and potential inappropriate medication among the elderly must be carefully assessed. Aim To find out polypharmacy and potential drug-drug interactions among elderly patients admitted and discharged in Department of Medicine. Materials and Methods This study was carried out on 100 patients above 65 years of age both males and females. Data was collected through review of case sheets. Polypharmacy was observed based on admission and discharge prescriptions. Frequently occurring drug-drug interactions were assessed using online checks. Results Mean number of drugs prescribed to patients on admission (7.61 ± 3.37) was more than that on discharge (5.48±2.46). More than half of these patients received 5 to 9 number of drugs. On admission 52.69% potential drug-drug interactions were observed and on discharge 52.91%. Most common drug interactions observed in both the groups were of moderate grade. Conclusion From the present study we can conclude that polypharmacy leads to more potential drug-drug interactions. To improve drug safety in this high-risk population, appropriate prescribing is very important. PMID:27042480

  11. [Drug-drug interactions in antirheumatic treatment].

    PubMed

    Krüger, K

    2012-04-01

    Clinically relevant drug-drug interactions contribute considerably to potentially dangerous drug side-effects and are frequently the reason for hospitalization. Nevertheless they are often overlooked in daily practice. For most antirheumatic drugs a vast number of interactions have been described but only a minority with clinical relevance. Several potentially important drug interactions exist for non-steroidal anti-inflammatory drugs (NSAIDs), methotrexate, azathioprine, mycophenolate-mofetil and especially for cyclosporin A. Most importantly co-medication with methotrexate and sulfmethoxazole trimethoprim as well as azathioprine and allopurinol carries the risk of severe, sometimes life-threatening consequences. Nevertheless, besides these well-known high-risk combinations in each case of polypharmacy with antirheumatic drugs it is necessary to bear in mind the possibility of drug interactions. As polypharmacy is a common therapeutic practice in older patients with rheumatic diseases, they are at special risk. PMID:22527215

  12. Cranberry juice ingestion and clinical drug-drug interaction potentials; review of case studies and perspectives.

    PubMed

    Srinivas, Nuggehally R

    2013-01-01

    Cranberry juice is a popular beverage with many health benefits. It has anthocyanins to supplement dietary needs. Based on in vitro evidence cranberry juice is an inhibitor of CYP enzymes and at higher amounts as potent as ketoconazole (CYP3A) and fluconazole (CYP2C9). There is, however, a discrepancy between in vitro and in vivo observations with respect to a number of substrates (cyclosporine, warfarin, flurbiprofen, tizanidine, diclofenac, amoxicillin, ceflacor); with the exception of a single report on midazolam, where there was a moderate increase in the AUC of midazolam in subjects pre-treated with cranberry juice. However, another study questions the clinical relevancy of in vivo pharmacokinetic interaction between cranberry juice and midazolam. The controversy may be due to a) under in vitro conditions all anthocyanin principles may be available to have a concerted effort in CYP inhibition; however, limited anthocyanin principles may be bioavailable with varying low levels in the in vivo studies; b) a faster clearance of the active anthocyanin principles under in vivo conditions may occur, leading to low threshold levels for CYP inhibition; c) efficient protein binding and/or rapid tissue uptake of the substrate may have precluded the drug availability to the enzymes in the in vivo studies. With respect to pharmacodynamic aspects, while the debate continues on the issue of an interaction between warfarin and cranberry juice, the summation of the pharmacodynamics data obtained in patients and healthy subjects from different prospectively designed and controlled clinical trials does not provide overwhelming support for the existence of a pharmacodynamic drug interaction for normal cranberry juice ingestion. However, it is apparent that consumption of large quantities of cranberry juice (about 1-2 L per day) or cranberry juice concentrates in supplements for an extended time period (>3-4 weeks) may temporally alter the effect of warfarin. Therefore, the total

  13. Best practices for the use of itraconazole as a replacement for ketoconazole in drug-drug interaction studies.

    PubMed

    Liu, Lichuan; Bello, Akintunde; Dresser, Mark J; Heald, Donald; Komjathy, Steven Ferenc; O'Mara, Edward; Rogge, Mark; Stoch, S Aubrey; Robertson, Sarah M

    2016-02-01

    Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug-drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLG's recommendations are based on careful review of available literature and internal industry experiences. PMID:26044116

  14. Human hepatoma cell lines on gas foaming templated alginate scaffolds for in vitro drug-drug interaction and metabolism studies.

    PubMed

    Stampella, A; Rizzitelli, G; Donati, F; Mazzarino, M; de la Torre, X; Botrè, F; Giardi, M F; Dentini, M; Barbetta, A; Massimi, M

    2015-12-25

    Liver in vitro systems that allow reliable prediction of major human in vivo metabolic pathways have a significant impact in drug screening and drug metabolism research. In the present study, a novel porous scaffold composed of alginate was prepared by employing a gas-in-liquid foaming approach. Galactose residues were introduced on scaffold surfaces to promote cell adhesion and to enhance liver specific functions of the entrapped HepG2/C3A cells. Hepatoma cells in the gal-alginate scaffold showed higher levels of liver specific products (albumin and urea) and were more responsive to specific inducers (e.g. dexamethasone) and inhibitors (e.g. ketoconazole) of the CYP3A4 system than in conventional monolayer culture. HepG2/C3A cells were also more efficient in terms of rapid elimination of testosterone, used as a model substance, at rates comparable to those of in vivo excretion. In addition, an improvement in metabolism of testosterone, in terms of phase II metabolite formation, was also observed when the more differentiated HepaRG cells were used. Together the data suggest that hepatocyte/gas templated alginate-systems provide an innovative high throughput platform for in vitro drug metabolism and drug-drug interaction studies, with broad fields of application, and might provide a valid tool for minimizing animal use in preclinical testing of human relevance. PMID:26456671

  15. Theoretical and experimental studies of the stability of drug-drug interact.

    PubMed

    Soares, Monica F R; Alves, Lariza D S; Nadvorny, Daniela; Soares-Sobrinho, José L; Rolim-Neto, Pedro J

    2016-11-01

    Several factors can intervene in the molecular properties and consequently in the stability of drugs. The molecular complexes formation often occur due to favor the formation of hydrogen bonds, leading the system to configuration more energy stable. This work we aim to investigate through theoretical and experimental methods the relation between stability and properties of molecular complexes the molecular complex formed between the drugs, efavirenz (EFV), lamivudine (3TC) and zidovudine (AZT). With this study was possible determining the most stable complex formed between the compounds evaluated. In addition the energy and structural properties of the complex formed in relation to its individual components allowed us to evaluate the stability of the same. PMID:27267283

  16. Pharmacokinetic drug-drug interaction study of ranolazine and metformin in subjects with type 2 diabetes mellitus.

    PubMed

    Zack, Julia; Berg, Jolene; Juan, Axel; Pannacciulli, Nicola; Allard, Martine; Gottwald, Mildred; Zhang, Heather; Shao, Yongwu; Ben-Yehuda, Ori; Jochelson, Phil

    2015-03-01

    Ranolazine and metformin may be frequently co-administered in subjects with chronic angina and co-morbid type 2 diabetes mellitus (T2DM). The potential for a drug-drug interaction was explored in two phase 1 clinical studies in subjects with T2DM to evaluate the pharmacokinetics and safety of metformin 1000 mg BID when administered with ranolazine 1000 mg BID (Study 1, N = 28) or ranolazine 500 mg BID (Study 2, N = 25) as compared to metformin alone. Co-administration of ranolazine 1000 mg BID with metformin 1000 mg BID resulted in 1.53- and 1.79-fold increases in steady-state metformin Cmax and AUCtau , respectively; co-administration of ranolazine 500 mg BID with metformin 1000 mg BID resulted in 1.22- and 1.37-fold increases in steady-state metformin Cmax and AUCtau , respectively. Co-administration of ranolazine and metformin was well tolerated in these T2DM subjects, with no serious adverse events or drug-related adverse events leading to discontinuation. The most common adverse events were nausea, diarrhea, and dizziness. These findings are consistent with a dose-related interaction between ranolazine and metformin, and suggest that a dose adjustment of metformin may not be required with ranolazine 500 mg BID; whereas, the metformin dose should not exceed 1700 mg of total daily dose when using ranolazine 1000 mg BID. PMID:27128216

  17. Participatory design for drug-drug interaction alerts.

    PubMed

    Luna, Daniel; Otero, Carlos; Almerares, Alfredo; Stanziola, Enrique; Risk, Marcelo; González Bernaldo de Quirós, Fernán

    2015-01-01

    The utilization of decision support systems, in the point of care, to alert drug-drug interactions has been shown to improve quality of care. Still, the use of these systems has not been as expected, it is believed, because of the difficulties in their knowledge databases; errors in the generation of the alerts and the lack of a suitable design. This study expands on the development of alerts using participatory design techniques based on user centered design process. This work was undertaken in three stages (inquiry, participatory design and usability testing) it showed that the use of these techniques improves satisfaction, effectiveness and efficiency in an alert system for drug-drug interactions, a fact that was evident in specific situations such as the decrease of errors to meet the specified task, the time, the workload optimization and users overall satisfaction in the system. PMID:25991099

  18. Drug-drug plasma protein binding interactions of ivacaftor.

    PubMed

    Schneider, Elena K; Huang, Johnny X; Carbone, Vincenzo; Baker, Mark; Azad, Mohammad A K; Cooper, Matthew A; Li, Jian; Velkov, Tony

    2015-06-01

    Ivacaftor is a novel cystic fibrosis (CF) transmembrane conductance regulator (CFTR) potentiator that improves the pulmonary function for patients with CF bearing a G551D CFTR-protein mutation. Because ivacaftor is highly bound (>97%) to plasma proteins, there is the strong possibility that co-administered CF drugs may compete for the same plasma protein binding sites and impact the free drug concentration. This, in turn, could lead to drastic changes in the in vivo efficacy of ivacaftor and therapeutic outcomes. This biochemical study compares the binding affinity of ivacaftor and co-administered CF drugs for human serum albumin (HSA) and α1 -acid glycoprotein (AGP) using surface plasmon resonance and fluorimetric binding assays that measure the displacement of site-selective probes. Because of their ability to strongly compete for the ivacaftor binding sites on HSA and AGP, drug-drug interactions between ivacaftor are to be expected with ducosate, montelukast, ibuprofen, dicloxacillin, omeprazole, and loratadine. The significance of these plasma protein drug-drug interactions is also interpreted in terms of molecular docking simulations. This in vitro study provides valuable insights into the plasma protein drug-drug interactions of ivacaftor with co-administered CF drugs. The data may prove useful in future clinical trials for a staggered treatment that aims to maximize the effective free drug concentration and clinical efficacy of ivacaftor. PMID:25707701

  19. Drug-drug interactions between clopidogrel and novel cardiovascular drugs.

    PubMed

    Pelliccia, Francesco; Rollini, Fabiana; Marazzi, Giuseppe; Greco, Cesare; Gaudio, Carlo; Angiolillo, Dominick J

    2015-10-15

    The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine. PMID:26341013

  20. Severe potential drug-drug interactions in older adults with dementia and associated factors

    PubMed Central

    Bogetti-Salazar, Michele; González-González, Cesar; Juárez-Cedillo, Teresa; Sánchez-García, Sergio; Rosas-Carrasco, Oscar

    2016-01-01

    OBJECTIVE: To identify the main severe potential drug-drug interactions in older adults with dementia and to examine the factors associated with these interactions. METHOD: This was a cross-sectional study. The enrolled patients were selected from six geriatrics clinics of tertiary care hospitals across Mexico City. The patients had received a clinical diagnosis of dementia based on the current standards and were further divided into the following two groups: those with severe drug-drug interactions (contraindicated/severe) (n=64) and those with non-severe drug-drug interactions (moderate/minor/absent) (n=117). Additional socio-demographic, clinical and caregiver data were included. Potential drug-drug interactions were identified using Micromedex Drug Reax 2.0® database. RESULTS: A total of 181 patients were enrolled, including 57 men (31.5%) and 124 women (68.5%) with a mean age of 80.11±8.28 years. One hundred and seven (59.1%) patients in our population had potential drug-drug interactions, of which 64 (59.81%) were severe/contraindicated. The main severe potential drug-drug interactions were caused by the combinations citalopram/anti-platelet (11.6%), clopidogrel/omeprazole (6.1%), and clopidogrel/aspirin (5.5%). Depression, the use of a higher number of medications, dementia severity and caregiver burden were the most significant factors associated with severe potential drug-drug interactions. CONCLUSIONS: Older people with dementia experience many severe potential drug-drug interactions. Anti-depressants, antiplatelets, anti-psychotics and omeprazole were the drugs most commonly involved in these interactions. Despite their frequent use, anti-dementia drugs were not involved in severe potential drug-drug interactions. The number and type of medications taken, dementia severity and depression in patients in addition to caregiver burden should be considered to avoid possible drug interactions in this population. PMID:26872079

  1. Drug-drug interaction and doping, part 1: an in vitro study on the effect of non-prohibited drugs on the phase I metabolic profile of toremifene.

    PubMed

    Mazzarino, Monica; de la Torre, Xavier; Fiacco, Ilaria; Palermo, Amelia; Botrè, Francesco

    2014-05-01

    The present study was designed to provide preliminary information on the potential impact of metabolic drug-drug interaction on the effectiveness of doping control strategies currently followed by the anti-doping laboratories to detect the intake of banned agents. In vitro assays based on the use of human liver microsomes and recombinant CYP isoforms were designed and performed to characterize the phase I metabolic profile of the prohibited agent toremifene, selected as a prototype drug of the class of selective oestrogen receptor modulators, both in the absence and in the presence of medicaments (fluconazole, ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, fluoxetine, paroxetine, nefazodone) not included in the World Anti-Doping Agency list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model developed in this study was adequate to simulate the in vivo metabolism of toremifene, confirming the results obtained in previous studies. Furthermore, our data also show that ketoconazole, itraconazole, miconazole and nefazodone cause a marked modification in the production of the metabolic products (i.e. hydroxylated and carboxylated metabolites) normally selected by the anti-doping laboratories as target analytes to detect toremifene intake; moderate variations were registered in the presence of fluconazole, paroxetine and fluoxetine; while no significant modifications were measured in the presence of ranitidine and cimetidine. This evidence imposes that the potential effect of drug-drug interactions is duly taken into account in anti-doping analysis, also for a broader significance of the analytical results. PMID:24431005

  2. Drug-drug interaction and doping, part 2: an in vitro study on the effect of non-prohibited drugs on the phase I metabolic profile of stanozolol.

    PubMed

    Mazzarino, Monica; de la Torre, Xavier; Fiacco, Ilaria; Botrè, Francesco

    2014-10-01

    The present study was designed to provide preliminary information on the potential impact of metabolic drug-drug interaction on the effectiveness of doping control strategies currently followed by the anti-doping laboratories to detect the intake of prohibited agents. In vitro assays based on the use of human liver microsomes and recombinant cytochrome P450 isoforms were developed and applied to characterize the phase I metabolic profile of the prohibited agent stanozolol, both in the absence and in the presence of substances (ketoconazole, itraconazole, miconazole, cimetidine, ranitidine, and nefazodone) not included in the World Anti-Doping Agency (WADA) list of prohibited substances and methods and frequently administered to athletes. The results show that the in vitro model utilized in this study is adequate to simulate the in vivo metabolism of stanozolol. Furthermore, our data showed that ketoconazole, itraconazole, miconazole, and nefazodone caused a marked modification in the production of the metabolic products (3'-hydroxy-stanozolol, 4β-hydroxy-stanozolol and 16β-hydroxy-stanozolol) normally selected by the anti-doping laboratories as target analytes to detect stanozolol intake. On the contrary, moderate variations were registered in the presence of cimetidine and no significant modifications were measured in the presence of ranitidine. This evidence confirms that the potential effect of drug-drug interactions is duly taken into account also in anti-doping analysis. PMID:24535830

  3. Making Transporter Models for Drug-Drug Interaction Prediction Mobile.

    PubMed

    Ekins, Sean; Clark, Alex M; Wright, Stephen H

    2015-10-01

    The past decade has seen increased numbers of studies publishing ligand-based computational models for drug transporters. Although they generally use small experimental data sets, these models can provide insights into structure-activity relationships for the transporter. In addition, such models have helped to identify new compounds as substrates or inhibitors of transporters of interest. We recently proposed that many transporters are promiscuous and may require profiling of new chemical entities against multiple substrates for a specific transporter. Furthermore, it should be noted that virtually all of the published ligand-based transporter models are only accessible to those involved in creating them and, consequently, are rarely shared effectively. One way to surmount this is to make models shareable or more accessible. The development of mobile apps that can access such models is highlighted here. These apps can be used to predict ligand interactions with transporters using Bayesian algorithms. We used recently published transporter data sets (MATE1, MATE2K, OCT2, OCTN2, ASBT, and NTCP) to build preliminary models in a commercial tool and in open software that can deliver the model in a mobile app. In addition, several transporter data sets extracted from the ChEMBL database were used to illustrate how such public data and models can be shared. Predicting drug-drug interactions for various transporters using computational models is potentially within reach of anyone with an iPhone or iPad. Such tools could help prioritize which substrates should be used for in vivo drug-drug interaction testing and enable open sharing of models. PMID:26199424

  4. Statin drug-drug interactions in a Romanian community pharmacy

    PubMed Central

    BADIU, RALUCA; BUCSA, CAMELIA; MOGOSAN, CRISTINA; DUMITRASCU, DAN

    2016-01-01

    Background and aim Statins are frequently prescribed for patients with dyslipidemia and have a well-established safety profile. However, when associated with interacting dugs, the risk of adverse effects, especially muscular toxicity, is increased. The objective of this study was to identify, characterize and quantify the prevalence of the potential drug-drug interactions (pDDIs) of statins in reimbursed prescriptions from a community pharmacy in Bucharest. Methods We analyzed the reimbursed prescriptions including statins collected during one month in a community pharmacy. The online program Medscape Drug Interaction Checker was used for checking the drug interactions and their classification based on severity: Serious – Use alternative, Significant – Monitor closely and Minor. Results 132 prescriptions pertaining to 125 patients were included in the analysis. Our study showed that 25% of the patients who were prescribed statins were exposed to pDDIs: 37 Serious and Significant interactions in 31 of the statins prescriptions. The statins involved were atorvastatin, simvastatin and rosuvastatin. Conclusions Statin pDDIs have a high prevalence and patients should be monitored closely in order to prevent the development of adverse effects that result from statin interactions. PMID:27152080

  5. Breast cancer resistance protein (ABCG2) in clinical pharmacokinetics and drug interactions: practical recommendations for clinical victim and perpetrator drug-drug interaction study design.

    PubMed

    Lee, Caroline A; O'Connor, Meeghan A; Ritchie, Tasha K; Galetin, Aleksandra; Cook, Jack A; Ragueneau-Majlessi, Isabelle; Ellens, Harma; Feng, Bo; Taub, Mitchell E; Paine, Mary F; Polli, Joseph W; Ware, Joseph A; Zamek-Gliszczynski, Maciej J

    2015-04-01

    Breast cancer resistance protein (BCRP; ABCG2) limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, immediate-release tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended. In the case of rosuvastatin, subjects with the organic anion-transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatin's cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design. PMID:25587128

  6. Drug-drug interactions affecting fluoroquinolones.

    PubMed

    Wijnands, G J; Vree, T B; Janssen, T J; Guelen, P J

    1989-12-29

    In a three-week study, the metabolism of the bronchodilator theophylline and its major metabolites formed by C-8 oxidation (1,3-dimethyluric acid) and N-demethylation (3-methylxanthine and 1-methyluric acid) was investigated in two healthy volunteers. Metabolic studies were performed following intravenous infusion of a single 6 mg/kg dose of aminophylline. During Week 1, theophylline was given alone (blank period), and during Weeks 2 and 3 it was given during oral coadministration of ofloxacin and enoxacin, respectively. Dosage of each quinolone was 200 mg twice daily for four days, starting three days prior to the theophylline infusion. During enoxacin coadministration, elimination half-lives of theophylline increased from 8.7 to 17.4 hours and from 6.1 to 12.3 hours, respectively. Total body clearance of theophylline decreased in both volunteers, whereas renal clearance did not alter. From this it was concluded that the decreased elimination results from a reduced metabolic clearance. During enoxacin coadministration, the formation of the metabolites 1-methyluric acid and 3-methylxanthine clearly was decreased, whereas the formation of 1,3-dimethyluric acid was less affected compared with the blank period. Interference with theophylline disposition by enoxacin is based predominantly on inhibition of microsomal N-demethylation. Ofloxacin comedication did not cause a change in the plasma parameters or renal excretion of theophylline and its metabolites compared with the blank period. PMID:2603893

  7. The need for translational research on drug-drug interactions.

    PubMed

    Hennessy, S; Flockhart, D A

    2012-05-01

    Drug-drug interactions (DDIs) are an important clinical and public health concern. Although DDI screening now occurs during drug development, it is difficult to predict clinical importance based on in vitro experiments. Furthermore, older drugs that were not screened may have interactions that have not yet been identified. In this Commentary, we review the importance of DDIs and argue that a translational research approach is needed to produce clinically actionable information as well as generalizable biological knowledge. PMID:22513312

  8. Incidence of potential drug-drug interactions with antidiabetic drugs.

    PubMed

    Samardzic, I; Bacic-Vrca, V

    2015-06-01

    In an effort to achieve normoglycemia more than one antidiabetic agent is usually needed. Diabetes is associated with several comorbidities and patients with diabetes are often treated with multiple medications. Therefore, patients with diabetes are especially exposed to drug-drug interactions (DDIs). The aim of this study was to analyse the incidence and type of potential DDIs of antidiabetic drugs in patients with diabetes. This retrospective study analyzed pharmacy record data of 225 patients with diabetes mellitus. Both type 1 and type 2 diabetic patients who were taking at least one antidiabetic agent during the period of six months were included. We investigated associated therapy in that period in order to identify potential DDIs with antidiabetic therapy. Potential interactions were identified by Lexicomp Lexi-Interat Online (Lexi-Comp, Inc., Hudson, USA) software which categorizes potential DDIs according to clinical significance in five types (A, B, C, D and X). Categories C, D and X are of clinical concern and always require medical attention (therapy monitoring, therapy modification or avoiding combination). We found that 80.9% of patients had at least one potential category C interaction while there were no D and X interactions. Most frequently encountered potential DDI (n = 176) included antidiabetic drugs and thiazide or thiazide like diuretics. Patients with diabetes are exposed to a large number of potential clinically significant DDIs that may require appropriate monitoring. Using databases of DDIs could be helpful in reducing the risk of potential clinically significant DDIs. PMID:26189304

  9. In vitro assessment of metabolic drug-drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies.

    PubMed

    Wang, Lifei; Zhang, Donglu; Raghavan, Nirmala; Yao, Ming; Ma, Li; Frost, Charles E; Frost, Charles A; Maxwell, Brad D; Chen, Shiang-yuan; He, Kan; Goosen, Theunis C; Humphreys, W Griffith; Grossman, Scott J

    2010-03-01

    Apixaban is an oral, direct, and highly selective factor Xa inhibitor in late-stage clinical development for the prevention and treatment of thromboembolic diseases. The metabolic drug-drug interaction potential of apixaban was evaluated in vitro. The compound did not show cytochrome P450 inhibition (IC(50) values >20 microM) in incubations of human liver microsomes with the probe substrates of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5. Apixaban did not show any effect at concentrations up to 20 muM on enzyme activities or mRNA levels of selected P450 enzymes (CYP1A2, 2B6, and 3A4/5) that are sensitive to induction in incubations with primary human hepatocytes. Apixaban showed a slow metabolic turnover in incubations of human liver microsomes with formation of O-demethylation (M2) and hydroxylation products (M4 and M7) as prominent in vitro metabolites. Experiments with human cDNA-expressed P450 enzymes and P450 chemical inhibitors and correlation with P450 activities in individual human liver microsomes demonstrated that the oxidative metabolism of apixaban for formation of all metabolites was predominantly catalyzed by CYP3A4/5 with a minor contribution of CYP1A2 and CYP2J2 for formation of M2. The contribution of CYP2C8, 2C9, and 2C19 to metabolism of apixaban was less significant. In addition, a human absorption, distribution, metabolism, and excretion study showed that more than half of the dose was excreted as unchanged parent (f(m CYP) <0.5), thus significantly reducing the overall metabolic drug-drug interaction potential of apixaban. Together with a low clinical efficacious concentration and multiple clearance pathways, these results demonstrate that the metabolic drug-drug interaction potential between apixaban and coadministered drugs is low. PMID:19940026

  10. Monitoring of drug-drug and drug-food interactions.

    PubMed

    Garabedian-Ruffalo, S M; Syrja-Farber, M; Lanius, P M; Plucinski, A

    1988-07-01

    A program for detecting and preventing potentially serious drug-drug and drug-food interactions is described. Two clinical pharmacists developed drug interaction alert (DIA) cards for each potential interaction to be monitored. The cards contain information about the proposed mechanism and potential result of the interaction, as well as information about how to monitor or circumvent the interaction. Staff pharmacists check for the occurrence of potential interactions daily as they verify the filling of the patient-medication cassettes; a poster of all the interactions that are included in the program is posted in each satellite pharmacy to serve as a quick reference for the pharmacists. When a pharmacist detects a potential interaction, he or she completes a DIA card and places it in the medication cassette drawer (if the notice is directed to the nurse) or on the front of the patient's chart (if the notice is directed to the physician). The program was introduced to hospital personnel through inservice education programs and departmental newsletters. The results of a quality assurance review indicated that 95 of 279 (34%) cards dispensed to nurses and 40 of 49 (82%) cards dispensed to physicians resulted in some form of action. The program to detect and prevent potentially serious drug-drug and drug-food interactions has been successful. PMID:3414718

  11. A Rapid Study of Botanical Drug-Drug Interaction with Protein by Re-ligand Fishing using Human Serum Albumin-Functionalized Magnetic Nanoparticles.

    PubMed

    Qing, Lin-Sen; Xue, Ying; Ding, Li-Sheng; Liu, Yi-Ming; Liang, Jian; Liao, Xun

    2015-12-01

    A great many active constituents of botanical drugs bind to human serum albumin (HSA) reversibly with a dynamic balance between the free- and bound-forms in blood. The curative or side effect of a drug depends on its free-form level, which is always influenced by other drugs, combined dosed or multi-constituents of botanical drugs. This paper presented a rapid and convenient methodology to investigate the drug-drug interactions with HSA. The interaction of two steroidal saponins, dioscin and pseudo-protodioscin, from a botanical drug was studied for their equilibrium time and equilibrium amount by re-ligand fishing using HSA functionalized magnetic nanoparticles. A clear competitive situation was obtained by this method. The equilibrium was reached soon about 15 s at a ratio of 0.44: 1. Furthermore, the interaction of pseudo-protodioscin to total steroidal saponins from DAXXK was also studied. The operation procedures of this method were faster and more convenient compared with other methods reported. PMID:26882690

  12. DRUG-DRUG INTERACTION PROFILES OF MEDICATION REGIMENS EXTRACTED FROM A DE-IDENTIFIED ELECTRONIC MEDICAL RECORDS SYSTEM.

    PubMed

    Butkiewicz, Mariusz; Restrepo, Nicole A; Haines, Jonathan L; Crawford, Dana C

    2016-01-01

    With age, the number of prescribed medications increases and subsequently raises the risk for adverse drug-drug interactions. These adverse effects lower quality of life and increase health care costs. Quantifying the potential burden of adverse effects before prescribing medications can be a valuable contribution to health care. This study evaluated medication lists extracted from a subset of the Vanderbilt de-identified electronic medical record system. Reported drugs were cross-referenced with the Kyoto Encyclopedia of Genes and Genomes DRUG database to identify known drug-drug interactions. On average, a medication regimen contained 6.58 medications and 2.68 drug-drug interactions. Here, we quantify the burden of potential adverse events from drug-drug interactions through drug-drug interaction profiles and include a number of alternative medications as provided by the Anatomical Therapeutic Chemical Classification System. PMID:27570646

  13. Mechanism of Drug-Drug Interactions Between Warfarin and Statins.

    PubMed

    Shaik, Abdul Naveed; Bohnert, Tonika; Williams, David A; Gan, Lawrence L; LeDuc, Barbara W

    2016-06-01

    The anticoagulant drug warfarin and the lipid-lowering statin drugs are commonly co-administered to patients with cardiovascular diseases. Clinically significant drug-drug interactions (DDIs) between these drugs have been recognized through case studies for many years, but the biochemical mechanisms causing these interactions have not been explained fully. Previous theories include kinetic alterations in cytochrome P-450-mediated drug metabolism or disturbances of drug-protein binding, leading to anticoagulant activity of warfarin; however, neither the enantioselective effects on warfarin metabolism nor the potential disruption of drug transporter function have been well investigated. This study investigated the etiology of the DDIs between warfarin and statins. Liquid chromatography-mass spectrometry methods were developed and validated to quantify racemic warfarin, 6 of its hydroxylated metabolites, and pure enantiomers of warfarin; these methods were applied to study the role of different absorption, distribution, metabolism, and excretion properties, leading to DDIs. Plasma protein binding displacement of warfarin was performed in the presence of statins using equilibrium dialysis method. Substrate kinetics of warfarin and pure enantiomers were performed with human liver microsomes to determine the kinetic parameters (Km and Vmax) for the formation of all 6 hydroxywarfarin metabolites, inhibition of warfarin metabolism in the presence of statins, was determined. Uptake transport studies of warfarin were performed using overexpressing HEK cell lines and efflux transport using human adenocarcinoma colonic cell line cells. Fluvastatin significantly displaced plasma protein binding of warfarin and pure enantiomers; no other statin resulted in significant displacement of warfarin. All the statins that inhibited the formation of 10-hydroxywarfarin, atorvastatin, pitavastatin, and simvastatin were highly potent compared to other statins; in contrast, only fluvastatin

  14. Prevalence and Correlates of Drug-drug Interactions in the Regional Hospital of Gjilan, Kosovo

    PubMed Central

    Shabani, Driton; Tahiri, Zejdush; Bara, Petrit; Hudhra, Klejda; Malaj, Ledian; Jucja, Besnik; Bozalia, Adnan; Burazeri, Genc

    2014-01-01

    Aim: Our aim was to assess the prevalence and socioeconomic and clinical correlates of drug-drug interactions among the adult population of transitional Kosovo. Methods: A cross-sectional study was conducted including a representative sample of 1921 patients aged ≥18 years (mean age: 57.8±11.2 years; 50.3% women; overall response: 96%) from the regional hospital of Gjilan, Kosovo, during 2011-2013. Potential drug-drug-interactions were assessed and clinical data as well as demographic and socioeconomic information were collected. Binary logistic regression was used to assess the correlates of drug-drug interactions. Results: Upon multivariable adjustment for all the demographic and socioeconomic factors as well as the clinical characteristics, drug-drug interactions were positively and significantly related to older age (OR=2.1, 95%CI=1.3-2.8), a lower educational attainment (OR=1.4, 95%CI=1.1-1.9), a longer hospitalization period (OR=2.7, 95%CI=2.1-3.6), presence of three groups of diseases [infectious diseases (OR=1.7, 95%CI=1.3-2.4), cardiovascular diseases (OR=1.8, 95%CI=1.4-2.6), respiratory diseases (OR=1.6, 95%CI=1.2-2.5)], presence of comorbid conditions (OR=3.2, 95%CI=2.3-4.4) and an intake of at least four drugs (OR=5.9, 95%CI=4.6-7.1). Conclusions: Our study provides important evidence on the prevalence and socioeconomic and clinical correlates of drug-drug interactions among the hospitalized patients in the regional hospital of Gjilan, Kosovo. Findings from our study should raise the awareness of decision-makers and policy makers about the prevalence and determinants of drug-drug interactions in the adult population of post-war Kosovo. PMID:25395892

  15. Clinically relevant drug-drug interactions between antiretrovirals and antifungals

    PubMed Central

    Vadlapatla, Ramya Krishna; Patel, Mitesh; Paturi, Durga K; Pal, Dhananjay; Mitra, Ashim K

    2015-01-01

    Introduction Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide. Areas covered Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations. Expert opinion Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echino-candins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections. PMID:24521092

  16. Inhaled loxapine and intramuscular lorazepam in healthy volunteers: a randomized placebo-controlled drug-drug interaction study.

    PubMed

    Spyker, Daniel A; Cassella, James V; Stoltz, Randall R; Yeung, Paul P

    2015-12-01

    Pharmacodynamic effects and safety of single-dose inhaled loxapine administered via the Staccato(®) system and intramuscular (IM) lorazepam in combination versus each agent alone were compared in a randomized, double-blind, crossover study in healthy volunteers. Subjects received: inhaled loxapine 10 mg + IM lorazepam 1 mg; inhaled loxapine 10 mg + IM placebo; IM lorazepam 1 mg + Staccato placebo in random order, each separated by a 3-day washout. Primary endpoints were maximum effect (minimum value) and area under the curve (AUC) from baseline to 2 h post treatment for respirations/min and pulse oximetry. Least-squares means (90% confidence interval [CI]) for concomitant treatment versus each agent alone were derived and equivalence (no difference) confirmed if the 90% CI was within 0.8-1.25. Blood pressure (BP), heart rate (HR), sedation (100-mm visual analog scale), and adverse events (AEs) were recorded. All 18 subjects (mean age, 20.4 years; 61% male) completed the study. There was no difference between inhaled loxapine + IM lorazepam and either agent alone on respiration or pulse oximetery during the 12-h postdose period, confirmed by 90% CIs for AUC and C min ratios. BP and HR were no different for inhaled loxapine + IM lorazepam and each agent alone over a 12-h postdose period. Although the central nervous system sedative effects were observed for each treatment in healthy volunteers, the effect was greater following concomitant lorazepam 1 mg IM + inhaled loxapine 10 mg administration. There were no deaths, serious AEs, premature discontinuations due to AEs, or treatment-related AEs. PMID:27022468

  17. In Vitro and In Vivo Mechanistic Studies toward Understanding the Role of 1-Aminobenzotriazole in Rat Drug-Drug Interactions.

    PubMed

    Boily, Marc-Olivier; Chauret, Nathalie; Laterreur, Julie; Leblond, François A; Boudreau, Chantal; Duquet, Marie-Claude; Lévesque, Jean-François; Ste-Marie, Line; Pichette, Vincent

    2015-12-01

    1-Aminobenzotriazole (ABT) is regularly used in vivo as a nonspecific and irreversible cytochrome P450 inhibitor to elucidate the role of metabolism on the pharmacokinetic profile of xenobiotics. However, few reports have considered the recent findings that ABT can alter drug absorption or have investigated the possible differential inhibition of ABT on intestinal and hepatic metabolism. To address these uncertainties, pharmacokinetic studies under well controlled and defined ABT pretreatment conditions (50 mg/kg, 1 hour ABT i.v. and 16 hours ABT p.o.) were conducted prior to the oral administration of metoprolol, a permeable P450 probe that undergoes extensive intestinal and hepatic metabolism. The pharmacokinetic profile of metoprolol was affected differently by the two ABT pretreatments. An increase in area under the curve of 16-fold with ABT p.o. and 6.5-fold with ABT i.v. was observed compared with control. Based on in vitro studies, this difference could not be attributed to a differential inhibition of intestinal and hepatic metabolism. In the ABT i.v. pretreatment group, the increase in area under the curve was also associated with a prolonged time at maximal concentration (24-fold versus control), suggesting a delay in absorption. This was further confirmed by the administration of a charcoal meal, which resulted in a 7-fold increase in stomach weights in the 1-hour ABT pretreated groups compared with the untreated or 16-hour ABT pretreated rats. Based on these results, we recommend pretreating rats with ABT p.o. 16 hours before the administration of a test compound to preserve the inhibitory effect on intestinal and hepatic metabolism and avoid the confounding effect on drug absorption. PMID:26438628

  18. USING SEMANTIC PREDICATIONS TO UNCOVER DRUG-DRUG INTERACTIONS IN CLINICAL DATA

    PubMed Central

    Zhang, Rui; Cairelli, Michael J.; Fiszman, Marcelo; Rosemblat, Graciela; Kilicoglu, Halil; Rindflesch, Thomas C.; Pakhomov, Serguei V.; Melton, Genevieve B.

    2014-01-01

    In this study we report on potential drug-drug interactions between drugs occurring in patient clinical data. Results are based on relationships in SemMedDB, a database of structured knowledge extracted from all MEDLINE citations (titles and abstracts) using SemRep. The core of our methodology is to construct two potential drug-drug interaction schemas, based on relationships extracted from SemMedDB. In the first schema, Drug1 and Drug2 interact through Drug1’s effect on some gene, which in turn affects Drug2. In the second, Drug1 affects Gene1, while Drug2 affects Gene2. Gene1 and Gene2, together, then have an effect on some biological function. After checking each drug pair from the medication lists of each of 22 patients, we found 19 known and 62 unknown drug-drug interactions using both schemas. For example, our results suggest that the interaction of Lisinopril, an ACE inhibitor commonly prescribed for hypertension, and the antidepressant sertraline can potentially increase the likelihood and possibly the severity of psoriasis. We also assessed the relationships extracted by SemRep from a linguistic perspective and found that the precision of SemRep was 0.58 for 300 randomly selected sentences from MEDLINE. Our study demonstrates that the use of structured knowledge in the form of relationships from the biomedical literature can support the discovery of potential drug-drug interactions occurring in patient clinical data. Moreover, SemMedDB provides a good knowledge resource for expanding the range of drugs, genes, and biological functions considered as elements in various drug-drug interaction pathways. PMID:24448204

  19. Prolonged Drug-Drug Interaction between Terbinafine and Perphenazine.

    PubMed

    Park, Young-Min

    2012-12-01

    I report here an elderly woman receiving perphenazine together with terbinafine. After 1 week of terbinafine treatment she experienced extrapyramidal symptoms and, in particular, akathisia. Her symptoms did not disappear for 6 weeks, and so at 2 weeks prior to this most recent admission she had stopped taking terbinafine. However, these symptoms persisted for 3 weeks after discontinuing terbinafine. It is well known that terbinafine inhibits CYP2D6 and that perphenazine is metabolized mainly by CYP2D6. Thus, when terbinafine and perphenazine are coadministrated, the subsequent increase in the concentration of perphenazine may induce extrapyramidal symptoms. Thus, terbinafine therapy may be associated with the induction and persistence of extrapyramidal symptoms, including akathisia. This case report emphasizes the importance of monitoring drug-drug interactions in patients undergoing terbinafine and perphenazine therapy. PMID:23251210

  20. Prolonged Drug-Drug Interaction between Terbinafine and Perphenazine

    PubMed Central

    2012-01-01

    I report here an elderly woman receiving perphenazine together with terbinafine. After 1 week of terbinafine treatment she experienced extrapyramidal symptoms and, in particular, akathisia. Her symptoms did not disappear for 6 weeks, and so at 2 weeks prior to this most recent admission she had stopped taking terbinafine. However, these symptoms persisted for 3 weeks after discontinuing terbinafine. It is well known that terbinafine inhibits CYP2D6 and that perphenazine is metabolized mainly by CYP2D6. Thus, when terbinafine and perphenazine are coadministrated, the subsequent increase in the concentration of perphenazine may induce extrapyramidal symptoms. Thus, terbinafine therapy may be associated with the induction and persistence of extrapyramidal symptoms, including akathisia. This case report emphasizes the importance of monitoring drug-drug interactions in patients undergoing terbinafine and perphenazine therapy. PMID:23251210

  1. Drug-Drug Interaction Extraction via Convolutional Neural Networks

    PubMed Central

    Liu, Shengyu; Tang, Buzhou; Chen, Qingcai; Wang, Xiaolong

    2016-01-01

    Drug-drug interaction (DDI) extraction as a typical relation extraction task in natural language processing (NLP) has always attracted great attention. Most state-of-the-art DDI extraction systems are based on support vector machines (SVM) with a large number of manually defined features. Recently, convolutional neural networks (CNN), a robust machine learning method which almost does not need manually defined features, has exhibited great potential for many NLP tasks. It is worth employing CNN for DDI extraction, which has never been investigated. We proposed a CNN-based method for DDI extraction. Experiments conducted on the 2013 DDIExtraction challenge corpus demonstrate that CNN is a good choice for DDI extraction. The CNN-based DDI extraction method achieves an F-score of 69.75%, which outperforms the existing best performing method by 2.75%. PMID:26941831

  2. Text Mining Driven Drug-Drug Interaction Detection

    PubMed Central

    Yan, Su; Jiang, Xiaoqian; Chen, Ying

    2014-01-01

    Identifying drug-drug interactions is an important and challenging problem in computational biology and healthcare research. There are accurate, structured but limited domain knowledge and noisy, unstructured but abundant textual information available for building predictive models. The difficulty lies in mining the true patterns embedded in text data and developing efficient and effective ways to combine heterogenous types of information. We demonstrate a novel approach of leveraging augmented text-mining features to build a logistic regression model with improved prediction performance (in terms of discrimination and calibration). Our model based on synthesized features significantly outperforms the model trained with only structured features (AUC: 96% vs. 91%, Sensitivity: 90% vs. 82% and Specificity: 88% vs. 81%). Along with the quantitative results, we also show learned “latent topics”, an intermediary result of our text mining module, and discuss their implications. PMID:25131635

  3. Text Mining Driven Drug-Drug Interaction Detection.

    PubMed

    Yan, Su; Jiang, Xiaoqian; Chen, Ying

    2013-01-01

    Identifying drug-drug interactions is an important and challenging problem in computational biology and healthcare research. There are accurate, structured but limited domain knowledge and noisy, unstructured but abundant textual information available for building predictive models. The difficulty lies in mining the true patterns embedded in text data and developing efficient and effective ways to combine heterogenous types of information. We demonstrate a novel approach of leveraging augmented text-mining features to build a logistic regression model with improved prediction performance (in terms of discrimination and calibration). Our model based on synthesized features significantly outperforms the model trained with only structured features (AUC: 96% vs. 91%, Sensitivity: 90% vs. 82% and Specificity: 88% vs. 81%). Along with the quantitative results, we also show learned "latent topics", an intermediary result of our text mining module, and discuss their implications. PMID:25131635

  4. Drug-Drug Interaction Extraction via Convolutional Neural Networks.

    PubMed

    Liu, Shengyu; Tang, Buzhou; Chen, Qingcai; Wang, Xiaolong

    2016-01-01

    Drug-drug interaction (DDI) extraction as a typical relation extraction task in natural language processing (NLP) has always attracted great attention. Most state-of-the-art DDI extraction systems are based on support vector machines (SVM) with a large number of manually defined features. Recently, convolutional neural networks (CNN), a robust machine learning method which almost does not need manually defined features, has exhibited great potential for many NLP tasks. It is worth employing CNN for DDI extraction, which has never been investigated. We proposed a CNN-based method for DDI extraction. Experiments conducted on the 2013 DDIExtraction challenge corpus demonstrate that CNN is a good choice for DDI extraction. The CNN-based DDI extraction method achieves an F-score of 69.75%, which outperforms the existing best performing method by 2.75%. PMID:26941831

  5. Using a Simulated Infobutton Linked to an Evidence-Based Resource to Research Drug-Drug Interactions: A Pilot Study with Third-Year Dental Students.

    PubMed

    Dragan, Irina F; Newman, Michael; Stark, Paul; Steffensen, Bjorn; Karimbux, Nadeem

    2015-11-01

    Many health professions students and clinicians are using evidence-based databases that allow for quicker and more accurate clinical decisions. The aims of this pilot study were to compare third-year dental students' speed and accuracy in researching questions about drug-drug interactions (DDI) when using two different methods: a simulated infobutton linked to the evidence-based clinical decision support resource UpToDate versus traditional Internet resources accessed through a computer or smart device. Students researched two simulated cases during two sessions. In the first session, half the students used the infobutton, while the other half used traditional electronic tools only. In the second session, ten days later, a cross-over took place. The sessions were timed, and after researching the case, students answered three questions on the use of antibiotics, analgesics, and local anesthetics. Of the 50 students who volunteered for the study, two were excluded, and 44 participated in both sessions and the exam. The results showed that the students took a similar amount of time to identify DDI whether they used the infobutton (mean=286.5 seconds) or traditional tools (265.2 seconds); the difference was not statistically significant (p=0.429). Their scores using the two research methods were similar in all three content areas: antibiotics (p=0.797), analgesics (p=0.850), and local anesthetics (p=0.850). In a post-intervention survey, students were generally favorable about infobutton and UpToDate, reporting the tool was easy to use (62.5%), provided the answer they were looking for (53.1%), was fast (50%), and they would use it again (68.8%). This pilot study found that the time and accuracy of these students conducting DDI research with the infobutton and UpToDate were about the same as using traditional Internet resources. PMID:26522641

  6. Using linked data for mining drug-drug interactions in electronic health records.

    PubMed

    Pathak, Jyotishman; Kiefer, Richard C; Chute, Christopher G

    2013-01-01

    By nature, healthcare data is highly complex and voluminous. While on one hand, it provides unprecedented opportunities to identify hidden and unknown relationships between patients and treatment outcomes, or drugs and allergic reactions for given individuals, representing and querying large network datasets poses significant technical challenges. In this research, we study the use of Semantic Web and Linked Data technologies for identifying drug-drug interaction (DDI) information from publicly available resources, and determining if such interactions were observed using real patient data. Specifically, we apply Linked Data principles and technologies for representing patient data from electronic health records (EHRs) at Mayo Clinic as Resource Description Framework (RDF), and identify potential drug-drug interactions (PDDIs) for widely prescribed cardiovascular and gastroenterology drugs. Our results from the proof-of-concept study demonstrate the potential of applying such a methodology to study patient health outcomes as well as enabling genome-guided drug therapies and treatment interventions. PMID:23920643

  7. Using Linked Data for Mining Drug-Drug Interactions in Electronic Health Records

    PubMed Central

    Pathak, Jyotishman; Kiefer, Richard C.; Chute, Christopher G.

    2014-01-01

    By nature, healthcare data is highly complex and voluminous. While on one hand, it provides unprecedented opportunities to identify hidden and unknown relationships between patients and treatment outcomes, or drugs and allergic reactions for given individuals, representing and querying large network datasets poses significant technical challenges. In this research, we study the use of Semantic Web and Linked Data technologies for identifying drug-drug interaction (DDI) information from publicly available resources, and determining if such interactions were observed using real patient data. Specifically, we apply Linked Data principles and technologies for representing patient data from electronic health records (EHRs) at Mayo Clinic as Resource Description Framework (RDF), and identify potential drug-drug interactions (PDDIs) for widely prescribed cardiovascular and gastroenterology drugs. Our results from the proof-of-concept study demonstrate the potential of applying such a methodology to study patient health outcomes as well as enabling genome-guided drug therapies and treatment interventions. PMID:23920643

  8. QSAR Modeling and Prediction of Drug-Drug Interactions.

    PubMed

    Zakharov, Alexey V; Varlamova, Ekaterina V; Lagunin, Alexey A; Dmitriev, Alexander V; Muratov, Eugene N; Fourches, Denis; Kuz'min, Victor E; Poroikov, Vladimir V; Tropsha, Alexander; Nicklaus, Marc C

    2016-02-01

    Severe adverse drug reactions (ADRs) are the fourth leading cause of fatality in the U.S. with more than 100,000 deaths per year. As up to 30% of all ADRs are believed to be caused by drug-drug interactions (DDIs), typically mediated by cytochrome P450s, possibilities to predict DDIs from existing knowledge are important. We collected data from public sources on 1485, 2628, 4371, and 27,966 possible DDIs mediated by four cytochrome P450 isoforms 1A2, 2C9, 2D6, and 3A4 for 55, 73, 94, and 237 drugs, respectively. For each of these data sets, we developed and validated QSAR models for the prediction of DDIs. As a unique feature of our approach, the interacting drug pairs were represented as binary chemical mixtures in a 1:1 ratio. We used two types of chemical descriptors: quantitative neighborhoods of atoms (QNA) and simplex descriptors. Radial basis functions with self-consistent regression (RBF-SCR) and random forest (RF) were utilized to build QSAR models predicting the likelihood of DDIs for any pair of drug molecules. Our models showed balanced accuracy of 72-79% for the external test sets with a coverage of 81.36-100% when a conservative threshold for the model's applicability domain was applied. We generated virtually all possible binary combinations of marketed drugs and employed our models to identify drug pairs predicted to be instances of DDI. More than 4500 of these predicted DDIs that were not found in our training sets were confirmed by data from the DrugBank database. PMID:26669717

  9. Impact of genetic polymorphisms and drug-drug interactions on clopidogrel and prasugrel response variability.

    PubMed

    Ancrenaz, V; Daali, Y; Fontana, P; Besson, M; Samer, C; Dayer, P; Desmeules, J

    2010-10-01

    Thienopyridine antiaggregating platelet agents (clopidogrel and prasugrel) act as irreversible P2Y12 receptor inhibitors. They are used with aspirin to prevent thrombotic complications after an acute coronary syndrome or percutaneous coronary intervention. A large interindividual variability in response to clopidogrel and to a lesser extent to prasugrel is observed and may be related to their metabolism. Clopidogrel and prasugrel are indeed prodrugs converted into their respective active metabolites by several cytochromes P450 (CYPs). Besides clopidogrel inactivation (85%) by esterases to the carboxylic acid, clopidogrel is metabolized by CYPs to 2-oxo-clopidogrel (15%) and further metabolized to an unstable but potent platelet-aggregating inhibitor. Prasugrel is more potent than clopidogrel with a better bioavailability and lower pharmacodynamic variability. Prasugrel is completely converted by esterases to an intermediate oxo-metabolite (R-95913) further bioactivated by CYPs. Numerous clinical studies have shown the influence of CYP2C19 polymorphism on clopidogrel antiplatelet activity. Moreover, unwanted drug-drug pharmacokinetic interactions influencing CYP2C19 activity and clopidogrel bioactivation such as with proton pump inhibitors remain a matter of intense controversy. Several studies have also demonstrated that CYP3A4/5 and CYP1A2 are important in clopidogrel bioactivation and should also be considered as potential targets for unwanted drug-drug interactions. Prasugrel bioactivation is mainly related to CYP3A4 and 2B6 activity and therefore the question of the effect of drug-drug interaction on its activity is open. The purpose of this review is to critically examine the current literature evaluating the influence of genetic and environmental factors such as unwanted drug-drug interaction affecting clopidogrel and prasugrel antiplatelet activity. PMID:20942779

  10. Intrapartum Magnesium Sulfate and the Potential for Cardiopulmonary Drug-Drug Interactions

    PubMed Central

    Campbell, Sarah C.; Stockmann, Chris; Balch, Alfred; Clark, Erin A.S.; Kamyar, Manijeh; Varner, Michael; Korgenski, E. Kent; Bonkowsky, Joshua L.; Spigarelli, Michael G.; Sherwin, Catherine M.T.

    2014-01-01

    Objective This study sought to determine the frequency of possible cardiopulmonary drug-drug interactions among pregnant women who received intrapartum magnesium sulfate (MgSO4). Methods Pregnant women admitted to an Intermountain Healthcare facility between January 2009 and October 2011 were studied if they received one or more doses of MgSO4. Concomitant medications were electronically queried from an electronic health records system. Adverse events were identified using administrative discharge codes. The frequency of cardiopulmonary drug-drug interactions was compared among women who did, and did not, receive aminoglycoside antibiotics, antacids / laxatives, calcium channel blockers, corticosteroids, diuretics, neuromuscular blocking agents, and vitamin D analogs, all of which are contraindicated for patients receiving MgSO4. Results Overall, 683 women received intrapartum MgSO4 during the study period. A total of 219 MgSO4 potentially interacting drugs were identified among 155 (23%) unique patients. The most commonly identified potentially interacting agents included calcium channel blockers (26%), diuretics (25%), and antacids / laxatives (19%). Longer hospital stays were significantly associated with increasing numbers of MgSO4 interacting drugs (P<0.001). Three of 53 (6%) women who received furosemide experienced a cardiac arrest, compared to 0 of 618 (0%) women who did not receive furosemide (Fisher’s Exact Test P<0.001). Conclusion Intrapartum administration of drugs that interact with MgSO4 is common and associated with prolonged hospital stays and potentially cardiopulmonary drug-drug interactions. Caution is warranted when prescribing MgSO4 in combination with known interacting medications. PMID:24487252

  11. Assessment of the consistency among three drug compendia in listing and ranking of drug-drug interactions

    PubMed Central

    Nikolić, Božana S.; Ilić, Maja S.

    2013-01-01

    Inconsistent information about drug-drug interactions can cause variations in prescribing, and possibly increase the incidence of morbidity and mortality. The aim of this study was to assess whether there is an inconsistency in drug-drug interaction listing and ranking in three authoritative, freely accessible online drug information sources: The British National Formulary; The Compendium about Drugs Licensed for Use in the United Kingdom (the Electronic Medicines Compendium) and the Compendium about Drugs Licensed for Use in the United States (the DailyMed). Information on drug-drug interactions for thirty drugs which have a high or medium potential for interactions have been selected for analysis. In total, 1971 drug-drug interactions were listed in all three drug information sources, of these 992 were ranked as the interactions with the potential of clinical significance. Comparative analysis identified that 63.98% of interactions were listed in only one drug information source, and 66.63% of interactions were ranked in only one drug information source. Only 15.12% listed and 11.19% ranked interactions were identified in all three information sources. Intraclass correlation coefficient indicated a weak correlation among the three drug information sources in listing (0.366), as well as in ranking drug interactions (0.467). This study showed inconsistency of information on drug-drug interaction for the selected drugs in three authoritative, freely accessible online drug information sources. The application of a uniform methodology in assessment of information, and then the presentation of information in a standardized format is required to prevent and adequately manage drug-drug interactions. PMID:24289762

  12. Incidence of Potential Drug-Drug Interaction and Related Factors in Hospitalized Neurological Patients in two Iranian Teaching Hospitals

    PubMed Central

    Namazi, Soha; Pourhatami, Shiva; Borhani-Haghighi, Afshin; Roosta, Sareh

    2014-01-01

    Background: Reciprocal drug interactions are among the most common causes of adverse drug reactions. We investigated the incidence and related risk factors associated with mutual drug interactions in relation to prescriptions written in the neurology wards of two major teaching hospitals in Shiraz, southern Iran. Methods: Data was collected from hand-written prescriptions on a daily basis. Mutual drug interactions were identified using Lexi-Comp 2012 version 1.9.1. Type D and X drug interactions were considered as potential drug-drug interactions. The potential risk factors associated with drug-drug interactions included the patient’s age and gender, number of medications and orders, length of hospitalization and the type of neurological disorder. To determine potential drug-drug interactions, relevant interventions were suggested to the physicians or nurses and the outcome of the interventions were documented. Results: The study comprised 589 patients, of which 53% were males and 47% females, with a mean age of 56.65±18.19 SD years. A total of 4942 drug orders and 3784 medications were prescribed among which 4539 drug-drug interactions were detected, including 4118 type C, 403 type D, and 18 type X. Using a logistic regression model, the number of medications, length of hospitalization and non-vascular type of the neurological disorder were found to be significantly associated with potential drug-drug interactions. From the total interventions, 74.24% were accepted by physicians and nurses. Conclusion: Potentially hazardous reciprocal drug interactions are common among patients in neurology wards. Clinical pharmacists can play a critical role in the prevention of drug-drug interactions in hospitalized patients. PMID:25429173

  13. Assessment of potential drug-drug interactions and its associated factors in the hospitalized cardiac patients.

    PubMed

    Murtaza, Ghulam; Khan, Muhammad Yasir Ghani; Azhar, Saira; Khan, Shujaat Ali; Khan, Tahir M

    2016-03-01

    Drug-drug interactions (DDIs) may result in the alteration of therapeutic response. Sometimes they may increase the untoward effects of many drugs. Hospitalized cardiac patients need more attention regarding drug-drug interactions due to complexity of their disease and therapeutic regimen. This research was performed to find out types, prevalence and association between various predictors of potential drug-drug interactions (pDDIs) in the Department of Cardiology and to report common interactions. This study was performed in the hospitalized cardiac patients at Ayub Teaching Hospital, Abbottabad, Pakistan. Patient charts of 2342 patients were assessed for pDDIs using Micromedex® Drug Information. Logistic regression was applied to find predictors of pDDIs. The main outcome measure in the study was the association of the potential drug-drug interactions with various factors such as age, gender, polypharmacy, and hospital stay of the patients. We identified 53 interacting-combinations that were present in total 5109 pDDIs with median number of 02 pDDIs per patient. Overall, 91.6% patients had at least one pDDI; 86.3% were having at least one major pDDI, and 84.5% patients had at least one moderate pDDI. Among 5109 identified pDDIs, most were of moderate (55%) or major severity (45%); established (24.2%), theoretical (18.8%) or probable (57%) type of scientific evidence. Top 10 common pDDIs included 3 major and 7 moderate interactions. Results obtained by multivariate logistic regression revealed a significant association of the occurrence of pDDIs in patient with age of 60 years or more (p < 0.001), hospital stay of 7 days or longer (p < 0.001) and taking 7 or more drugs (p < 0.001). We found a high prevalence for pDDIs in the Department of Cardiology, most of which were of moderate severity. Older patients, patients with longer hospital stay and with elevated number of prescribed drugs were at higher risk of pDDIs. PMID:27013915

  14. [Drug-drug interactions in the elderly : Which ones really matter?].

    PubMed

    Bitter, K; Schlender, J F; Woltersdorf, R

    2016-07-01

    Pharmacotherapy in the elderly is challenging due to age-related physiological changes, high interindividual variability, and increasing frequency of multimorbidity. The resulting polypharmacy increases the risk of drug-drug interactions and requires an individual risk assessment. Some drug-drug interactions are documented to be associated with harm in older adults including intoxication, gastrointestinal bleeding, or falls. Therefore, they are considered to be of special importance in the elderly. Moreover, frequent risk factors and continuous physiological alterations in the elderly should be taken into account during risk assessment. This review exemplifies clinically relevant drug-drug interactions and risk factors in the elderly. In addition, assessment tools as well as prevention and management strategies for clinical practice are presented. PMID:27294383

  15. Concomitant therapy in people with epilepsy: potential drug-drug interactions and patient awareness.

    PubMed

    Eyal, Sara; Rasaby, Sivan; Ekstein, Dana

    2014-02-01

    People with epilepsy (PWE) may use prescription and over-the-counter (OTC) drugs for the treatment of concomitant diseases. Combinations of these drugs, as well as dietary supplements, with antiepileptic drugs (AEDs) may lead to reduced control of seizures and of coexisting medical conditions and increased risk of adverse drug reactions (ADRs). The aims of this study were to obtain comprehensive lists of medications, dietary supplements, botanicals, and specific food components used by adult PWE and to evaluate the potential for interactions involving AEDs and patients' awareness of such potential interactions. We conducted a prospective, questionnaire-based study of PWE attending the Hadassah-Hebrew University Epilepsy Clinic over a period of 7months. The questionnaire interview included the listing of medications, medicinal herbs, dietary supplements, and specific food components consumed and the knowledge of potential drug-drug interactions (DDIs), and it was conducted by a pharmacist. Drug-drug interactions were analyzed via the Micromedex online database. Out of 179 patients who attended the clinic over the study period, we interviewed 73 PWE, of which 71 were included in our final analysis. The mean number of AEDs consumed per subject was 1.7 (SD: 0.8, range: 1-4). Forty (56%) subjects were also treated with other prescription and/or OTC medications, and thirty-four (48%) took dietary supplements. Drug families most prone to DDIs involving AEDs included antipsychotic agents, selective serotonin reuptake inhibitors, and statins. Two-thirds of study participants (67%) knew that DDIs may lead to ADRs, but only half (56%) were aware of the potential for reduced seizure control. Only 44% always reported treatment with AEDs to medical professionals. This study provides for the first time a comprehensive picture of prescription and OTC drugs and food supplements used by PWE. Despite a considerable potential for DDIs involving AEDs, patient awareness is limited

  16. Resolving anaphoras for the extraction of drug-drug interactions in pharmacological documents

    PubMed Central

    2010-01-01

    Background Drug-drug interactions are frequently reported in the increasing amount of biomedical literature. Information Extraction (IE) techniques have been devised as a useful instrument to manage this knowledge. Nevertheless, IE at the sentence level has a limited effect because of the frequent references to previous entities in the discourse, a phenomenon known as 'anaphora'. DrugNerAR, a drug anaphora resolution system is presented to address the problem of co-referring expressions in pharmacological literature. This development is part of a larger and innovative study about automatic drug-drug interaction extraction. Methods The system uses a set of linguistic rules drawn by Centering Theory over the analysis provided by a biomedical syntactic parser. Semantic information provided by the Unified Medical Language System (UMLS) is also integrated in order to improve the recognition and the resolution of nominal drug anaphors. Besides, a corpus has been developed in order to analyze the phenomena and evaluate the current approach. Each possible case of anaphoric expression was looked into to determine the most effective way of resolution. Results An F-score of 0.76 in anaphora resolution was achieved, outperforming significantly the baseline by almost 73%. This ad-hoc reference line was developed to check the results as there is no previous work on anaphora resolution in pharmalogical documents. The obtained results resemble those found in related-semantic domains. Conclusions The present approach shows very promising results in the challenge of accounting for anaphoric expressions in pharmacological texts. DrugNerAr obtains similar results to other approaches dealing with anaphora resolution in the biomedical domain, but, unlike these approaches, it focuses on documents reflecting drug interactions. The Centering Theory has proved being effective at the selection of antecedents in anaphora resolution. A key component in the success of this framework is the

  17. Potential drug-drug interactions in cardiothoracic intensive care unit of a pulmonary teaching hospital.

    PubMed

    Farzanegan, Behrooz; Alehashem, Maryam; Bastani, Marjan; Baniasadi, Shadi

    2015-02-01

    Little is known about clinically significant drug-drug interactions (DDIs) in respiratory settings. DDIs are more likely to occur in critically ill patients due to complex pharmacotherapy regimens and organ dysfunctions. The aim of this study was to identify the pattern of potential DDIs (pDDIs) occurring in cardiothoracic intensive care unit (ICU) of a pulmonary hospital. A prospective observational study was conducted for 6 months. All pDDIs for admitted patients in cardiothoracic ICU were identified with Lexi-Interact program and assessed by a clinical pharmacologist. The interacting drugs, reliability, mechanisms, potential outcomes, and clinical management were evaluated for severe and contraindicated interactions. The study included 195 patients. Lung cancer (14.9%) was the most common diagnosis followed by tracheal stenosis (14.3%). The rate of pDDIs was 720.5/100 patients. Interactions were more commonly observed in transplant patients. 17.7% of pDDIs were considered as severe and contraindicated interactions. Metabolism (54.8%) and additive (24.2%) interactions were the most frequent mechanisms leading to pDDIs, and azole antifungals and fluoroquinolones were the main drug classes involved. The pattern of pDDIs in cardiothoracic ICU differs from other ICU settings. Specialized epidemiological knowledge of drug interactions may help clinical practitioners to reduce the risk of adverse drug events. PMID:25369984

  18. Albumin Supplement Affects the Metabolism and Metabolism-Related Drug-Drug Interaction of Fenoprofen Enantiomers.

    PubMed

    Wang, Nan; Wang, Feng; Meng, Yu; Yang, Guo-Hui; Chen, Ju-Wu; Wang, Jia-Xiang

    2015-07-01

    The influence of albumin towards the metabolism behavior of fenoprofen enantiomers and relevant drug-drug interaction was investigated in the present study. The metabolic behavior of fenoprofen enantiomers was compared in a phase II metabolic incubation system with and without bovine serum albumin (BSA). BSA supplement increased the binding affinity parameter (Km) of (R)-fenoprofen towards human liver microsomes (HLMs) from 148.3 to 214.4 μM. In contrast, BSA supplement decreased the Km of (S)-fenoprofen towards HLMs from 218.2 to 123.5 μM. For maximum reaction velocity (Vmax), the addition of BSA increased the Vmax of (R)-fenoprofen from 1.3 to 1.6 nmol/min/mg protein. In the contrast, BSA supplement decreased the Vmax value from 3.3 to 1.5 nmol/min/mg protein. Andrographolide-fenoprofen interaction was used as an example to investigate the influence of BSA supplement towards fenoprofen-relevant drug-drug interaction. The addition of 0.2% BSA in the incubation system significantly decreased the inhibition potential of andrographolide towards (R)-fenoprofen metabolism (P < 0.001). Different from (R)-fenoprofen, the addition of BSA significantly increased the inhibition potential of andrographolide towards the metabolism of (S)-fenoprofen. BSA supplement also changed the inhibition kinetic type and parameter of andrographolide towards the metabolism of (S)-fenoprofen. In conclusion, albumin supplement changes the metabolic behavior of fenoprofen enantiomers and the fenoprofen-andrographolide interaction. PMID:26037509

  19. A Successful Model and Visual Design for Creating Context-Aware Drug-Drug Interaction Alerts

    PubMed Central

    Duke, Jon D.; Bolchini, Davide

    2011-01-01

    Evaluating the potential harm of a drug-drug interaction (DDI) requires knowledge of a patient’s relevant co-morbidities and risk factors. Current DDI alerts lack such patient-specific contextual data. In this paper, we present an efficient model for integrating pertinent patient data into DDI alerts. This framework is designed to be interoperable across multiple drug knowledge bases and clinical information systems. To evaluate the model, we generated a set of contextual DDI data using our local drug knowledge base then conducted an evaluation study of a prototype contextual alert design. The alert received favorable ratings from study subjects, who agreed it was an improvement over traditional alerts and was likely to support clinical management and save physician time. This framework may ultimately help reduce alert fatigue through the dynamic display of DDI alerts based on patient risk. PMID:22195086

  20. Potential Drug-drug Interactions in Post-CCU of a Teaching Hospital.

    PubMed

    Haji Aghajani, Mohammad; Sistanizad, Mohammad; Abbasinazari, Mohammad; Abiar Ghamsari, Mahdieh; Ayazkhoo, Ladan; Safi, Olia; Kazemi, Katayoon; Kouchek, Mehran

    2013-01-01

    Drug-drug interactions (DDIs) can lead to increased toxicity or reduction in therapeutic efficacy. This study was designed to assess the incidence of potential drug interactions (PDI) and rank their clinical value in post coronary care unit (Post-CCU) of a teaching hospital in Tehran, Iran. In this prospective study, three pharmacists with supervision of a clinical pharmacist actively gathered necessary information for detection of DDIs. Data were tabulated according to the combinations of drugs in treatment chart. Verification of potential drug interactions was carried out using the online Lexi-Interact™ 2011. A total of 203 patients (113 males and 90 females) were enrolled in the study. The mean age of patients was 61 ± 12.55 years (range = 26-93). A total of 90 drugs were prescribed to 203 patients and most prescribed drugs were atorvastatin, clopidogrel and metoprolol. Mean of drugs was 11.22 per patient. A total of 3166 potential drug interactions have been identified by Lexi- Interact™, 149 (4.71%) and 55 (1.73%) of which were categorized as D and X, respectively. The most serious interactions were clopidogrel+omeprazole and metoprolol+salbutamol. Drug interactions leading to serious adverse effects are to be cautiously watched for when multiple drugs are used simultaneously. In settings with multiple drug use attendance of a pharmacist or clinical pharmacist, taking the responsibility for monitoring drug interactions and notifying the physician about potential problems could decrease the harm in patient and increase the patient safety. PMID:24250596

  1. Adverse events caused by potential drug-drug interactions in an intensive care unit of a teaching hospital

    PubMed Central

    Alvim, Mariana Macedo; da Silva, Lidiane Ayres; Leite, Isabel Cristina Gonçalves; Silvério, Marcelo Silva

    2015-01-01

    Objective To evaluate the incidence of potential drug-drug interactions in an intensive care unit of a hospital, focusing on antimicrobial drugs. Methods This cross-sectional study analyzed electronic prescriptions of patients admitted to the intensive care unit of a teaching hospital between January 1 and March 31, 2014 and assessed potential drug-drug interactions associated with antimicrobial drugs. Antimicrobial drug consumption levels were expressed in daily doses per 100 patient-days. The search and classification of the interactions were based on the Micromedex® system. Results The daily prescriptions of 82 patients were analyzed, totaling 656 prescriptions. Antimicrobial drugs represented 25% of all prescription drugs, with meropenem, vancomycin and ceftriaxone being the most prescribed medications. According to the approach of daily dose per 100 patient-days, the most commonly used antimicrobial drugs were cefepime, meropenem, sulfamethoxazole + trimethoprim and ciprofloxacin. The mean number of interactions per patient was 2.6. Among the interactions, 51% were classified as contraindicated or significantly severe. Highly significant interactions (clinical value 1 and 2) were observed with a prevalence of 98%. Conclusion The current study demonstrated that antimicrobial drugs are frequently prescribed in intensive care units and present a very high number of potential drug-drug interactions, with most of them being considered highly significant. PMID:26761473

  2. Pharmacokinetics and pharmacodynamics of propofol and fentanyl in patients undergoing abdominal aortic surgery - a study of pharmacodynamic drug-drug interactions.

    PubMed

    Wiczling, Paweł; Bieda, Krzysztof; Przybyłowski, Krzysztof; Hartmann-Sobczyńska, Roma; Borsuk, Agnieszka; Matysiak, Jan; Kokot, Zenon J; Sobczyński, Paweł; Grześkowiak, Edmund; Bienert, Agnieszka

    2016-07-01

    Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target-controlled infusion system. Fentanyl 2-3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non-linear mixed-effect model (NONMEM 7.2 software) was conducted. Two-compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect-site concentrations through an additive Emax model. Context-sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol-fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two-fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26990035

  3. Herb-drug, food-drug, nutrient-drug, and drug-drug interactions: mechanisms involved and their medical implications.

    PubMed

    Sørensen, Janina Maria

    2002-06-01

    Adverse drug reactions (ADRs) and iatrogenic diseases have been identified as significant factors responsible for patient morbidity and mortality. Significant studies on drug metabolism in humans have been published during the last few years, offering a deeper comprehension of the mechanisms underlying adverse drug reactions and interactions. More understanding of these mechanisms, and of recent advances in laboratory technology, can help to evaluate potential drug interactions when drugs are prescribed concurrently. Increasing knowledge of interindividual variation in drug breakdown capacity and recent findings concerning the influence of environment, diet, nutrients, and herbal products can be used to reduce ADRs and iatrogenic diseases. Reviewed data suggest that drug treatment should be increasingly custom tailored to suit the individual patient and that appropriately co-prescribed diet and herbal remedies, could increase drug efficacy and lessen drug toxicity. This review focuses mainly on recently published research material. The cytochrome p450 enzymes, their role in metabolism, and their mechanisms of action are reviewed, and their role in drug-drug interactions are discussed. Drug-food and drug-herb interactions have garnered attention. Interdisciplinary communication among medical herbalists, medical doctors, and dietetic experts needs to be improved and encouraged. Internet resources for obtaining current information regarding drug-drug, drug-herb, and drug-nutrient interactions are provided. PMID:12165187

  4. Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension.

    PubMed

    Venitz, Jürgen; Zack, Julia; Gillies, Hunter; Allard, Martine; Regnault, Jean; Dufton, Christopher

    2012-12-01

    The authors review the basic pharmacology and potential for adverse drug-drug interactions (DDIs) of bosentan and ambrisentan, the 2 endothelin receptor antagonists currently approved for pulmonary arterial hypertension (PAH) treatment. Bosentan, an endothelin (ET) receptor-type ET(A) and ET(B) antagonist, is metabolized to active metabolites by and an inducer of cytochrome P450 (CYP)2C9 and CYP3A. Ambrisentan, a selective ET(A) receptor antagonist, is metabolized primarily by uridine 5'diphosphate glucuronosyltransferases (UGTs) 1A9S, 2B7S, and 1A3S and, to a lesser extent, by CYP3A and CYP2C19. Drug interactions observed with bosentan DDI studies have demonstrated a potential for significant clinical implications during PAH management: bosentan is contraindicated with cyclosporine A and glyburide, and additional monitoring/dose adjustments are required when coadministered with hormonal contraceptives, simvastatin, lopinavir/ritonavir, and rifampicin. As bosentan carries a boxed warning regarding risks of liver injury and showed dose-dependant increases in serum aminotransferase abnormalities, drug interactions that increase bosentan exposure are of particular clinical concern. Ambrisentan DDI studies performed to date have shown only one clinically relevant DDI, an interaction with cyclosporine A that requires ambrisentan dose reduction. As the treatment of PAH moves toward multimodal combination therapy, scrutiny should be placed on ensuring that drug combinations achieve maximal clinical benefit while minimizing side effects. PMID:22205719

  5. Renal Transporter-Mediated Drug-Drug Interactions: Are They Clinically Relevant?

    PubMed

    Lepist, Eve-Irene; Ray, Adrian S

    2016-07-01

    The kidney, through the distinct processes of passive glomerular filtration and active tubular secretion, plays an important role in the elimination of numerous endobiotics (eg, hormones, metabolites), toxins, nutrients, and drugs. Renal transport pathways mediating active tubular secretion and reabsorption in the proximal tubule are complex, involving apical and basolateral transporters acting in concert. Detailed studies of the molecular mechanisms of net active tubular secretion have established the involvement of multiple transporters with overlapping substrate specificity mediating competing secretion and reabsorption pathways. Although drug interactions arising from inhibition of renal transporters are rare relative to other mechanisms, they can involve commonly administered drugs (eg, cimetidine, metformin), may be underappreciated due to muted effects on plasma pharmacokinetics relative to tissue levels, can affect narrow-therapeutic-index medications (eg, antiarrhythmic, oncology medications), and may disproportionately affect sensitive populations where polypharmacy is common (eg, the elderly, diabetics). In particular, there is the potential for larger-magnitude interactions in subjects with reduced glomerular filtration rates due to the increased relative contribution of tubular secretion. The assessment of additional endpoints in drug-drug interaction studies including pharmacodynamics, positron emission tomography imaging, and metabolomics promises to expand our understanding of the clinical relevance of renal drug interactions. PMID:27385181

  6. Drug-Drug Interaction Associated with Mold-Active Triazoles among Hospitalized Patients.

    PubMed

    Andes, David; Azie, Nkechi; Yang, Hongbo; Harrington, Rachel; Kelley, Caroline; Tan, Ruo-Ding; Wu, Eric Q; Franks, Billy; Kristy, Rita; Lee, Edward; Khandelwal, Nikhil; Spalding, James

    2016-06-01

    The majority of hospitalized patients receiving mold-active triazoles are at risk of drug-drug interactions (DDIs). Efforts are needed to increase awareness of DDIs that pose a serious risk of adverse events. Triazoles remain the most commonly utilized antifungals. Recent developments have included the mold-active triazoles (MATs) itraconazole, voriconazole, and posaconazole, which are first-line agents for the treatment of filamentous fungal infections but have the potential for DDIs. This objective of this study was to evaluate the prevalence of triazole DDIs. Hospitalized U.S. adults with MAT use were identified in the Cerner HealthFacts database, which contained data from over 150 hospitals (2005 to 2013). The severities of DDIs with MATs were categorized, using drug labels and the drug information from the Drugdex system (Thompson Micromedex), into four groups (contraindicated, major, moderate, and minor severity). DDIs of minor severity were not counted. A DDI event was considered to have occurred if the following two conditions were met: (i) the patient used at least one drug with a classification of at least a moderate interaction with the MAT during the hospitalization and (ii) there was a period of overlap between the administration of the MAT and that of the interacting drug of at least 1 day. A total of 6,962 hospitalizations with MAT use were identified. Among them, 88% of hospitalizations with voriconazole use, 86% of hospitalizations with itraconazole use, and 93% of hospitalizations with posaconazole use included the use of a concomitant interacting drug. A total of 68% of hospitalizations with posaconazole use, 34% of hospitalizations with itraconazole use, and 20% of hospitalizations with voriconazole use included the use of at least one drug with a DDI of contraindicated severity. A total of 83% of hospitalizations with posaconazole use, 61% of hospitalizations with itraconazole use, and 82% of hospitalizations with voriconazole use included the

  7. The Effect of CYP2D6 Drug-Drug Interactions on Hydrocodone Effectiveness

    PubMed Central

    Monte, Andrew A.; Heard, Kennon J.; Campbell, Jenny; Hamamura, D.; Weinshilboum, Richard M.; Vasiliou, Vasilis

    2014-01-01

    Objectives The hepatic cytochrome 2D6 (CYP2D6) is a saturable enzyme responsible for metabolism of approximately 25% of known pharmaceuticals. CYP interactions can alter the efficacy of prescribed medications. Hydrocodone is largely dependent on CYP2D6 metabolism for analgesia, ondansetron is inactivated by CYP2D6, and oxycodone analgesia is largely independent of CYP2D6. The objective was to determine if CYP2D6 medication co-ingestion decreases the effectiveness of hydrocodone. Methods This was a prospective observational study conducted in an academic U.S. emergency department (ED). Subjects were included if they had self-reported pain or nausea; and were excluded if they were unable to speak English, were less than 18 years of age, had liver or renal failure, or carried diagnoses of chronic pain or cyclic vomiting. Detailed drug ingestion histories for the preceding 48 hours prior to the ED visit were obtained. The patient's pain and nausea were quantified using a 100-millimeter visual analogue scale (VAS) at baseline prior to drug administration and following doses of hydrocodone, oxycodone, or ondansetron. We used a mixed model with random subject effect to determine the interaction between CYP2D6 drug ingestion and study drug effectiveness. Odds ratios (OR) were calculated to compare clinically significant VAS changes between CYP2D6 users and non-users. Results Two hundred fifty (49.8%) of the 502 subjects enrolled had taken at least one CYP2D6 substrate, inhibitor, or inducing pharmaceutical, supplement, or illicit drug in the 48 hours prior to ED presentation. CYP2D6-drug users were one third as likely to respond to hydrocodone (OR 0.33, 95% CI = 0.1 to 0.8), and more than three times as likely as non-users to respond to ondansetron (OR 3.4, 95% CI = 1.3 to 9.1). There was no significant difference in oxycodone effectiveness between CYP2D6 users and non-users (OR 0.53, 95% CI = 0.3 to 1.1). Conclusions CYP2D6 drug-drug interactions appear to change

  8. Transporters and drug-drug interactions: important determinants of drug disposition and effects.

    PubMed

    König, Jörg; Müller, Fabian; Fromm, Martin F

    2013-07-01

    Uptake and efflux transporters determine plasma and tissue concentrations of a broad variety of drugs. They are localized in organs such as small intestine, liver, and kidney, which are critical for drug absorption and elimination. Moreover, they can be found in important blood-tissue barriers such as the blood-brain barrier. Inhibition or induction of drug transporters by coadministered drugs can alter pharmacokinetics and pharmacodynamics of the victim drugs. This review will summarize in particular clinically observed drug-drug interactions attributable to inhibition or induction of intestinal export transporters [P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)], to inhibition of hepatic uptake transporters [organic anion transporting polypeptides (OATPs)], or to inhibition of transporter-mediated [organic anion transporters (OATs), organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATEs), P-gp] renal secretion of xenobiotics. Available data on the impact of nutrition on transport processes as well as genotype-dependent, transporter-mediated drug-drug interactions will be discussed. We will also present and discuss data on the variable extent to which information on the impact of transporters on drug disposition is included in summaries of product characteristics of selected countries (SPCs). Further work is required regarding a better understanding of the role of the drug metabolism-drug transport interplay for drug-drug interactions and on the extrapolation of in vitro findings to the in vivo (human) situation. PMID:23686349

  9. Drug-Drug Interaction Studies of Paliperidone and Divalproex Sodium Extended-Release Tablets in Healthy Participants and Patients with Psychiatric Disorders.

    PubMed

    Remmerie, Bart; Ariyawansa, Jay; De Meulder, Marc; Coppola, Danielle; Berwaerts, Joris

    2016-06-01

    The objective of these 2 phase 1, open-label, 2-treatment, single-sequence studies was to evaluate the effect of repeated oral doses of divalproex sodium extended-release (ER) on the pharmacokinetics (PK) of a single dose of paliperidone ER in healthy participants (study 1), and the effect of multiple doses of paliperidone ER on the steady-state PK of valproic acid (VPA) in patients with psychiatric disorders (study 2), respectively. In study 1 healthy participants received, in a fixed sequential order, treatment A, paliperidone ER 12 mg (day 1); treatment B, VPA 1000 mg (2 × 500 mg divalproex sodium ER) once daily (days 5 to 18) and paliperidone ER 12 mg (day 15). In study 2 patients received treatment A, VPA (days 1-7); treatment B, VPA + paliperidone ER 12 mg (days 8-12). Divalproex sodium ER doses (study 2) were individualized such that systemic therapeutic VPA exposure from prior treatment was maintained on entry into the study. PK assessments were performed at prespecified time points (paliperidone days 1 and 15 [study 1]; VPA days 7 and 12 [study 2]). The oral bioavailability of paliperidone was increased by an estimated 51% (Cmax ) and 51%-52% (AUCs) when coadministered with divalproex sodium ER. No effect on the steady-state plasma concentration of VPA was observed following repeated coadministration with paliperidone ER: the 90%CI around the VPA exposure ratios for the 2 treatments was within the 80%-125% bioequivalence criteria for Cmax,ss and AUCτ . Both VPA and paliperidone ER were well tolerated, and no new safety concerns were identified. PMID:26412032

  10. Drug-drug interactions and Idiosyncratic Hepatotoxicity in the Liver Transplant setting

    PubMed Central

    Tischer, Sarah; Fontana, Robert J.

    2016-01-01

    Preliminary studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C have demonstrated dramatic increases in tacrolimus, cyclosporine, and the mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldepravir are 2nd generation protease inhibitors which may have improved efficacy and tolerability profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based therapies are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes. PMID:24280292

  11. Detection of potential drug-drug interactions for outpatients across hospitals.

    PubMed

    Yeh, Yu-Ting; Hsu, Min-Hui; Chen, Chien-Yuan; Lo, Yu-Sheng; Liu, Chien-Tsai

    2014-02-01

    The National Health Insurance Administration (NHIA) has adopted smart cards (or NHI-IC cards) as health cards to carry patients' medication histories across hospitals in Taiwan. The aims of this study are to enhance a computerized physician order entry system to support drug-drug interaction (DDI) checking based on a patient's medication history stored in his/her NHI-IC card. For performance evaluation, we developed a transaction tracking log to keep track of every operation on NHI-IC cards. Based on analysis of the transaction tracking log from 1 August to 31 October 2007, physicians read patients' NHI-IC cards in 71.01% (8,246) of patient visits; 33.02% (2,723) of the card reads showed at least one medicine currently being taken by the patient, 82.94% of which were prescribed during the last visit. Among 10,036 issued prescriptions, seven prescriptions (0.09%) contained at least one drug item that might interact with the currently-taken medicines stored in NHI-IC cards and triggered pop-up alerts. This study showed that the capacity of an NHI-IC card is adequate to support DDI checking across hospitals. Thus, the enhanced computerized physician order entry (CPOE) system can support better DDI checking when physicians are making prescriptions and provide safer medication care, particularly for patients who receive medication care from different hospitals. PMID:24473112

  12. Drug-Drug Interactions within Protein Cavities Probed by Triplet-Triplet Energy Transfer.

    PubMed

    Nuin, Edurne; Jiménez, M Consuelo; Sastre, Germán; Andreu, Inmaculada; Miranda, Miguel A

    2013-05-16

    A new direct and noninvasive methodology based on transient absorption spectroscopy has been developed to probe the feasibility of drug-drug interactions within a common protein binding site. The simultaneous presence of (R)-cinacalcet (CIN) and (S)-propranolol (PPN) within human or bovine α1-acid glycoproteins (AAGs) is revealed by detection of (3)CIN* as the only transient species after laser flash photolysis of CIN/PPN/AAG mixtures at 308 nm. This is the result of triplet-triplet energy transfer from (3)PPN* to CIN, which requires close contact between the two drugs within the same biological compartment. Similar results are obtained with nabumetone and CIN as donor/acceptor partners. This new methodology can, in principle, be extended to a variety of drug/drug/biomolecule combinations. PMID:26282966

  13. Is pomegranate juice a potential perpetrator of clinical drug-drug interactions? Review of the in vitro, preclinical and clinical evidence.

    PubMed

    Srinivas, Nuggehally R

    2013-12-01

    The area of fruit juice-drug interaction has received wide attention with numerous scientific and clinical investigations performed and reported for scores of drugs metabolized by CYP3A4/CYP2C9. While grapefruit juice has been extensively studied with respect to its drug-drug interaction potential, numerous other fruit juices such as cranberry juice, orange juice, grape juice, pineapple juice and pomegranate juice have also been investigated for its potential to show drug-drug interaction of any clinical relevance. This review focuses on establishing any relevance for clinical drug-drug interaction potential with pomegranate juice, which has been shown to produce therapeutic benefits over a wide range of disease areas. The review collates and evaluates relevant published in vitro, preclinical and clinical evidence of the potential of pomegranate juice to be a perpetrator in drug-drug interactions mediated by CYP3A4 and CYP2C9. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug-drug interaction was not established based on the limited case studies. PMID:23673492

  14. A novel algorithm for analyzing drug-drug interactions from MEDLINE literature.

    PubMed

    Lu, Yin; Shen, Dan; Pietsch, Maxwell; Nagar, Chetan; Fadli, Zayd; Huang, Hong; Tu, Yi-Cheng; Cheng, Feng

    2015-01-01

    Drug-drug interaction (DDI) is becoming a serious clinical safety issue as the use of multiple medications becomes more common. Searching the MEDLINE database for journal articles related to DDI produces over 330,000 results. It is impossible to read and summarize these references manually. As the volume of biomedical reference in the MEDLINE database continues to expand at a rapid pace, automatic identification of DDIs from literature is becoming increasingly important. In this article, we present a random-sampling-based statistical algorithm to identify possible DDIs and the underlying mechanism from the substances field of MEDLINE records. The substances terms are essentially carriers of compound (including protein) information in a MEDLINE record. Four case studies on warfarin, ibuprofen, furosemide and sertraline implied that our method was able to rank possible DDIs with high accuracy (90.0% for warfarin, 83.3% for ibuprofen, 70.0% for furosemide and 100% for sertraline in the top 10% of a list of compounds ranked by p-value). A social network analysis of substance terms was also performed to construct networks between proteins and drug pairs to elucidate how the two drugs could interact. PMID:26612138

  15. Content and Usability Evaluation of Patient Oriented Drug-Drug Interaction Websites.

    PubMed

    Adam, Terrence J; Vang, Joseph

    2015-01-01

    Drug-Drug Interactions (DDI) are an important source of preventable adverse drug events and a common reason for hospitalization among patients on multiple drug therapy regimens. DDI information systems are important patient safety tools with the capacity to identify and warn health professionals of clinically significant DDI risk. While substantial research has been completed on DDI information systems in professional settings such as community, hospital, and independent pharmacies; there has been limited research on DDI systems offered through online websites directly for use by ambulatory patients. The focus of this project is to test patient oriented website capacity to correctly identify drug interactions among well established and clinically significant medication combinations and convey clinical risk data to patients. The patient education capability was assessed by evaluating website Information Capacity, Patient Usability and Readability. The study results indicate that the majority of websites identified which met the inclusion and exclusion criteria operated similarly, but vary in risk severity assessment and are not optimally patient oriented to effectively deliver risk information. The limited quality of information and complex medical term content complicate DDI risk data conveyance and the sites may not provide optimal information delivery to allow medication consumers to understand and manage their medication regimens. PMID:26958159

  16. Content and Usability Evaluation of Patient Oriented Drug-Drug Interaction Websites

    PubMed Central

    Adam, Terrence J.; Vang, Joseph

    2015-01-01

    Drug-Drug Interactions (DDI) are an important source of preventable adverse drug events and a common reason for hospitalization among patients on multiple drug therapy regimens. DDI information systems are important patient safety tools with the capacity to identify and warn health professionals of clinically significant DDI risk. While substantial research has been completed on DDI information systems in professional settings such as community, hospital, and independent pharmacies; there has been limited research on DDI systems offered through online websites directly for use by ambulatory patients. The focus of this project is to test patient oriented website capacity to correctly identify drug interactions among well established and clinically significant medication combinations and convey clinical risk data to patients. The patient education capability was assessed by evaluating website Information Capacity, Patient Usability and Readability. The study results indicate that the majority of websites identified which met the inclusion and exclusion criteria operated similarly, but vary in risk severity assessment and are not optimally patient oriented to effectively deliver risk information. The limited quality of information and complex medical term content complicate DDI risk data conveyance and the sites may not provide optimal information delivery to allow medication consumers to understand and manage their medication regimens. PMID:26958159

  17. Adverse drug reactions and drug-drug interactions with over-the-counter NSAIDs.

    PubMed

    Moore, Nicholas; Pollack, Charles; Butkerait, Paul

    2015-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have a long history of safe and effective use as both prescription and over-the-counter (OTC) analgesics/antipyretics. The mechanism of action of all NSAIDs is through reversible inhibition of cyclooxygenase enzymes. Adverse drug reactions (ADRs) including gastrointestinal bleeding as well as cardiovascular and renal effects have been reported with NSAID use. In many cases, ADRs may occur because of drug-drug interactions (DDIs) between the NSAID and a concomitant medication. For example, DDIs have been reported when NSAIDs are coadministered with aspirin, alcohol, some antihypertensives, antidepressants, and other commonly used medications. Because of the pharmacologic nature of these interactions, there is a continuum of risk in that the potential for an ADR is dependent on total drug exposure. Therefore, consideration of dose and duration of NSAID use, as well as the type or class of comedication administered, is important when assessing potential risk for ADRs. Safety findings from clinical studies evaluating prescription-strength NSAIDs may not be directly applicable to OTC dosing. Health care providers can be instrumental in educating patients that using OTC NSAIDs at the lowest effective dose for the shortest required duration is vital to balancing efficacy and safety. This review discusses some of the most clinically relevant DDIs reported with NSAIDs based on major sites of ADRs and classes of medication, with a focus on OTC ibuprofen, for which the most data are available. PMID:26203254

  18. Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor

    PubMed Central

    Chen, Jiezhong; Raymond, Kenneth

    2006-01-01

    Rifampicin, an important drug in the treatment of tuberculosis, is used extensively despite its broad effects on drug-drug interactions, creating serious problems. The clinical importance of such interactions includes autoinduction leading to suboptimal or failed treatment. The concomitantly administered effects of rifampicin on other drugs can result in their altered metabolism or transportation that are metabolised by cytochromes P450 or transported by p-glycoprotein in the gastrointestinal tract and liver. This review paper summarises recent findings with emphases on the molecular mechanisms used to explain these broad drug-drug interactions. In general, rifampicin can act on a pattern: rifampicin activates the nuclear pregnane X receptor that in turn affects cytochromes P450, glucuronosyltransferases and p-glycoprotein activities. This pattern of action may explain many of the rifampicin inducing drug-drug interactions. However, effects through other mechanisms have also been reported and these make any explanation of such drug-drug interactions more complex. PMID:16480505

  19. Physiologically based pharmacokinetic modeling of disposition and drug-drug interactions for atorvastatin and its metabolites.

    PubMed

    Zhang, Tao

    2015-09-18

    Atorvastatin is the most commonly used of all statins to lower cholesterol. Atorvastatin is extensively metabolized in both gut and liver to produce several active metabolites. The purpose of the present study is to develop a physiologically based pharmacokinetic (PBPK) model for atorvastatin and its two primary metabolites, 2-hydroxy-atorvastatin acid and atorvastatin lactone, using in vitro and in vivo data. The model was used to predict the pharmacokinetic profiles and drug-drug interaction (DDI) effect for atorvastatin and its metabolites in different DDI scenarios. The predictive performance of the model was assessed by comparing predicted results to observed data after coadministration of atorvastatin with different medications such as itraconazole, clarithromycin, cimetidine, rifampin and phenytoin. This population based PBPK model was able to describe the concentration-time profiles of atorvastatin and its two metabolites reasonably well in the absence or presence of those drugs at different dose regimens. The predicted maximum concentration (Cmax), area under the concentration-time curve (AUC) values and between-phase ratios were in good agreement with clinically observed data. The model has also revealed the importance of different metabolic pathways on the disposition of atorvastatin metabolites. This PBPK model can be utilized to assess the safety and efficacy of atorvastatin in the clinic. This study demonstrated the feasibility of applying PBPK approach to predict the DDI potential of drugs undergoing complex metabolism. PMID:26116278

  20. Quantitative evaluation of drug-drug interaction potentials by in vivo information- guided prediction approach.

    PubMed

    Chen, Feng; Hu, Zhe-Yi; Jia, Wei-Wei; Lu, Jing-Tao; Zhao, Yuan-Sheng

    2014-01-01

    Drug-drug interaction (DDI) is one important topic in drug discovery, drug development and clinical practice. Recently, a novel approach, in vivo information-guided prediction (IVIP), was introduced for predicting the magnitude of pharmacokinetic DDIs which are caused by changes in cytochrome P450 (CYP) activity. This approach utilizes two parameters, i.e. CR (the apparent contribution of the target metabolizing enzyme to the clearance of the substrate drug) and IX (the apparent effect of a perpetrator on the target CYP) to describe the magnitude of DDI between a perpetrator and a victim drug. The essential concept of this method assumes that at a given dose level, the IX for a given perpetrator remains constant whatever the victim drug is. Usually, this IVIP method is only based on information from clinical studies and does not need in vitro information. In this review, basic concept, application and extension, as well as pros and cons of the IVIP method were presented. How to apply this approach was also discussed. Thus far, this method displayed good performance in predicting DDIs associated with CYPs, and can be used to forecast the magnitude of a large number of possible DDIs, of which only a small portion have been investigated in clinical studies. The key concept of this static approach could even be implemented in dynamic modeling to assess risks of DDIs involving drug transporters. PMID:25705907

  1. Computerized techniques pave the way for drug-drug interaction prediction and interpretation

    PubMed Central

    Safdari, Reza; Ferdousi, Reza; Aziziheris, Kamal; Niakan-Kalhori, Sharareh R.; Omidi, Yadollah

    2016-01-01

    Introduction: Health care industry also patients penalized by medical errors that are inevitable but highly preventable. Vast majority of medical errors are related to adverse drug reactions, while drug-drug interactions (DDIs) are the main cause of adverse drug reactions (ADRs). DDIs and ADRs have mainly been reported by haphazard case studies. Experimental in vivo and in vitro researches also reveals DDI pairs. Laboratory and experimental researches are valuable but also expensive and in some cases researchers may suffer from limitations. Methods: In the current investigation, the latest published works were studied to analyze the trend and pattern of the DDI modelling and the impacts of machine learning methods. Applications of computerized techniques were also investigated for the prediction and interpretation of DDIs. Results: Computerized data-mining in pharmaceutical sciences and related databases provide new key transformative paradigms that can revolutionize the treatment of diseases and hence medical care. Given that various aspects of drug discovery and pharmacotherapy are closely related to the clinical and molecular/biological information, the scientifically sound databases (e.g., DDIs, ADRs) can be of importance for the success of pharmacotherapy modalities. Conclusion: A better understanding of DDIs not only provides a robust means for designing more effective medicines but also grantees patient safety. PMID:27525223

  2. The role of metabolites in predicting drug-drug interactions: Focus on irreversible P450 inhibition

    PubMed Central

    VandenBrink, Brooke M.; Isoherranen, Nina

    2010-01-01

    Irreversible inhibition of cytochrome P450 enzymes can cause significant drug-drug interactions (DDIs). Formation of metabolites is fundamental for the inactivation of P450 enzymes. Of the 19 inactivators with a known mechanism of inactivation, 10 have circulating metabolites that are known to be on path to inactive P450. The fact that inactivation usually requires multiple metabolic steps implies that predicting in vivo interactions may require complex models, and in vitro data generated from each metabolite. The data reviewed here suggest that circulating metabolites are much more important in in vivo P450 inhibition than is currently acknowledged. PMID:20047147

  3. Detection of Drug-Drug Interactions by Modeling Interaction Profile Fingerprints

    PubMed Central

    Vilar, Santiago; Uriarte, Eugenio; Santana, Lourdes; Tatonetti, Nicholas P.; Friedman, Carol

    2013-01-01

    Drug-drug interactions (DDIs) constitute an important problem in postmarketing pharmacovigilance and in the development of new drugs. The effectiveness or toxicity of a medication could be affected by the co-administration of other drugs that share pharmacokinetic or pharmacodynamic pathways. For this reason, a great effort is being made to develop new methodologies to detect and assess DDIs. In this article, we present a novel method based on drug interaction profile fingerprints (IPFs) with successful application to DDI detection. IPFs were generated based on the DrugBank database, which provided 9,454 well-established DDIs as a primary source of interaction data. The model uses IPFs to measure the similarity of pairs of drugs and generates new putative DDIs from the non-intersecting interactions of a pair. We described as part of our analysis the pharmacological and biological effects associated with the putative interactions; for example, the interaction between haloperidol and dicyclomine can cause increased risk of psychosis and tardive dyskinesia. First, we evaluated the method through hold-out validation and then by using four independent test sets that did not overlap with DrugBank. Precision for the test sets ranged from 0.4–0.5 with more than two fold enrichment factor enhancement. In conclusion, we demonstrated the usefulness of the method in pharmacovigilance as a DDI predictor, and created a dataset of potential DDIs, highlighting the etiology or pharmacological effect of the DDI, and providing an exploratory tool to facilitate decision support in DDI detection and patient safety. PMID:23520498

  4. Predicting Pharmacodynamic Drug-Drug Interactions through Signaling Propagation Interference on Protein-Protein Interaction Networks

    PubMed Central

    Park, Kyunghyun; Kim, Docyong; Ha, Suhyun; Lee, Doheon

    2015-01-01

    As pharmacodynamic drug-drug interactions (PD DDIs) could lead to severe adverse effects in patients, it is important to identify potential PD DDIs in drug development. The signaling starting from drug targets is propagated through protein-protein interaction (PPI) networks. PD DDIs could occur by close interference on the same targets or within the same pathways as well as distant interference through cross-talking pathways. However, most of the previous approaches have considered only close interference by measuring distances between drug targets or comparing target neighbors. We have applied a random walk with restart algorithm to simulate signaling propagation from drug targets in order to capture the possibility of their distant interference. Cross validation with DrugBank and Kyoto Encyclopedia of Genes and Genomes DRUG shows that the proposed method outperforms the previous methods significantly. We also provide a web service with which PD DDIs for drug pairs can be analyzed at http://biosoft.kaist.ac.kr/targetrw. PMID:26469276

  5. Clinical assessment of drug-drug interactions of tasimelteon, a novel dual melatonin receptor agonist.

    PubMed

    Ogilvie, Brian W; Torres, Rosarelis; Dressman, Marlene A; Kramer, William G; Baroldi, Paolo

    2015-09-01

    Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual melatonin receptor agonist that demonstrates specificity and high affinity for melatonin receptor types 1 and 2 (MT1 and MT2 receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug-drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%. PMID:25851638

  6. Evaluation and Quantitative Prediction of Renal Transporter-Mediated Drug-Drug Interactions.

    PubMed

    Feng, Bo; Varma, Manthena V

    2016-07-01

    With numerous drugs cleared renally, inhibition of uptake transporters localized on the basolateral membrane of renal proximal tubule cells, eg, organic anion transporters (OATs) and organic cation transporters (OCTs), may lead to clinically meaningful drug-drug interactions (DDIs). Additionally, clinical evidence for the possible involvement of efflux transporters, such as P-glycoprotein (P-gp) and multidrug and toxin extrusion protein 1/2-K (MATE1/2-K), in the renal DDIs is emerging. Herein, we review recent progress regarding mechanistic understanding of transporter-mediated renal DDIs as well as the quantitative predictability of renal DDIs using static and physiologically based pharmacokinetic (PBPK) models. Generally, clinical DDI data suggest that the magnitude of plasma exposure changes attributable to renal DDIs is less than 2-fold, unlike the DDIs associated with inhibition of cytochrome P-450s and/or hepatic uptake transporters. It is concluded that although there is a need for risk assessment early in drug development, current available data imply that safety concerns related to the renal DDIs are generally low. Nevertheless, consideration must be given to the therapeutic index of the victim drug and potential risk in a specific patient population (eg, renal impairment). Finally, in vitro transporter data and clinical pharmacokinetic parameters obtained from the first-in-human studies have proven useful in support of quantitative prediction of DDIs associated with inhibition of renal secretory transporters, OATs or OCTs. PMID:27385169

  7. P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms.

    PubMed

    McDonald, Matthew G; Au, Nicholas T; Rettie, Allan E

    2015-11-01

    In this study, IC50 shift and time-dependent inhibition (TDI) experiments were carried out to measure the ability of amiodarone (AMIO), and its circulating human metabolites, to reversibly and irreversibly inhibit CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activities in human liver microsomes. The [I]u/Ki,u values were calculated and used to predict in vivo AMIO drug-drug interactions (DDIs) for pharmaceuticals metabolized by these four enzymes. Based on these values, the minor metabolite N,N-didesethylamiodarone (DDEA) is predicted to be the major cause of DDIs with xenobiotics primarily metabolized by CYP1A2, CYP2C9, or CYP3A4, while AMIO and its N-monodesethylamiodarone (MDEA) derivative are the most likely cause of interactions involving inhibition of CYP2D6 metabolism. AMIO drug interactions predicted from the reversible inhibition of the four P450 activities were found to be in good agreement with the magnitude of reported clinical DDIs with lidocaine, warfarin, metoprolol, and simvastatin. The TDI experiments showed DDEA to be a potent inactivator of CYP1A2 (KI = 0.46 μM, kinact = 0.030 minute(-1)), while MDEA was a moderate inactivator of both CYP2D6 (KI = 2.7 μM, kinact = 0.018 minute(-1)) and CYP3A4 (KI = 2.6 μM, kinact = 0.016 minute(-1)). For DDEA and MDEA, mechanism-based inactivation appears to occur through formation of a metabolic intermediate complex. Additional metabolic studies strongly suggest that CYP3A4 is the primary microsomal enzyme involved in the metabolism of AMIO to both MDEA and DDEA. In summary, these studies demonstrate both the diversity of inhibitory mechanisms with AMIO and the need to consider metabolites as the culprit in inhibitory P450-based DDIs. PMID:26296708

  8. Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing

    PubMed Central

    Udrescu, Lucreţia; Sbârcea, Laura; Topîrceanu, Alexandru; Iovanovici, Alexandru; Kurunczi, Ludovic; Bogdan, Paul; Udrescu, Mihai

    2016-01-01

    Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection algorithms, we link the network clusters to 9 relevant pharmacological properties. Out of the 1141 drugs from the DrugBank 4.1 database, our extensive literature survey and cross-checking with other databases such as Drugs.com, RxList, and DrugBank 4.3 confirm the predicted properties for 85% of the drugs. As such, we argue that network analysis offers a high-level grasp on a wide area of pharmacological aspects, indicating possible unaccounted interactions and missing pharmacological properties that can lead to drug repositioning for the 15% drugs which seem to be inconsistent with the predicted property. Also, by using network centralities, we can rank drugs according to their interaction potential for both simple and complex multi-pathology therapies. Moreover, our clustering approach can be extended for applications such as analyzing drug-target interactions or phenotyping patients in personalized medicine applications. PMID:27599720

  9. Clustering drug-drug interaction networks with energy model layouts: community analysis and drug repurposing.

    PubMed

    Udrescu, Lucreţia; Sbârcea, Laura; Topîrceanu, Alexandru; Iovanovici, Alexandru; Kurunczi, Ludovic; Bogdan, Paul; Udrescu, Mihai

    2016-01-01

    Analyzing drug-drug interactions may unravel previously unknown drug action patterns, leading to the development of new drug discovery tools. We present a new approach to analyzing drug-drug interaction networks, based on clustering and topological community detection techniques that are specific to complex network science. Our methodology uncovers functional drug categories along with the intricate relationships between them. Using modularity-based and energy-model layout community detection algorithms, we link the network clusters to 9 relevant pharmacological properties. Out of the 1141 drugs from the DrugBank 4.1 database, our extensive literature survey and cross-checking with other databases such as Drugs.com, RxList, and DrugBank 4.3 confirm the predicted properties for 85% of the drugs. As such, we argue that network analysis offers a high-level grasp on a wide area of pharmacological aspects, indicating possible unaccounted interactions and missing pharmacological properties that can lead to drug repositioning for the 15% drugs which seem to be inconsistent with the predicted property. Also, by using network centralities, we can rank drugs according to their interaction potential for both simple and complex multi-pathology therapies. Moreover, our clustering approach can be extended for applications such as analyzing drug-target interactions or phenotyping patients in personalized medicine applications. PMID:27599720

  10. Estimation of Severe Drug-Drug Interaction Warnings by Medical Specialist Groups for Austrian Nationwide eMedication

    PubMed Central

    Sauter, S. K.; Neuhofer, L. M.; Edlinger, D.; Grossmann, W.; Wolzt, M.; Endel, G.; Gall, W.

    2014-01-01

    Summary Objective The objective of this study is to estimate the amount of severe drug-drug interaction warnings per medical specialist group triggered by prescribed drugs of a patient before and after the introduction of a nationwide eMedication system in Austria planned for 2015. Methods The estimations of interaction warnings are based on patients’ prescriptions of a single health care professional per patient, as well as all patients’ prescriptions from all visited health care professionals. We used a research database of the Main Association of Austrian Social Security Organizations that contains health claims data of the years 2006 and 2007. Results The study cohort consists of about 1 million patients, with 26.4 million prescribed drugs from about 3,400 different health care professionals. The estimation of interaction warnings show a heterogeneous pattern of severe drug-drug-interaction warnings across medical specialist groups. Conclusion During an eMedication implementation it must be taken into consideration that different medical specialist groups require customized support. PMID:25298801

  11. Clinical pharmacology profile of boceprevir, a hepatitis C virus NS3 protease inhibitor: focus on drug-drug interactions.

    PubMed

    Khalilieh, Sauzanne; Feng, Hwa-Ping; Hulskotte, Ellen G J; Wenning, Larissa A; Butterton, Joan R

    2015-06-01

    Boceprevir is a potent, orally administered ketoamide inhibitor that targets the active site of the hepatitis C virus (HCV) non-structural (NS) 3 protease. The addition of boceprevir to peginterferon plus ribavirin resulted in higher rates of sustained virologic response (SVR) than for peginterferon plus ribavirin alone in phase III studies in both previously treated and untreated patients with HCV infection. Because boceprevir is metabolized by metabolic routes common to many other drugs, and is an inhibitor of cytochrome P450 (CYP) 3A4/5, there is a high potential for drug-drug interactions when boceprevir is administered with other therapies, particularly when treating patients with chronic HCV infection who are often receiving other medications concomitantly. Boceprevir is no longer widely used in the US or EU due to the introduction of second-generation treatments for HCV infection. However, in many other geographic regions, first-generation protease inhibitors such as boceprevir continue to form an important treatment option for patients with HCV infection. This review summarizes the interactions between boceprevir and other therapeutic agents commonly used in this patient population, indicating dose adjustment requirements where needed. Most drug interactions do not affect boceprevir plasma concentrations to a clinically meaningful extent, and thus efficacy is likely to be maintained when boceprevir is coadministered with the majority of other therapeutics. Overall, the drug-drug interaction profile of boceprevir suggests that this agent is suitable for use in a wide range of HCV-infected patients receiving concomitant therapies. PMID:25787025

  12. Use of PET Imaging to Evaluate Transporter-Mediated Drug-Drug Interactions.

    PubMed

    Langer, Oliver

    2016-07-01

    Several membrane transporters belonging to the adenosine triphosphate-binding cassette (ABC) and solute carrier (SLC) families can transport drugs and drug metabolites and thereby exert an effect on drug absorption, distribution, and excretion, which may potentially lead to transporter-mediated drug-drug interactions (DDIs). Some transporter-mediated DDIs may lead to changes in organ distribution of drugs (eg, brain, liver, kidneys) without affecting plasma concentrations. Positron emission tomography (PET) is a noninvasive imaging method that allows studying of the distribution of radiolabeled drugs to different organs and tissues and is therefore the method of choice to quantitatively assess transporter-mediated DDIs on a tissue level. There are 2 approaches to how PET can be used in transporter-mediated DDI studies. When the drug of interest is a potential perpetrator of DDIs, it may be administered in unlabeled form to assess its influence on tissue distribution of a generic transporter-specific PET tracer (probe substrate). When the drug of interest is a potential victim of DDIs, it may be radiolabeled with carbon-11 or fluorine-18 and used in combination with a prototypical transporter inhibitor (eg, rifampicin). PET has already been used both in preclinical species and in humans to assess the effects of transporter-mediated DDIs on drug disposition in different organ systems, such as brain, liver, and kidneys, for which examples are given in the present review article. Given the growing importance of membrane transporters with respect to drug safety and efficacy, PET is expected to play an increasingly important role in future drug development. PMID:27385172

  13. A Single Kernel-Based Approach to Extract Drug-Drug Interactions from Biomedical Literature

    PubMed Central

    Zhang, Yijia; Lin, Hongfei; Yang, Zhihao; Wang, Jian; Li, Yanpeng

    2012-01-01

    When one drug influences the level or activity of another drug this is known as a drug-drug interaction (DDI). Knowledge of such interactions is crucial for patient safety. However, the volume and content of published biomedical literature on drug interactions is expanding rapidly, making it increasingly difficult for DDIs database curators to detect and collate DDIs information manually. In this paper, we propose a single kernel-based approach to extract DDIs from biomedical literature. This novel kernel-based approach can effectively make full use of syntactic structural information of the dependency graph. In particular, our approach can efficiently represent both single subgraph topological information and the relation of two subgraphs in the dependency graph. Experimental evaluations showed that our single kernel-based approach can achieve state-of-the-art performance on the publicly available DDI corpus without exploiting multiple kernels or additional domain resources. PMID:23133662

  14. Computing with evidence Part II: An evidential approach to predicting metabolic drug-drug interactions.

    PubMed

    Boyce, Richard; Collins, Carol; Horn, John; Kalet, Ira

    2009-12-01

    We describe a novel experiment that we conducted with the Drug Interaction Knowledge-base (DIKB) to determine which combinations of evidence enable a rule-based theory of metabolic drug-drug interactions to make the most optimal set of predictions. The focus of the experiment was a group of 16 drugs including six members of the HMG-CoA-reductase inhibitor family (statins). The experiment helped identify evidence-use strategies that enabled the DIKB to predict significantly more interactions present in a validation set than the most rigorous strategy developed by drug experts with no loss of accuracy. The best-performing strategies included evidence types that would normally be of lesser predictive value but that are often more accessible than more rigorous types. Our experimental methods represent a new approach to leveraging the available scientific evidence within a domain where important evidence is often missing or of questionable value for supporting important assertions. PMID:19539050

  15. A linguistic rule-based approach to extract drug-drug interactions from pharmacological documents

    PubMed Central

    2011-01-01

    Background A drug-drug interaction (DDI) occurs when one drug influences the level or activity of another drug. The increasing volume of the scientific literature overwhelms health care professionals trying to be kept up-to-date with all published studies on DDI. Methods This paper describes a hybrid linguistic approach to DDI extraction that combines shallow parsing and syntactic simplification with pattern matching. Appositions and coordinate structures are interpreted based on shallow syntactic parsing provided by the UMLS MetaMap tool (MMTx). Subsequently, complex and compound sentences are broken down into clauses from which simple sentences are generated by a set of simplification rules. A pharmacist defined a set of domain-specific lexical patterns to capture the most common expressions of DDI in texts. These lexical patterns are matched with the generated sentences in order to extract DDIs. Results We have performed different experiments to analyze the performance of the different processes. The lexical patterns achieve a reasonable precision (67.30%), but very low recall (14.07%). The inclusion of appositions and coordinate structures helps to improve the recall (25.70%), however, precision is lower (48.69%). The detection of clauses does not improve the performance. Conclusions Information Extraction (IE) techniques can provide an interesting way of reducing the time spent by health care professionals on reviewing the literature. Nevertheless, no approach has been carried out to extract DDI from texts. To the best of our knowledge, this work proposes the first integral solution for the automatic extraction of DDI from biomedical texts. PMID:21489220

  16. Risk Assessment of Mechanism-Based Inactivation in Drug-Drug Interactions

    PubMed Central

    Fujioka, Yasushi; Kunze, Kent L.

    2012-01-01

    Drug-drug interactions (DDIs) that occur via mechanism-based inactivation of cytochrome P450 are of serious concern. Although several predictive models have been published, early risk assessment of MBIs is still challenging. For reversible inhibitors, the DDI risk categorization using [I]/Ki ([I], the inhibitor concentration; Ki, the inhibition constant) is widely used in drug discovery and development. Although a simple and reliable methodology such as [I]/Ki categorization for reversible inhibitors would be useful for mechanism-based inhibitors (MBIs), comprehensive analysis of an analogous measure reflecting in vitro potency for inactivation has not been reported. The aim of this study was to evaluate whether the term λ/kdeg (λ, first-order inactivation rate at a given MBI concentration; kdeg, enzyme degradation rate constant) would be useful in the prediction of the in vivo DDI risk of MBIs. Twenty-one MBIs with both in vivo area under the curve (AUC) change of marker substrates and in vitro inactivation parameters were identified in the literature and analyzed. The results of this analysis show that in vivo DDIs with >2-fold change of object drug AUC can be identified with the cutoff value of λ/kdeg = 1, where unbound steady-state Cmax is used for inhibitor concentration. However, the use of total Cmax led to great overprediction of DDI risk. The risk assessment using λ/kdeg coupled with unbound Cmax can be useful for the DDI risk evaluation of MBIs in drug discovery and development. PMID:22685217

  17. Polypharmacy, Drug-Drug Interactions, and Potentially Inappropriate Medications in Older HIV-Infected Adults

    PubMed Central

    Greene, Meredith; Steinman, Michael A.; McNicholl, Ian R.; Valcour, Victor

    2014-01-01

    Objectives To describe the frequency of medication-related problems in older HIV-infected adults Design Retrospective chart review Setting And Participants Community dwelling HIV-infected adults age 60 and older and age and sex-matched HIV-uninfected adults Measurements Total number of medications, potentially inappropriate medications as defined by the modified Beers criteria, anticholinergic drug burden as defined by the Anticholinergic Risk Scale, and drug-drug interactions using Lexi-Interact online drug interactions database. Results Of 89 HIV-infected participants, most were Caucasian (91%) and male (94%) with a median age of 64 (range 60-82). Common comorbidities included hyperlipidemia, hypertension, and depression. Participants were taking a median of 13 medications (range 2-38), of which only a median of 4 were antiretrovirals. At least one potentially inappropriate medication was prescribed in 46 participants (52%). Sixty-two (70%) participants had at least one Category D (consider therapy modification) drug-drug interaction and 10 (11%) had a Category X (avoid combination) interaction. One-third of these interactions were between two non-antiretroviral medications. We identified 15 participants (17%) with an anticholinergic risk scale score ≥3. In contrast, HIV-uninfected participants were taking a median of 6 medications, 29% had at least one potentially inappropriate medication, and 4% had an anticholinergic risk scale score ≥ 3 (p-value <0.05 for each comparison except p=0.07 for anticholinergic burden). Conclusion HIV-infected older adults have a high frequency of medication-related problems, of which a large portion is due to medications used to treat comorbid diseases. These medication issues were substantially higher than HIV-uninfected participants. Attention to the principles of geriatric prescribing is needed as this population ages in order to minimize complications from multiple medication use. PMID:24576251

  18. Pharmacokinetic drug-drug interaction assessment between LCZ696, an angiotensin receptor neprilysin inhibitor, and hydrochlorothiazide, amlodipine, or carvedilol.

    PubMed

    Hsiao, Hsiu-Ling; Langenickel, Thomas Heiko; Greeley, Michael; Roberts, John; Zhou, Wei; Pal, Parasar; Rebello, Sam; Rajman, Iris; Sunkara, Gangadhar

    2015-11-01

    LCZ696 is a first-in-class angiotensin receptor neprilysin inhibitor in development for treatments of hypertension and heart failure indications. In 3 separate studies, pharmacokinetic drug-drug interactions (DDIs) potential was assessed when LCZ696 was coadministered with hydrochlorothiazide (HCTZ), amlodipine, or carvedilol. The studies used a open-label, single-sequence, 3-period, crossover design in healthy subjects. Blood samples were collected to determine the pharmacokinetic parameters of LCZ696 analytes (AHU377, LBQ657, and valsartan), HCTZ, amlodipine, or carvedilol (R[+]- and S[-]-carvedilol) for statistical analysis. When coadministered LCZ696 with HCTZ, the 90% CIs of the geometric mean ratios of AUCtau,ss of HCTZ and that of LBQ657 were within a 0.80-1.25 interval, whereas HCTZ Cmax,ss decreased by 26%, LBQ657 Cmax,ss increased by 19%, and the AUCtau,ss and Cmax,ss of valsartan increased by 14% and 16%, respectively. Pharmacokinetics of amlodipine, R(+)- and S(-)-carvedilol, or LBQ657 were not altered after coadministration of LCZ696 with amlodipine or carvedilol. Coadministration of LCZ696 400 mg once daily (qd) with HCTZ 25 mg qd, amlodipine 10 mg qd, or carvedilol 25 mg twice a day (bid) had no clinically relevant pharmacokinetic drug-drug interactions. LCZ696, HCTZ, amlodipine, and carvedilol were safe and well tolerated when given alone or concomitantly in the investigated studies. PMID:27137712

  19. Drug-Drug Interactions between Sofosbuvir and Ombitasvir-Paritaprevir-Ritonavir with or without Dasabuvir.

    PubMed

    King, Jennifer R; Dutta, Sandeep; Cohen, Daniel; Podsadecki, Thomas J; Ding, Bifeng; Awni, Walid M; Menon, Rajeev M

    2016-02-01

    The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT

  20. Pharmacokinetic drug-drug interaction and their implication in clinical management

    PubMed Central

    Palleria, Caterina; Di Paolo, Antonello; Giofrè, Chiara; Caglioti, Chiara; Leuzzi, Giacomo; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2013-01-01

    Drug-drug interactions (DDIs) are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline, PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications. PMID:24516494

  1. Statin-associated rhabdomyolysis triggered by drug-drug interaction with itraconazole.

    PubMed

    Dybro, Anne Mette; Damkier, Per; Rasmussen, Torsten Bloch; Hellfritzsch, Maja

    2016-01-01

    A 47-year-old woman had been treated with high-dose simvastatin for several years. After systemic treatment with the antifungal agent itraconazole, she developed muscle pain and highly elevated levels of creatine kinase and myoglobin. Muscle biopsy was compatible with statin-associated rhabdomyolysis, probably caused by a drug-drug interaction between simvastatin and itraconazole. The patient made full recovery. Three commonly used statins-simvastatin, atorvastatin and lovastatin-are metabolised by the liver enzyme CYP3A4. Several potent inhibitors of this enzyme are known, for example, azole antifungal agents such as itraconazole and posaconazole. If antifungal treatment is indicated in a patient using a CYP3A4-metabolised statin, we recommend (1) topical administration of the antifungal agent if possible, (2) the use of a non-CYP3A4-inhibiting antifungal drug such as terbinafine or (3) temporary discontinuation of statin treatment. PMID:27605198

  2. Identification and Mechanistic Investigation of Drug-Drug Interactions Associated with Myopathy – A Translational Approach

    PubMed Central

    Han, Xu; Quinney, Sara K.; Wang, Zhiping; Zhang, Pengyue; Duke, Jon; Desta, Zeruesenay; Elmendorf, Jeffrey S.; Flockhart, David A.; Li, L

    2015-01-01

    Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% CI = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00) and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the FDA Adverse Event Reporting System. PMID:25975815

  3. Identification and Mechanistic Investigation of Drug-Drug Interactions Associated With Myopathy: A Translational Approach.

    PubMed

    Han, X; Quinney, S K; Wang, Z; Zhang, P; Duke, J; Desta, Z; Elmendorf, J S; Flockhart, D A; Li, L

    2015-09-01

    Myopathy is a group of muscle diseases that can be induced or exacerbated by drug-drug interactions (DDIs). We sought to identify clinically important myopathic DDIs and elucidate their underlying mechanisms. Five DDIs were found to increase the risk of myopathy based on analysis of observational data from the Indiana Network of Patient Care. Loratadine interacted with simvastatin (relative risk 95% confidence interval [CI] = [1.39, 2.06]), alprazolam (1.50, 2.31), ropinirole (2.06, 5.00), and omeprazole (1.15, 1.38). Promethazine interacted with tegaserod (1.94, 4.64). In vitro investigation showed that these DDIs were unlikely to result from inhibition of drug metabolism by CYP450 enzymes or from inhibition of hepatic uptake via the membrane transporter OATP1B1/1B3. However, we did observe in vitro synergistic myotoxicity of simvastatin and desloratadine, suggesting a role in loratadine-simvastatin interaction. This interaction was epidemiologically confirmed (odds ratio 95% CI = [2.02, 3.65]) using the data from the US Food and Drug Administration Adverse Event Reporting System. PMID:25975815

  4. Toward a complete dataset of drug-drug interaction information from publicly available sources.

    PubMed

    Ayvaz, Serkan; Horn, John; Hassanzadeh, Oktie; Zhu, Qian; Stan, Johann; Tatonetti, Nicholas P; Vilar, Santiago; Brochhausen, Mathias; Samwald, Matthias; Rastegar-Mojarad, Majid; Dumontier, Michel; Boyce, Richard D

    2015-06-01

    Although potential drug-drug interactions (PDDIs) are a significant source of preventable drug-related harm, there is currently no single complete source of PDDI information. In the current study, all publically available sources of PDDI information that could be identified using a comprehensive and broad search were combined into a single dataset. The combined dataset merged fourteen different sources including 5 clinically-oriented information sources, 4 Natural Language Processing (NLP) Corpora, and 5 Bioinformatics/Pharmacovigilance information sources. As a comprehensive PDDI source, the merged dataset might benefit the pharmacovigilance text mining community by making it possible to compare the representativeness of NLP corpora for PDDI text extraction tasks, and specifying elements that can be useful for future PDDI extraction purposes. An analysis of the overlap between and across the data sources showed that there was little overlap. Even comprehensive PDDI lists such as DrugBank, KEGG, and the NDF-RT had less than 50% overlap with each other. Moreover, all of the comprehensive lists had incomplete coverage of two data sources that focus on PDDIs of interest in most clinical settings. Based on this information, we think that systems that provide access to the comprehensive lists, such as APIs into RxNorm, should be careful to inform users that the lists may be incomplete with respect to PDDIs that drug experts suggest clinicians be aware of. In spite of the low degree of overlap, several dozen cases were identified where PDDI information provided in drug product labeling might be augmented by the merged dataset. Moreover, the combined dataset was also shown to improve the performance of an existing PDDI NLP pipeline and a recently published PDDI pharmacovigilance protocol. Future work will focus on improvement of the methods for mapping between PDDI information sources, identifying methods to improve the use of the merged dataset in PDDI NLP algorithms

  5. [OATP1B1 in drug-drug interactions between traditional Chinese medicine Danshensu and rosuvastatin].

    PubMed

    Wen, Jin-hua; Wei, Xiao-hua; Cheng, Xiao-hua; Zuo, Rong; Peng, Hong-wei; Lü, Yan-ni; Zhou, Jian; Zheng, Xue-lian; Cai, Jun; Xiong, Yu-qing; Cao, Li

    2016-01-01

    The study was designed to explore the drug-drug interactions mechanisms mediated by OATP1B1 between traditional Chinese medicine Danshensu and rosuvastatin. First, the changes of rosuvastatin pharmacokinetics were investigated in presence of Danshensu in rats. Then, the primary rat hepatocytes model was established to explore the effects of Danshensu on the uptake of rosuvastatin by hepatocytes. Finally, HEK293T cells with overexpression of OATP1B1*a and OATP1B1*5 were established using a lentiviral delivery system to explore the effects of Danshensu on the uptake of rosuvastatin. Rosuvastatin pharmacokinetic parameters of C(max0, AUCO(0-t), AUC(0-∞) were increased about 123%, 194% and 195%, by Danshensu in rats, while the CL z/F value was decreased by 60%. Uptake of rosuvastatin in the primary rat hepatocytes was decreased by 3.13%, 41.15% and 74.62%, respectively in the presence of 20, 40 and 80 μmol x L(-1) Danshensu. The IC50 parameters was (53.04 ± 2.43) μmol x L(-1). The inhibitory effect of Danshensu on OATP1B1 mediated transport of rosuvastatin was related to the OATP1B1 gene type. In OATP1B1*5-HEK293T mutant cells, transport of rosuvastatin were reduced by (39.11 ± 4.94)% and (63.61 ± 3.94)%, respectively, by Danshensu at 1 and 10 μmol x L(-1). While transport of rosuvastatin was reduced by (8.22 ± 2.40)% and (11.56 ± 3.04)% and in OATP1B1*1a cells, respectively. Danshensu significantly altered the pharmacokinetics of rosuvastatin in rats, which was related to competitive inhibition of transport by OATPJBI. Danshensu exhibited a significant activity in the inhibition of rosuvastatin transport by OATP1B1*5-HEK293T, but not by OATP1B1*1a, suggesting a dependence on OATP1B1 sequence. PMID:27405165

  6. Similarity-based modeling in large-scale prediction of drug-drug interactions.

    PubMed

    Vilar, Santiago; Uriarte, Eugenio; Santana, Lourdes; Lorberbaum, Tal; Hripcsak, George; Friedman, Carol; Tatonetti, Nicholas P

    2014-09-01

    Drug-drug interactions (DDIs) are a major cause of adverse drug effects and a public health concern, as they increase hospital care expenses and reduce patients' quality of life. DDI detection is, therefore, an important objective in patient safety, one whose pursuit affects drug development and pharmacovigilance. In this article, we describe a protocol applicable on a large scale to predict novel DDIs based on similarity of drug interaction candidates to drugs involved in established DDIs. The method integrates a reference standard database of known DDIs with drug similarity information extracted from different sources, such as 2D and 3D molecular structure, interaction profile, target and side-effect similarities. The method is interpretable in that it generates drug interaction candidates that are traceable to pharmacological or clinical effects. We describe a protocol with applications in patient safety and preclinical toxicity screening. The time frame to implement this protocol is 5-7 h, with additional time potentially necessary, depending on the complexity of the reference standard DDI database and the similarity measures implemented. PMID:25122524

  7. Pharmacokinetic and Pharmacodynamic Analyses of Drug-Drug Interactions between Iguratimod and Warfarin.

    PubMed

    Yamamoto, Tetsuya; Hasegawa, Kyoko; Onoda, Makoto; Tanaka, Keiichi

    2016-01-01

    Iguratimod (IGU), a disease-modifying antirheumatic drug launched in September 2012, has been reported to carry a risk of severe hemorrhages through a suspected interaction with warfarin (WF) in the all-case surveillance and early postmarketing-phase vigilance. To elucidate possible mechanisms of adverse interaction between IGU and WF, we analyzed the effects of IGU on the pharmacodynamics and pharmacokinetics of WF in rats. IGU was orally administered to male Wistar rats once daily for 5 d at 10 or 30 mg/kg in combination with WF at an oral dose of 0.25 mg/kg. Coadministration of IGU 30 mg/kg enhanced the anticoagulant activity of WF; prolonged blood coagulation time (prothrombin time and activated partial thromboplastin time) and decreased levels of vitamin K (VK)-dependent blood coagulation factors (II, VII, IX, and X) were observed. On the other hand, the pharmacokinetic parameters of WF including maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24 h) were not affected by the combination with IGU. IGU alone did not change blood coagulation time at doses up to 100 mg/kg, while VK-dependent blood coagulation factors decreased slightly at 30 and 100 mg/kg. These results suggest that the pharmacodynamic effect of IGU on VK-dependent blood coagulation factors is involved in the mechanism of drug-drug interaction of IGU with WF. PMID:27252068

  8. Extracting Drug-Drug Interaction from the Biomedical Literature Using a Stacked Generalization-Based Approach

    PubMed Central

    He, Linna; Yang, Zhihao; Zhao, Zhehuan; Lin, Hongfei; Li, Yanpeng

    2013-01-01

    Drug-drug interaction (DDI) detection is particularly important for patient safety. However, the amount of biomedical literature regarding drug interactions is increasing rapidly. Therefore, there is a need to develop an effective approach for the automatic extraction of DDI information from the biomedical literature. In this paper, we present a Stacked Generalization-based approach for automatic DDI extraction. The approach combines the feature-based, graph and tree kernels and, therefore, reduces the risk of missing important features. In addition, it introduces some domain knowledge based features (the keyword, semantic type, and DrugBank features) into the feature-based kernel, which contribute to the performance improvement. More specifically, the approach applies Stacked generalization to automatically learn the weights from the training data and assign them to three individual kernels to achieve a much better performance than each individual kernel. The experimental results show that our approach can achieve a better performance of 69.24% in F-score compared with other systems in the DDI Extraction 2011 challenge task. PMID:23785452

  9. Extracting drug-drug interactions from literature using a rich feature-based linear kernel approach

    PubMed Central

    Kim, Sun; Yeganova, Lana; Wilbur, W. John

    2015-01-01

    Identifying unknown drug interactions is of great benefit in the early detection of adverse drug reactions. Despite existence of several resources for drug-drug interaction (DDI) information, the wealth of such information is buried in a body of unstructured medical text which is growing exponentially. This calls for developing text mining techniques for identifying DDIs. The state-of-the-art DDI extraction methods use Support Vector Machines (SVMs) with non-linear composite kernels to explore diverse contexts in literature. While computationally less expensive, linear kernel-based systems have not achieved a comparable performance in DDI extraction tasks. In this work, we propose an efficient and scalable system using a linear kernel to identify DDI information. The proposed approach consists of two steps: identifying DDIs and assigning one of four different DDI types to the predicted drug pairs. We demonstrate that when equipped with a rich set of lexical and syntactic features, a linear SVM classifier is able to achieve a competitive performance in detecting DDIs. In addition, the one-against-one strategy proves vital for addressing an imbalance issue in DDI type classification. Applied to the DDIExtraction 2013 corpus, our system achieves an F1 score of 0.670, as compared to 0.651 and 0.609 reported by the top two participating teams in the DDIExtraction 2013 challenge, both based on non-linear kernel methods. PMID:25796456

  10. Extracting drug-drug interactions from literature using a rich feature-based linear kernel approach.

    PubMed

    Kim, Sun; Liu, Haibin; Yeganova, Lana; Wilbur, W John

    2015-06-01

    Identifying unknown drug interactions is of great benefit in the early detection of adverse drug reactions. Despite existence of several resources for drug-drug interaction (DDI) information, the wealth of such information is buried in a body of unstructured medical text which is growing exponentially. This calls for developing text mining techniques for identifying DDIs. The state-of-the-art DDI extraction methods use Support Vector Machines (SVMs) with non-linear composite kernels to explore diverse contexts in literature. While computationally less expensive, linear kernel-based systems have not achieved a comparable performance in DDI extraction tasks. In this work, we propose an efficient and scalable system using a linear kernel to identify DDI information. The proposed approach consists of two steps: identifying DDIs and assigning one of four different DDI types to the predicted drug pairs. We demonstrate that when equipped with a rich set of lexical and syntactic features, a linear SVM classifier is able to achieve a competitive performance in detecting DDIs. In addition, the one-against-one strategy proves vital for addressing an imbalance issue in DDI type classification. Applied to the DDIExtraction 2013 corpus, our system achieves an F1 score of 0.670, as compared to 0.651 and 0.609 reported by the top two participating teams in the DDIExtraction 2013 challenge, both based on non-linear kernel methods. PMID:25796456

  11. Effects of Shared Electronic Health Record Systems on Drug-Drug Interaction and Duplication Warning Detection

    PubMed Central

    Rinner, Christoph; Grossmann, Wilfried; Sauter, Simone Katja; Wolzt, Michael; Gall, Walter

    2015-01-01

    Shared electronic health records (EHRs) systems can offer a complete medication overview of the prescriptions of different health care providers. We use health claims data of more than 1 million Austrians in 2006 and 2007 with 27 million prescriptions to estimate the effect of shared EHR systems on drug-drug interaction (DDI) and duplication warnings detection and prevention. The Austria Codex and the ATC/DDD information were used as a knowledge base to detect possible DDIs. DDIs are categorized as severe, moderate, and minor interactions. In comparison to the current situation where only DDIs between drugs issued by a single health care provider can be checked, the number of warnings increases significantly if all drugs of a patient are checked: severe DDI warnings would be detected for 20% more persons, and the number of severe DDI warnings and duplication warnings would increase by 17%. We show that not only do shared EHR systems help to detect more patients with warnings but DDIs are also detected more frequently. Patient safety can be increased using shared EHR systems. PMID:26682218

  12. Design Features of Drug-Drug Interaction Trials Between Antivirals and Oral Contraceptives.

    PubMed

    Ayala, Ruben C; Arya, Vikram; Younis, Islam R

    2016-05-01

    The aim of this work was to explore the major design features of drug-drug interaction trials between antiviral medications (AVs) and oral contraceptives (OCs). Information on these trials (n = 27) was collected from approved drug labels and clinical pharmacology reviews conducted by the U.S. Food and Drug Administration. The primary objective of all trials was to evaluate changes in OC exposure following the coadministration of AVs. In addition, an evaluation of potential pharmacodynamic interaction was performed in 10 of these trials. Twenty-two trials were open label with a fixed-sequence design, and 5 trials used a double-blind crossover design. The trials were conducted using one, two, or three 28-day ovulatory cycles in 10, 8, and 9 trials, respectively. Only 1 trial enrolled HIV-infected women. The median number of women in a trial was 20 (range, 12 to 52). Norethindrone/ethinyl estradiol (EE) combination was the most commonly used OC (n = 16, 59%) followed by norgestimate/EE (n = 9, 33%). Labeling recommendations were based on exposure changes in 25 cases and on safety observations in the trial in 2 cases. In conclusion, a wide variety of trial designs was used, and there is no preferred design. The answer to the exposure question can be achieved using multiple designs. PMID:26384089

  13. Drug-drug Interaction Discovery Using Abstraction Networks for “National Drug File – Reference Terminology” Chemical Ingredients

    PubMed Central

    Ochs, Christopher; Zheng, Ling; Gu, Huanying; Perl, Yehoshua; Geller, James; Kapusnik-Uner, Joan; Zakharchenko, Aleksandr

    2015-01-01

    The National Drug File – Reference Terminology (NDF-RT) is a large and complex drug terminology. NDF-RT provides important information about clinical drugs, e.g., their chemical ingredients, mechanisms of action, dosage form and physiological effects. Within NDF-RT such information is represented using tens of thousands of roles. It is difficult to comprehend large, complex terminologies like NDF-RT. In previous studies, we introduced abstraction networks to summarize the content and structure of terminologies. In this paper, we introduce the Ingredient Abstraction Network to summarize NDF-RT’s Chemical Ingredients and their associated drugs. Additionally, we introduce the Aggregate Ingredient Abstraction Network, for controlling the granularity of summarization provided by the Ingredient Abstraction Network. The Ingredient Abstraction Network is used to support the discovery of new candidate drug-drug interactions (DDIs) not appearing in First Databank, Inc.’s DDI knowledgebase. PMID:26958234

  14. Impact of drug-drug and drug-disease interactions on gait speed in community-dwelling older adults

    PubMed Central

    Naples, Jennifer G.; Marcum, Zachary A.; Perera, Subashan; Newman, Anne B.; Greenspan, Susan L.; Gray, Shelly L.; Bauer, Douglas C.; Simonsick, Eleanor M.; Shorr, Ronald I.; Hanlon, Joseph T.

    2016-01-01

    Background Gait speed decline, an early marker of functional impairment, is a sensitive predictor of adverse health outcomes in older adults. The effect of potentially inappropriate prescribing on gait speed decline is not well known. Objective To determine if potentially inappropriate drug interactions impair functional status as measured by gait speed. Methods The sample included 2,402 older adults with medication and gait speed data from the Health, Aging and Body Composition study. The independent variable was the frequency of drug-disease and/or drug-drug interactions at baseline and three additional years. The main outcome was a clinically meaningful gait speed decline ≥ 0.1 m/s the year following drug interaction assessment. Adjusted odds ratios and 95% confidence intervals were calculated using multivariate generalized estimating equations for both the overall sample and a sample stratified by gait speed at time of drug interaction assessment. Results The prevalence of drug-disease and drug-drug interactions ranged from 7.6–9.3% and 10.5–12.3%, respectively, with few participants (3.8–5.7%) having multiple drug interactions. At least 22% of participants had a gait speed decline of ≥ 0.1 m/s annually. Drug interactions were not significantly associated with gait speed decline overall or in the stratified sample of fast walkers. There was some evidence, however, that drug interactions increased the risk of gait speed decline among those participants with slower gait speeds, though p values did not reach statistical significance (adjusted odds ratio 1.22, 95% confidence intervals 0.96–1.56, p=0.11). Moreover, a marginally significant dose-response relationship was seen with multiple drug interactions and gait speed decline (adjusted odds ratio 1.40; 95% confidence intervals 0.95–2.04, p=0.08). Conclusions Drug interactions may increase the likelihood of gait speed decline among older adults with evidence of preexisting debility. Future studies

  15. Discovery and explanation of drug-drug interactions via text mining.

    PubMed

    Percha, Bethany; Garten, Yael; Altman, Russ B

    2012-01-01

    Drug-drug interactions (DDIs) can occur when two drugs interact with the same gene product. Most available information about gene-drug relationships is contained within the scientific literature, but is dispersed over a large number of publications, with thousands of new publications added each month. In this setting, automated text mining is an attractive solution for identifying gene-drug relationships and aggregating them to predict novel DDIs. In previous work, we have shown that gene-drug interactions can be extracted from Medline abstracts with high fidelity - we extract not only the genes and drugs, but also the type of relationship expressed in individual sentences (e.g. metabolize, inhibit, activate and many others). We normalize these relationships and map them to a standardized ontology. In this work, we hypothesize that we can combine these normalized gene-drug relationships, drawn from a very broad and diverse literature, to infer DDIs. Using a training set of established DDIs, we have trained a random forest classifier to score potential DDIs based on the features of the normalized assertions extracted from the literature that relate two drugs to a gene product. The classifier recognizes the combinations of relationships, drugs and genes that are most associated with the gold standard DDIs, correctly identifying 79.8% of assertions relating interacting drug pairs and 78.9% of assertions relating noninteracting drug pairs. Most significantly, because our text processing method captures the semantics of individual gene-drug relationships, we can construct mechanistic pharmacological explanations for the newly-proposed DDIs. We show how our classifier can be used to explain known DDIs and to uncover new DDIs that have not yet been reported. PMID:22174296

  16. A graph kernel based on context vectors for extracting drug-drug interactions.

    PubMed

    Zheng, Wei; Lin, Hongfei; Zhao, Zhehuan; Xu, Bo; Zhang, Yijia; Yang, Zhihao; Wang, Jian

    2016-06-01

    The clinical recognition of drug-drug interactions (DDIs) is a crucial issue for both patient safety and health care cost control. Thus there is an urgent need that DDIs be extracted automatically from biomedical literature by text-mining techniques. Although the top-ranking DDIs systems explore various features of texts, these features can't yet adequately express long and complicated sentences. In this paper, we present an effective graph kernel which makes full use of different types of contexts to identify DDIs from biomedical literature. In our approach, the relations among long-range words, in addition to close-range words, are obtained by the graph representation of a parsed sentence. Context vectors of a vertex, an iterative vectorial representation of all labeled nodes adjacent and nonadjacent to it, adequately capture the direct and indirect substructures' information. Furthermore, the graph kernel considering the distance between context vectors is used to detect DDIs. Experimental results on the DDIExtraction 2013 corpus show that our system achieves the best detection and classification performance (F-score) of DDIs (81.8 and 68.4, respectively). Especially for the Medline-2013 dataset, our system outperforms the top-ranking DDIs systems by F-scores of 10.7 and 12.2 in detection and classification, respectively. PMID:27012903

  17. Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel.

    PubMed

    Cortés, Javier; Swain, Sandra M; Kudaba, Iveta; Hauschild, Maik; Patel, Taral; Grincuka, Elza; Masuda, Norikazu; McNally, Virginia; Ross, Graham; Brewster, Mike; Marier, Jean-François; Trinh, My My; Garg, Amit; Nijem, Ihsan; Visich, Jennifer; Lum, Bert L; Baselga, José

    2013-11-01

    Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer. PMID:23969513

  18. DINTO: Using OWL Ontologies and SWRL Rules to Infer Drug-Drug Interactions and Their Mechanisms.

    PubMed

    Herrero-Zazo, María; Segura-Bedmar, Isabel; Hastings, Janna; Martínez, Paloma

    2015-08-24

    The early detection of drug-drug interactions (DDIs) is limited by the diffuse spread of DDI information in heterogeneous sources. Computational methods promise to play a key role in the identification and explanation of DDIs on a large scale. However, such methods rely on the availability of computable representations describing the relevant domain knowledge. Current modeling efforts have focused on partial and shallow representations of the DDI domain, failing to adequately support computational inference and discovery applications. In this paper, we describe a comprehensive ontology for DDI knowledge (DINTO), which is the first formal representation of different types of DDIs and their mechanisms and its application in the prediction of DDIs. This project has been developed using currently available semantic web technologies, standards, and tools, and we have demonstrated that the combination of drug-related facts in DINTO and Semantic Web Rule Language (SWRL) rules can be used to infer DDIs and their different mechanisms on a large scale. The ontology is available from https://code.google.com/p/dinto/. PMID:26147071

  19. Consensus Recommendations for Systematic Evaluation of Drug-Drug Interaction Evidence for Clinical Decision Support

    PubMed Central

    Scheife, Richard T.; Hines, Lisa E.; Boyce, Richard D.; Chung, Sophie P.; Momper, Jeremiah; Sommer, Christine D.; Abernethy, Darrell R.; Horn, John; Sklar, Stephen J.; Wong, Samantha K.; Jones, Gretchen; Brown, Mary; Grizzle, Amy J.; Comes, Susan; Wilkins, Tricia Lee; Borst, Clarissa; Wittie, Michael A.; Rich, Alissa; Malone, Daniel C.

    2015-01-01

    Background Healthcare organizations, compendia, and drug knowledgebase vendors use varying methods to evaluate and synthesize evidence on drug-drug interactions (DDIs). This situation has a negative effect on electronic prescribing and medication information systems that warn clinicians of potentially harmful medication combinations. Objective To provide recommendations for systematic evaluation of evidence from the scientific literature, drug product labeling, and regulatory documents with respect to DDIs for clinical decision support. Methods A conference series was conducted to develop a structured process to improve the quality of DDI alerting systems. Three expert workgroups were assembled to address the goals of the conference. The Evidence Workgroup consisted of 15 individuals with expertise in pharmacology, drug information, biomedical informatics, and clinical decision support. Workgroup members met via webinar from January 2013 to February 2014. Two in-person meetings were conducted in May and September 2013 to reach consensus on recommendations. Results We developed expert-consensus answers to three key questions: 1) What is the best approach to evaluate DDI evidence?; 2) What evidence is required for a DDI to be applicable to an entire class of drugs?; and 3) How should a structured evaluation process be vetted and validated? Conclusion Evidence-based decision support for DDIs requires consistent application of transparent and systematic methods to evaluate the evidence. Drug information systems that implement these recommendations should be able to provide higher quality information about DDIs in drug compendia and clinical decision support tools. PMID:25556085

  20. The prevalence of major potential drug-drug interactions at a University health centre pharmacy in Jamaica

    PubMed Central

    Kennedy-Dixon, Tracia-Gay; Gossell-Williams, Maxine; Hall, Jannel; Anglin-Brown, Blossom

    2015-01-01

    Objective: To identify major potential drug-drug interactions (DDIs) on prescriptions filled at the University Health Centre Pharmacy, Mona Campus, Jamaica. Methods: This investigation utilised a cross-sectional analysis on all prescriptions with more than one drug that were filled at the Health Centre Pharmacy between November 2012 and February 2013. Potential DDIs were identified using the online Drug Interactions Checker database of Drugs.com. Results: During the period of the study, a total of 2814 prescriptions were analysed for potential DDIs. The prevalence of potential DDIs found during the study period was 49.82%. Major potential DDIs accounted for 4.7 % of the total number of interactions detected, while moderate potential DDIs and minor potential DDIs were 80.8 % and 14.5 % respectively. The three most frequently occurring major potential DDIs were amlodipine and simvastatin (n=46), amiloride and losartan (n=27) and amiloride and lisinopril (n=16). Conclusion: This study has highlighted the need for educational initiatives to ensure that physicians and pharmacists collaborate in an effort to minimise the risks to the patients. These interactions are avoidable for the most part, as the use of online tools can facilitate the selection of therapeutic alternatives or guide decisions for closer patient monitoring and thus reduce the risks of adverse events. PMID:26759615

  1. Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling.

    PubMed

    Posada, Maria M; Bacon, James A; Schneck, Karen B; Tirona, Rommel G; Kim, Richard B; Higgins, J William; Pak, Y Anne; Hall, Stephen D; Hillgren, Kathleen M

    2015-03-01

    Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen. PMID:25504564

  2. Potential drug-drug interactions in prescriptions dispensed in community and hospital pharmacies in East of Iran

    PubMed Central

    Dirin, Mandana Moradi; Mousavi, Sarah; Afshari, Amir Reza; Tabrizian, Kaveh; Ashrafi, Mohammad Hossein

    2014-01-01

    Objective: This study aim to evaluate and compare type and prevalence of drug-drug interactions (DDIs) in prescriptions dispensed in both community and hospital setting in Zabol, Iran. Methods: A total of 2796 prescriptions were collected from community and inpatient and outpatient pharmacy of Amir-al-momenin only current acting hospital in Zabol, Iran. The prescriptions were processed using Lexi-Comp drug interaction software. The identified DDIs were categorized into five classes (A, B, C, D, X). Findings: Overall 41.6% of prescriptions had at last one potential DDI. The most common type of interactions was type C (66%). The percentage of drug interactions in community pharmacies were significantly lower than hospital pharmacies (P < 0.0001). Conclusion: Our results indicate that patients in Zabol are at high risk of adverse drug reactions caused by medications due to potential DDIs. Appropriate education for physicians about potentially harmful DDIs, as well as active participation of pharmacists in detection and prevention of drug-related injuries, could considerably prevent the consequence of DDIs among patients. PMID:25328901

  3. Extraction of pharmacokinetic evidence of drug-drug interactions from the literature.

    PubMed

    Kolchinsky, Artemy; Lourenço, Anália; Wu, Heng-Yi; Li, Lang; Rocha, Luis M

    2015-01-01

    Drug-drug interaction (DDI) is a major cause of morbidity and mortality and a subject of intense scientific interest. Biomedical literature mining can aid DDI research by extracting evidence for large numbers of potential interactions from published literature and clinical databases. Though DDI is investigated in domains ranging in scale from intracellular biochemistry to human populations, literature mining has not been used to extract specific types of experimental evidence, which are reported differently for distinct experimental goals. We focus on pharmacokinetic evidence for DDI, essential for identifying causal mechanisms of putative interactions and as input for further pharmacological and pharmacoepidemiology investigations. We used manually curated corpora of PubMed abstracts and annotated sentences to evaluate the efficacy of literature mining on two tasks: first, identifying PubMed abstracts containing pharmacokinetic evidence of DDIs; second, extracting sentences containing such evidence from abstracts. We implemented a text mining pipeline and evaluated it using several linear classifiers and a variety of feature transforms. The most important textual features in the abstract and sentence classification tasks were analyzed. We also investigated the performance benefits of using features derived from PubMed metadata fields, various publicly available named entity recognizers, and pharmacokinetic dictionaries. Several classifiers performed very well in distinguishing relevant and irrelevant abstracts (reaching F1≈0.93, MCC≈0.74, iAUC≈0.99) and sentences (F1≈0.76, MCC≈0.65, iAUC≈0.83). We found that word bigram features were important for achieving optimal classifier performance and that features derived from Medical Subject Headings (MeSH) terms significantly improved abstract classification. We also found that some drug-related named entity recognition tools and dictionaries led to slight but significant improvements, especially in

  4. Criteria for assessing high-priority drug-drug interactions for clinical decision support in electronic health records

    PubMed Central

    2013-01-01

    Background High override rates for drug-drug interaction (DDI) alerts in electronic health records (EHRs) result in the potentially dangerous consequence of providers ignoring clinically significant alerts. Lack of uniformity of criteria for determining the severity or validity of these interactions often results in discrepancies in how these are evaluated. The purpose of this study was to identify a set of criteria for assessing DDIs that should be used for the generation of clinical decision support (CDS) alerts in EHRs. Methods We conducted a 20-year systematic literature review of MEDLINE and EMBASE to identify characteristics of high-priority DDIs. These criteria were validated by an expert panel consisting of medication knowledge base vendors, EHR vendors, in-house knowledge base developers from academic medical centers, and both federal and private agencies involved in the regulation of medication use. Results Forty-four articles met the inclusion criteria for assessing characteristics of high-priority DDIs. The panel considered five criteria to be most important when assessing an interaction- Severity, Probability, Clinical Implications of the interaction, Patient characteristics, and the Evidence supporting the interaction. In addition, the panel identified barriers and considerations for being able to utilize these criteria in medication knowledge bases used by EHRs. Conclusions A multi-dimensional approach is needed to understanding the importance of an interaction for inclusion in medication knowledge bases for the purpose of CDS alerting. The criteria identified in this study can serve as a first step towards a uniform approach in assessing which interactions are critical and warrant interruption of a provider’s workflow. PMID:23763856

  5. pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development.

    PubMed

    Zhang, L; Wu, F; Lee, S C; Zhao, H; Zhang, L

    2014-08-01

    Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated. PMID:24733008

  6. Drug-metabolism mechanism: Knowledge-based population pharmacokinetic approach for characterizing clobazam drug-drug interactions.

    PubMed

    Tolbert, Dwain; Bekersky, Ihor; Chu, Hui-May; Ette, Ene I

    2016-03-01

    A metabolic mechanism-based characterization of antiepileptic drug-drug interactions (DDIs) with clobazam in patients with Lennox-Gastaut syndrome (LGS) was performed using a population pharmacokinetic (PPK) approach. To characterize potential DDIs with clobazam, pharmacokinetic (PK) data from 153 patients with LGS in study OV-1012 (NCT00518713) and 18 healthy participants in bioavailability study OV-1017 were pooled. Antiepileptic drugs (AEDs) were grouped based on their effects on the cytochrome P450 (CYP) isozymes responsible for the metabolism of clobazam and its metabolite, N-desmethylclobazam (N-CLB): CYP3A inducers (phenobarbital, phenytoin, and carbamazepine), CYP2C19 inducers (valproic acid, phenobarbital, phenytoin, and carbamazepine), or CYP2C19 inhibitors (felbamate, oxcarbazepine). CYP3A4 inducers-which did not affect the oral clearance of clobazam-significantly increased the formation of N-CLB by 9.4%, while CYP2C19 inducers significantly increased the apparent elimination rate of N-CLB by 10.5%, resulting in a negligible net change in the PK of the active metabolite. CYP2C19 inhibitors did not affect N-CLB elimination. Because concomitant use of AEDs that are either CYP450 inhibitors or inducers with clobazam in the treatment of LGS patients had negligible to no effect on clobazam PK in this study, dosage adjustments may not be required for clobazam in the presence of the AEDs investigated here. PMID:26224203

  7. The current status of time dependent CYP inhibition assay and in silico drug-drug interaction predictions.

    PubMed

    Yan, Zhengyin; Caldwell, Gary W

    2012-01-01

    Various CYP time-dependent inhibition (TDI) assays have been widely implemented in drug discovery and development which has led to great success in positively identifying compounds with mechanism-base inhibition liability. However, drug-drug interaction (DDI) predictions by various in-silico models utilizing kinetic parameters obtained from TDI assays have met with significant challenges including questionable kinetic data, over-simplified in-vitro models and unreliable mathematic algorithms. Although significant efforts have been made to standardize the TDI assay and refine mathematical models, recent evaluation studies have revealed that the kinetic parameters of TDI, the most important in-vitro data required by all DDI prediction models, are significantly impacted by a variety of experimental variables including microsomal protein concentration, metabolic stability, CYP-specific probes, and post-incubation time. This review attempts to provide medicinal chemists a brief overview on the current status of TDI assays, determination of kinetic parameters and in silico DDI predictions with emphasis on the complexity of the TDI kinetics and limitations of current in-vitro models and DDI prediction methodologies. PMID:22571791

  8. Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction.

    PubMed

    Nishimura, Toshihiko; Nishimura, Toshiko; Hu, Yajing; Wu, Manhong; Pham, Edward; Suemizu, Hiroshi; Elazar, Menashe; Liu, Michael; Idilman, Ramazan; Yurdaydin, Cihan; Angus, Peter; Stedman, Catherine; Murphy, Brian; Glenn, Jeffrey; Nakamura, Masato; Nomura, Tatsuji; Chen, Yuan; Zheng, Ming; Fitch, William L; Peltz, Gary

    2013-02-01

    Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment. PMID:23143674

  9. Induction of P-glycoprotein expression and activity by Aconitum alkaloids: Implication for clinical drug-drug interactions.

    PubMed

    Wu, Jinjun; Lin, Na; Li, Fangyuan; Zhang, Guiyu; He, Shugui; Zhu, Yuanfeng; Ou, Rilan; Li, Na; Liu, Shuqiang; Feng, Lizhi; Liu, Liang; Liu, Zhongqiu; Lu, Linlin

    2016-01-01

    The Aconitum species, which mainly contain bioactive Aconitum alkaloids, are frequently administered concomitantly with other herbal medicines or chemical drugs in clinics. The potential risk of drug-drug interactions (DDIs) arising from co-administration of Aconitum alkaloids and other drugs against specific targets such as P-glycoprotein (P-gp) must be evaluated. This study focused on the effects of three representative Aconitum alkaloids: aconitine (AC), benzoylaconine (BAC), and aconine, on the expression and activity of P-gp. We observed that Aconitum alkaloids increased P-gp expression in LS174T and Caco-2 cells in the order AC > BAC > aconine. Nuclear receptors were involved in the induction of P-gp. AC and BAC increased the P-gp transport activity. Strikingly, intracellular ATP levels and mitochondrial mass also increased. Furthermore, exposure to AC decreased the toxicity of vincristine and doxorubicin towards the cells. In vivo, AC significantly up-regulated the P-gp protein levels in the jejunum, ileum, and colon of FVB mice, and protected them against acute AC toxicity. Taken together, the findings of our in vitro and in vivo experiments indicate that AC can induce P-gp expression, and that co-administration of AC with P-gp substrate drugs may cause DDIs. Our findings have important implications for Aconitum therapy in clinics. PMID:27139035

  10. Potential drug-drug interactions in hospitalized patients with chronic heart failure and chronic obstructive pulmonary disease

    PubMed Central

    Roblek, Tina; Trobec, Katja; Mrhar, Ales

    2014-01-01

    Introduction Polypharmacy is common in patients with chronic heart failure (HF) and/or chronic obstructive pulmonary disease (COPD), but little is known about the prevalence and significance of drug-drug interactions (DDIs). This study evaluates DDIs in hospitalized patients. Material and methods We retrospectively screened medical charts over a 6-month period for diagnosis of chronic HF and/or COPD. Potential DDIs were evaluated using Lexi-Interact software. Results Seven hundred and seventy-eight patients were included in the study (median age 75 years, 61% men). The median number of drugs on admission and discharge was 6 (interquartile range (IQR) 4–9) and 7 (IQR 5–), respectively (p = 0.10). We recorded 6.5 ±5.7 potential DDIs per patient on admission and 7.2 ±5.6 on discharge (p = 0.2). From admission to discharge, type-C and type-X potential DDIs increased (p < 0.05 for both). Type X interactions were rare (< 1%), with the combination of a β-blocker and a β2 agonist being the most common (64%). There were significantly more type-C and type-D potential DDIs in patients with chronic HF as compared to patients with COPD (p < 0.001). Patients with concomitant chronic HF and COPD had more type-C and type-X potential DDIs when compared to those with individual disease (p < 0.005). An aldosterone antagonist and ACE inhibitor/ARB were prescribed to 3% of chronic HF patients with estimated glomerular filtration rate < 30 ml/(min × 1.73 m2). Conclusions The DDIs are common in patients with chronic HF and/or COPD, but only a few appear to be of clinical significance. The increase in potential DDIs from admission to discharge may reflect better guideline implementation rather than poor clinical practice. PMID:25395943

  11. Pharmacologic Therapy for Posttraumatic Stress Disorder: Review of Prescriptions and Potential Drug-Drug Interactions in a Military Cohort

    PubMed Central

    Jablonski, Kara L.; Devore, Maria D.; Ryan, Margaret A.; Streeter, Emily L.; Tolentino, Jerlyn C.; Klinski, Angelica A.; Bahlawan, Nahed

    2015-01-01

    Objective: To describe outpatient prescription treatment for active-duty military members with posttraumatic stress disorder (PTSD). Medical records were screened for drug-drug interactions with PTSD-related medications and for adverse drug events. Method: A retrospective chart review was conducted of the medical records of active-duty service members aged 18 to 65 years who had a diagnosis of PTSD (ICD-9 criteria) and received psychiatric treatment at Naval Hospital Camp Pendleton, Camp Pendleton, California, between October 1, 2010, and October 31, 2010. Prescription medication treatment over a 6-month period (October 1, 2010, through March 31, 2011) was reviewed. Results: Among 275 patients, 243 (88.4%) had at least 1 prescription dispensed and 219 (79.6%) had at least 1 PTSD-related medication dispensed. More than 1 PTSD-related medication was dispensed to 153 (55.6%) patients. The most common medication classes dispensed were selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) (35.1%), novel antidepressants (15.6%), and anticonvulsants (15.0%). The most frequently dispensed PTSD-related medications were zolpidem: 149 (9.8%), sertraline: 147 (9.7%), gabapentin: 134 (8.8%), prazosin: 111 (7.3%), and trazodone: 110 (7.2%). In the subgroup of 219 patients who received PTSD-related medications, overlapping periods of treatment between an SSRI and another PTSD-related medication occurred in 58 (26.5%) patients. Potential drug-drug interactions with this combination involved 44 (20.1%) patients; no adverse drug events were reported. Among these 44 patients, 55 different potential drug-drug interactions were identified. Conclusions: Patients receiving medications for PTSD are frequently treated with SSRIs or SNRIs and are likely to be prescribed more than 1 PTSD-related medication. PMID:27057415

  12. Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions

    PubMed Central

    Arimany-Nardi, Cristina; Minuesa, Gerard; Keller, Thorsten; Erkizia, Itziar; Koepsell, Hermann; Martinez-Picado, Javier; Pastor-Anglada, Marçal

    2016-01-01

    Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level. PMID:27445813

  13. Role of Human Organic Cation Transporter 1 (hOCT1) Polymorphisms in Lamivudine (3TC) Uptake and Drug-Drug Interactions.

    PubMed

    Arimany-Nardi, Cristina; Minuesa, Gerard; Keller, Thorsten; Erkizia, Itziar; Koepsell, Hermann; Martinez-Picado, Javier; Pastor-Anglada, Marçal

    2016-01-01

    Lamivudine (3TC), a drug used in the treatment of HIV infection, needs to cross the plasma membrane to exert its therapeutic action. Human Organic cation transporter 1 (hOCT1), encoded by the SLC22A1 gene, is the transporter responsible for its uptake into target cells. As SLC22A1 is a highly polymorphic gene, the aim of this study was to determine how SNPs in the OCT1-encoding gene affected 3TC internalization and its interaction with other co-administered drugs. HEK293 cells stably transfected with either the wild type form or the polymorphic variants of hOCT1 were used to perform kinetic and drug-drug interaction studies. Protein co-immunoprecipitation was used to assess the impact of selected polymorphic cysteines on the oligomerization of the transporter. Results showed that 3TC transport efficiency was reduced in all polymorphic variants tested (R61C, C88R, S189L, M420del, and G465R). This was not caused by lack of oligomerization in case of variants located at the transporter extracellular loop (R61C and C88R). Drug-drug interaction measurements showed that co-administered drugs [abacavir (ABC), zidovudine (AZT), emtricitabine (FTC), tenofovir diproxil fumarate (TDF), efavirenz (EFV) and raltegravir (RAL)], differently inhibited 3TC uptake depending upon the polymorphic variant analyzed. These data highlight the need for accurate analysis of drug transporter polymorphic variants of clinical relevance, because polymorphisms can impact on substrate (3TC) translocation but even more importantly they can differentially affect drug-drug interactions at the transporter level. PMID:27445813

  14. Prediction of Drug-Drug Interactions Arising from CYP3A induction Using a Physiologically Based Dynamic Model.

    PubMed

    Almond, Lisa M; Mukadam, Sophie; Gardner, Iain; Okialda, Krystle; Wong, Susan; Hatley, Oliver; Tay, Suzanne; Rowland-Yeo, Karen; Jamei, Masoud; Rostami-Hodjegan, Amin; Kenny, Jane R

    2016-06-01

    Using physiologically based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine the most appropriate model refinement. When the maximal fold induction (Indmax) for rifampicin was increased (from 8 to 16) in both the liver and the gut, or when the Indmax was increased in the gut but not in liver, there was a decrease in bias and increased precision compared with the base model (Indmax = 8) [geometric mean fold error (GMFE) 2.12 vs. 1.48 and 1.77, respectively]. Induction parameters (mRNA and activity), determined for rifampicin, carbamazepine, phenytoin, and phenobarbital in hepatocytes from four donors, were then used to evaluate use of the refined rifampicin model for calibration. Calibration of mRNA and activity data for other inducers using the refined rifampicin model led to more accurate DDI predictions compared with the initial model (activity GMFE 1.49 vs. 1.68; mRNA GMFE 1.35 vs. 1.46), suggesting that robust in vivo reference values can be used to overcome interdonor and laboratory-to-laboratory variability. Use of uncalibrated data also performed well (GMFE 1.39 and 1.44 for activity and mRNA). As a result of experimental variability (i.e., in donors and protocols), it is prudent to fully characterize in vitro induction with prototypical inducers to give an understanding of how that particular system extrapolates to the in vivo situation when using an uncalibrated approach. PMID:27026679

  15. Prediction of Drug-Drug Interactions Arising from CYP3A induction Using a Physiologically Based Dynamic Model

    PubMed Central

    Mukadam, Sophie; Gardner, Iain; Okialda, Krystle; Wong, Susan; Hatley, Oliver; Tay, Suzanne; Rowland-Yeo, Karen; Jamei, Masoud; Rostami-Hodjegan, Amin; Kenny, Jane R.

    2016-01-01

    Using physiologically based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine the most appropriate model refinement. When the maximal fold induction (Indmax) for rifampicin was increased (from 8 to 16) in both the liver and the gut, or when the Indmax was increased in the gut but not in liver, there was a decrease in bias and increased precision compared with the base model (Indmax = 8) [geometric mean fold error (GMFE) 2.12 vs. 1.48 and 1.77, respectively]. Induction parameters (mRNA and activity), determined for rifampicin, carbamazepine, phenytoin, and phenobarbital in hepatocytes from four donors, were then used to evaluate use of the refined rifampicin model for calibration. Calibration of mRNA and activity data for other inducers using the refined rifampicin model led to more accurate DDI predictions compared with the initial model (activity GMFE 1.49 vs. 1.68; mRNA GMFE 1.35 vs. 1.46), suggesting that robust in vivo reference values can be used to overcome interdonor and laboratory-to-laboratory variability. Use of uncalibrated data also performed well (GMFE 1.39 and 1.44 for activity and mRNA). As a result of experimental variability (i.e., in donors and protocols), it is prudent to fully characterize in vitro induction with prototypical inducers to give an understanding of how that particular system extrapolates to the in vivo situation when using an uncalibrated approach. PMID:27026679

  16. Development of an ADME and drug-drug interactions knowledge database for the acceleration of drug discovery and development.

    PubMed

    Petitet, François; Barberan, Olivier; Dubus, Elodie; Ijjaali, Ismail; Donlan, Mary; Ollivier, Sophie; Michel, André

    2006-12-01

    It is widely recognised that predicting or determining the absorption, distribution, metabolism and excretion (ADME) properties of a compound as early as possible in the drug discovery process helps to prevent costly late-stage failures. Although in recent years high-throughput in vitro absorption distribution metabolism excretion toxicity (ADMET) screens have been implemented, more efficient in silico filters are still highly needed to predict and model the most relevant metabolic and pharmacokinetic end points, and thereby accelerate drug discovery and development. The usefulness of the data generated and published for the chemist, biologist or project manager who ultimately wants to understand and optimise the ADME properties of lead compounds cannot be argued with. Collecting and comparing data is an overwhelming task for the time-pressed scientist. Aureus Pharma provides a uniquely specialised solution for knowledge generation in drug discovery. AurSCOPE(®) ADME/DDI (drug-drug interaction) is a fully annotated, structured knowledge database containing all the pertinent biological and chemical information on the metabolic properties of drugs. This Aureus knowledge database has proven to be highly useful in designing predictive models and identifying potential drug-drug interactions. PMID:23495997

  17. Evaluation of a New Molecular Entity as a Victim of Metabolic Drug-Drug Interactions-an Industry Perspective.

    PubMed

    Bohnert, Tonika; Patel, Aarti; Templeton, Ian; Chen, Yuan; Lu, Chuang; Lai, George; Leung, Louis; Tse, Susanna; Einolf, Heidi J; Wang, Ying-Hong; Sinz, Michael; Stearns, Ralph; Walsky, Robert; Geng, Wanping; Sudsakorn, Sirimas; Moore, David; He, Ling; Wahlstrom, Jan; Keirns, Jim; Narayanan, Rangaraj; Lang, Dieter; Yang, Xiaoqing

    2016-08-01

    Under the guidance of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), scientists from 20 pharmaceutical companies formed a Victim Drug-Drug Interactions Working Group. This working group has conducted a review of the literature and the practices of each company on the approaches to clearance pathway identification (fCL), estimation of fractional contribution of metabolizing enzyme toward metabolism (fm), along with modeling and simulation-aided strategy in predicting the victim drug-drug interaction (DDI) liability due to modulation of drug metabolizing enzymes. Presented in this perspective are the recommendations from this working group on: 1) strategic and experimental approaches to identify fCL and fm, 2) whether those assessments may be quantitative for certain enzymes (e.g., cytochrome P450, P450, and limited uridine diphosphoglucuronosyltransferase, UGT enzymes) or qualitative (for most of other drug metabolism enzymes), and the impact due to the lack of quantitative information on the latter. Multiple decision trees are presented with stepwise approaches to identify specific enzymes that are involved in the metabolism of a given drug and to aid the prediction and risk assessment of drug as a victim in DDI. Modeling and simulation approaches are also discussed to better predict DDI risk in humans. Variability and parameter sensitivity analysis were emphasized when applying modeling and simulation to capture the differences within the population used and to characterize the parameters that have the most influence on the prediction outcome. PMID:27052879

  18. Drug-drug interactions in inpatient and outpatient settings in Iran: a systematic review of the literature

    PubMed Central

    2014-01-01

    Drug-drug interactions (DDIs) are an important type of adverse drug events. Yet overall incidence and pattern of DDIs in Iran has not been well documented and little information is available about the strategies that have been used for their prevention. The purpose of this study was to systematically review the literature on the incidence and pattern of DDIs in Iran as well as the used strategies for their prevention. PubMed, Scopus, electronic Persian databases, and Google Scholar were searched to identify published studies on DDIs in Iran. Additionally, the reference lists of all retrieved articles were reviewed to identify additional relevant articles. Eligible studies were those that analyzed original data on the incidence of DDIs in inpatient or outpatient settings in Iran. Articles about one specific DDI and drug interactions with herbs, diseases, and nutrients were excluded. The quality of included studies was assessed using quality assessment criteria. Database searches yielded 1053 potentially eligible citations. After removing duplicates, screening titles and abstracts, and reading full texts, 34 articles were found to be relevant. The quality assessment of the included studies showed a relatively poor quality. In terms of study setting, 18 and 16 studies have been conducted in inpatient and outpatient settings, respectively. All studies focused on potential DDIs while no study assessed actual DDIs. The median incidence of potential DDIs in outpatient settings was 8.5% per prescription while it was 19.2% in inpatient settings. The most indicated factor influencing DDIs incidence was patient age. The most involved drug classes in DDIs were beta blockers, angiotensin-converting-enzyme inhibitors (ACEIs), diuretic agents, and non-steroidal anti-inflammatory drugs (NSAIDs). Thirty-one studies were observational and three were experimental in which the strategies to reduce DDIs were applied. Although almost all studies concluded that the incidence of potential

  19. Mechanism of Drug-Drug Interactions Mediated by Human Cytochrome P450 CYP3A4 Monomer

    PubMed Central

    Denisov, Ilia G.; Grinkova, Yelena V.; Baylon, Javier L.; Tajkhorshid, Emad; Sligar, Stephen G.

    2016-01-01

    Using Nanodiscs, we quantitate the heterotropic interaction between two different drugs mediated by monomeric CYP3A4 incorporated into a native-like membrane environment. The mechanism of this interaction is deciphered by global analysis of multiple turnover experiments performed under identical conditions using the pure substrates progesterone (PGS) and carbamazepine (CBZ) and their mixtures. Activation of CBZ epoxidation and simultaneous inhibition of PGS hydroxylation are measured and quantitated through differences in their respective affinities towards both a remote allosteric site and the productive catalytic site near the heme iron. Preferred binding of PGS at the allosteric site and higher preference of CBZ binding at the productive site give rise to a non-trivial drug-drug interaction. Molecular dynamics simulations indicate functionally important conformational changes caused by PGS binding at the allosteric site and by two CBZ molecules positioned inside the substrate binding pocket. Structural changes involving Phe-213, Phe-219, and Phe-241 are suggested to be responsible for the observed synergetic effects and positive allosteric interactions between these two substrates. Such a mechanism is likely of general relevance to the mutual heterotropic effects caused by biologically active compounds which exhibit different patterns of interaction with the distinct allosteric and productive sites of CYP3A4, as well as other xenobiotic metabolizing cytochromes P450 that are also involved in drug-drug interactions. Importantly, this work demonstrates that a monomeric CYP3A4 can display the full spectrum of activation and cooperative effects that are observed in hepatic membranes. PMID:25777547

  20. Managing potential drug-drug interactions between gastric acid-reducing agents and antiretroviral therapy: experience from a large HIV-positive cohort.

    PubMed

    Lewis, J M; Stott, K E; Monnery, D; Seden, K; Beeching, N J; Chaponda, M; Khoo, S; Beadsworth, M B J

    2016-02-01

    Drug-drug interactions between antiretroviral therapy and other drugs are well described. Gastric acid-reducing agents are one such class. However, few data exist regarding the frequency of and indications for prescription, nor risk assessment in the setting of an HIV cohort receiving antiretroviral therapy. To assess prevalence of prescription of gastric acid-reducing agents and drug-drug interaction within a UK HIV cohort, we reviewed patient records for the whole cohort, assessing demographic data, frequency and reason for prescription of gastric acid-reducing therapy. Furthermore, we noted potential drug-drug interaction and whether risk had been documented and mitigated. Of 701 patients on antiretroviral therapy, 67 (9.6%) were prescribed gastric acid-reducing therapy. Of these, the majority (59/67 [88.1%]) were prescribed proton pump inhibitors. We identified four potential drug-drug interactions, which were appropriately managed by temporally separating the administration of gastric acid-reducing agent and antiretroviral therapy, and all four of these patients remained virally suppressed. Gastric acid-reducing therapy, in particular proton pump inhibitor therapy, appears common in patients prescribed antiretroviral therapy. Whilst there remains a paucity of published data, our findings are comparable to those in other European cohorts. Pharmacovigilance of drug-drug interactions in HIV-positive patients is vital. Education of patients and staff, and accurate data-gathering tools, will enhance patient safety. PMID:25721922

  1. Development and application of a UPLC-MS/MS method for simultaneous determination of fenofibric acid and berberine in rat plasma: application to the drug-drug pharmacokinetic interaction study of fenofibrate combined with berberine after oral administration in rats.

    PubMed

    Li, Guofei; Yang, Fan; Liu, Mei; Su, Xianying; Zhao, Mingming; Zhao, Limei

    2016-07-01

    With the purpose of carrying out pharmacokinetic interaction studies ofnberberine (BBR) and fenofibrate (FBT), an UPLC-MS/MS method has been developed and validated. The analytes, BBR and fenofibric acid (FBA, metabolite of FBT) and the internal standard, tetrahydropalmatine, were extracted with dichloromethane-diethyl ether (3:2, v/v) and separated on an Agilent Eclipse XDB C18 column using a mobile phase composed of acetonitrile and water. With positive ion electrospray ionization, the analytes were monitored on a triple quadrupole mass spectrometer in multiple reaction monitoring mode. Linear calibration curves were obtained over the concentration ranges of 0.1-100.0 ng/mL for BBR and 10.0-50,000.0 ng/mL for FBA. For BBR and FBA, the intra- and inter-day precisions were <11.5 and 11.9%, respectively. The accuracy was within 11.7% and 11.3%. The mean recoveries of BBR at three concentrations of 0.2, 20.0, 80.0 ng/mL were >85.6%, and those of FBA at three concentrations of 20.0, 2500.0, 40,000.0 ng/mL were >87.9%. Consequently, the proposed method was applied to the pharmacokinetic interaction study of FBT combined with BBR after oral administration in rats and was proved to be sensitive, specific and reliable to analyze BBR and FBA in biological samples simultaneously. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26577601

  2. Evaluation of change in the skin concentration of tazarotene and betamethasone dipropionate based on drug-drug interaction for transdermal drug delivery in miniature pig.

    PubMed

    Yu, Biao; Ma, Pengcheng; Yuan, Linwen; Chen, Dingding; Yang, Jin

    2015-05-01

    1. The present study was designed to investigate drug-drug interaction in a new combination cream which contains both tazarotene (TZRT) and betamethasone dipropionate (BTMSDP) by comparing the pharmacokinetic (PK) behaviors of TZRT, BTMSDP, and their major metabolites, tazarotenic acid (TZRTAC) and betamethasone (BTMS) with those in the commonly prescribed TZRT gel and BTMSDP cream. 2. The trial was performed on six Bama mini-pigs. The different regions on the back side of each pig were randomly assigned to one of three treatment groups: TZRT 0.05% gel, BTMSDP 0.05% cream, and combination cream. The stratum corneum and epidermis-dermis samples were collected at various times after drug administration and analyzed for TZRT, TZRTAC, BTMSDP, and BTMS by LC-MS/MS. Compared with TZRT gel alone, TZRT + BTMSDP did not significantly change the PK profiles of TZRT; neither did BTMSDP + TZRT significantly change the PK profiles of BTMSDP, compared with the BTMSDP cream alone. In addition, the concentrations of TZRTAC and BTMS in most samples were below the lower limit of quantitation (LLOQ). 3. The results suggest that there was no significant drug-drug interaction trend between TZRT and BTMSDP in the process of transdermal permeation of combination cream into the stratum corneum and epidermis-dermis of mini-pigs. PMID:25410121

  3. Drug-Drug Interactions Based on Pharmacogenetic Profile between Highly Active Antiretroviral Therapy and Antiblastic Chemotherapy in Cancer Patients with HIV Infection.

    PubMed

    Berretta, Massimiliano; Caraglia, Michele; Martellotta, Ferdinando; Zappavigna, Silvia; Lombardi, Angela; Fierro, Carla; Atripaldi, Luigi; Muto, Tommaso; Valente, Daniela; De Paoli, Paolo; Tirelli, Umberto; Di Francia, Raffaele

    2016-01-01

    The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the natural approach of HIV-related cancers. Several studies have shown that intensive antiblastic chemotherapy (AC) is feasible in HIV-infected patients with cancer, and that the outcome is similar to that of HIV-negative patients receiving the same AC regimens. However, the concomitant use of HAART and AC can result in drug accumulation or possible toxicity with consequent decreased efficacy of one or both classes of drugs. In fact, many AC agents are preferentially metabolized by CYP450 and drug-drug interactions (DDIs) with HAART are common. Therefore, it is important that HIV patients with cancer in HAART receiving AC treatment at the same time receive an individualized cancer management plan based on their liver and renal functions, their level of bone marrow suppression, their mitochondrial dysfunction, and their genotype profile. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, in order to maximize the efficacy of antiblastic therapy and minimize the risk of drug-drug interaction, a useful list of pharmacogenomic markers is provided. PMID:27065862

  4. Clinical drug-drug interactions of bosentan, a potent endothelial receptor antagonist, with various drugs: Physiological role of enzymes and transporters.

    PubMed

    Srinivas, Nuggehally R

    2016-07-01

    Bosentan, an endothelin-1 (ET) receptor antagonist is an important drug for the effective management of patients with pulmonary arterial hypertension. Bosentan has a rather complicated pharmacokinetics in humans involving multiple physiological components that have a profound influence on its drug disposition. Bosentan is mainly metabolized by cytochrome P450 (CYP) 3A4 and 2C9 enzymes with the involvement of multiple transporters that control its hepatic uptake and biliary excretion. The involvement of phase 2 metabolism of bosentan is a key to have an enhanced biliary excretion of the drug-related products. While bosentan exhibits high protein binding restricting the drug from extensive distribution and significant urinary excretion, bosentan induces its own metabolism by an increased expression of CYP3A4 on repeated dosing. Due to the above properties, bosentan has the potential to display drug-drug interaction with the co-administered drugs, either being a perpetrator or a victim. The intent of this review is manifold: a) to summarize the physiological role of CYP enzymes and hepatic-biliary transporters; b) to discuss the mechanism(s) involved in the purported liver injury caused by bosentan; c) to tabulate the numerous clinical drug-drug interaction studies involving the physiological interplay with CYP and/or transporters; d) to provide some perspectives on dosing strategy of bosentan. PMID:27045668

  5. Improving Detection of Arrhythmia Drug-Drug Interactions in Pharmacovigilance Data through the Implementation of Similarity-Based Modeling.

    PubMed

    Vilar, Santiago; Lorberbaum, Tal; Hripcsak, George; Tatonetti, Nicholas P

    2015-01-01

    Identification of Drug-Drug Interactions (DDIs) is a significant challenge during drug development and clinical practice. DDIs are responsible for many adverse drug effects (ADEs), decreasing patient quality of life and causing higher care expenses. DDIs are not systematically evaluated in pre-clinical or clinical trials and so the FDA U. S. Food and Drug Administration relies on post-marketing surveillance to monitor patient safety. However, existing pharmacovigilance algorithms show poor performance for detecting DDIs exhibiting prohibitively high false positive rates. Alternatively, methods based on chemical structure and pharmacological similarity have shown promise in adverse drug event detection. We hypothesize that the use of chemical biology data in a post hoc analysis of pharmacovigilance results will significantly improve the detection of dangerous interactions. Our model integrates a reference standard of DDIs known to cause arrhythmias with drug similarity data. To compare similarity between drugs we used chemical structure (both 2D and 3D molecular structure), adverse drug side effects, chemogenomic targets, drug indication classes, and known drug-drug interactions. We evaluated the method on external reference standards. Our results showed an enhancement of sensitivity, specificity and precision in different top positions with the use of similarity measures to rank the candidates extracted from pharmacovigilance data. For the top 100 DDI candidates, similarity-based modeling yielded close to twofold precision enhancement compared to the proportional reporting ratio (PRR). Moreover, the method helps in the DDI decision making through the identification of the DDI in the reference standard that generated the candidate. PMID:26068584

  6. Are We Heeding the Warning Signs? Examining Providers’ Overrides of Computerized Drug-Drug Interaction Alerts in Primary Care

    PubMed Central

    Slight, Sarah P.; Seger, Diane L.; Nanji, Karen C.; Cho, Insook; Maniam, Nivethietha; Dykes, Patricia C.; Bates, David W.

    2013-01-01

    Background Health IT can play a major role in improving patient safety. Computerized physician order entry with decision support can alert providers to potential prescribing errors. However, too many alerts can result in providers ignoring and overriding clinically important ones. Objective To evaluate the appropriateness of providers’ drug-drug interaction (DDI) alert overrides, the reasons why they chose to override these alerts, and what actions they took as a consequence of the alert. Design A cross-sectional, observational study of DDI alerts generated over a three-year period between January 1st, 2009, and December 31st, 2011. Setting Primary care practices affiliated with two Harvard teaching hospitals. The DDI alerts were screened to minimize the number of clinically unimportant warnings. Participants A total of 24,849 DDI alerts were generated in the study period, with 40% accepted. The top 62 providers with the highest override rate were identified and eight overrides randomly selected for each (a total of 496 alert overrides for 438 patients, 3.3% of the sample). Results Overall, 68.2% (338/496) of the DDI alert overrides were considered appropriate. Among inappropriate overrides, the therapeutic combinations put patients at increased risk of several specific conditions including: serotonin syndrome (21.5%, n=34), cardiotoxicity (16.5%, n=26), or sharp falls in blood pressure or significant hypotension (28.5%, n=45). A small number of drugs and DDIs accounted for a disproportionate share of alert overrides. Of the 121 appropriate alert overrides where the provider indicated they would “monitor as recommended”, a detailed chart review revealed that only 35.5% (n=43) actually did. Providers sometimes reported that patients had already taken interacting medications together (15.7%, n=78), despite no evidence to confirm this. Conclusions and Relevance We found that providers continue to override important and useful alerts that are likely to cause

  7. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole.

    PubMed

    Pawluk, Shane Ashley; Roels, Craig Allan; Wilby, Kyle John; Ensom, Mary H H

    2015-04-01

    Medications indicated for helminthes and other parasitic infections are frequently being used in mass populations in endemic areas. Currently, there is a lack of guidance for clinicians on how to appropriately manage drug interactions when faced with patients requiring short-term anthelmintic therapy with albendazole or mebendazole while concurrently taking other agents. The objective of this review was to systematically summarize and evaluate published literature on the pharmacokinetics of albendazole or mebendazole when taken with other interacting medications. A search of MEDLINE (1946 to October 2014), EMBASE (1974 to October 2014), International Pharmaceutical Abstracts (1970 to October 2014), Google, and Google Scholar was conducted for articles describing the pharmacokinetics of albendazole or mebendazole when given with other medications (and supplemented by a bibliographic review of all relevant articles). Altogether, 17 articles were included in the review. Studies reported data on pharmacokinetic parameters for albendazole or mebendazole when taken with cimetidine, dexamethasone, ritonavir, phenytoin, carbamazepine, phenobarbital, ivermectin, praziquantel, diethylcarbamazine, azithromycin, and levamisole. Cimetidine increased the elimination half-life of albendazole and maximum concentration (Cmax) of mebendazole; dexamethasone increased the area under the plasma concentration-time curve (AUC) of albendazole; levamisole decreased the Cmax of albendazole; anticonvulsants (phenytoin, phenobarbital, carbamazepine) decreased the AUC of albendazole; praziquantel increased the AUC of albendazole; and ritonavir decreased the AUC of both albendazole and mebendazole. No major interactions were found with ivermectin, azithromycin, or diethylcarbamazine. Future research is required to clarify the clinical relevance of the interactions observed. PMID:25691367

  8. Semi-mechanistic physiologically-based pharmacokinetic modeling of clinical glibenclamide pharmacokinetics and drug-drug-interactions.

    PubMed

    Greupink, Rick; Schreurs, Marieke; Benne, Marina S; Huisman, Maarten T; Russel, Frans G M

    2013-08-16

    We studied if the clinical pharmacokinetics and drug-drug interactions (DDIs) of the sulfonylurea-derivative glibenclamide can be simulated via a physiologically-based pharmacokinetic modeling approach. To this end, a glibenclamide PBPK-model was build in Simcyp using in vitro physicochemical and biotransformation data of the drug, and was subsequently optimized using plasma disappearance data observed after i.v. administration. The model was validated against data observed after glibenclamide oral dosing, including DDIs. We found that glibenclamide pharmacokinetics could be adequately modeled if next to CYP metabolism an active hepatic uptake process was assumed. This hepatic uptake process was subsequently included in the model in a non-mechanistic manner. After an oral dose of 0.875 mg predicted Cmax and AUC were 39.7 (95% CI:37.0-42.7)ng/mL and 108 (95% CI: 96.9-120)ng/mLh, respectively, which is in line with observed values of 43.6 (95% CI: 37.7-49.5)ng/mL and 133 (95% CI: 107-159)ng/mLh. For a 1.75 mg oral dose, the predicted and observed values were 82.5 (95% CI:76.6-88.9)ng/mL vs 91.1 (95% CI: 67.9-115.9) for Cmax and 224 (95% CI: 202-248) vs 324 (95% CI: 197-451)ng/mLh for AUC, respectively. The model correctly predicted a decrease in exposure after rifampicin pre-treatment. An increase in glibenclamide exposure after clarithromycin co-treatment was predicted, but the magnitude of the effect was underestimated because part of this DDI is the result of an interaction at the transporter level. Finally, the effects of glibenclamide and fluconazol co-administration were simulated. Our simulations indicated that co-administration of this potent CYP450 inhibitor will profoundly increase glibenclamide exposure, which is in line with clinical observations linking the glibenclamide-fluconazol combination to an increased risk of hypoglycemia. In conclusion, glibenclamide pharmacokinetics and its CYP-mediated DDIs can be simulated via PBPK-modeling. In addition, our

  9. Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets.

    PubMed

    Saxena, Aaruni; Balaramnavar, Vishal M; Hohlfeld, Thomas; Saxena, Anil K

    2013-12-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with the anti-platelet activity of aspirin at the level of the platelet cyclooxygenase-1 (COX-1) enzyme. In order to examine the interference of common NSAIDs with the anti-platelet activity of aspirin the human platelet rich plasma from voluntary donors was used for arachidonic acid-induced aggregation and determination of thromboxane synthesis. Further, docking studies were used to explain the molecular basis of the NSAID/aspirin interaction. The experimental results showed that celecoxib, dipyrone (active metabolite), ibuprofen, flufenamic acid, naproxen, nimesulide, oxaprozin, and piroxicam significantly interfere with the anti-platelet activity of aspirin, while diclofenac, ketorolac and acetaminophen do not. Docking studies suggested that NSAIDs forming hydrogen bonds with Ser530, Arg120, Tyr385 and other amino acids of the COX-1 hydrophobic channel interfere with antiplatelet activity of aspirin while non interfering NSAIDs do not form relevant hydrogen bond interactions within the aspirin binding site. In conclusion, docking analysis of NSAID interactions at the COX-1 active site appears useful to predict their interference with the anti-platelet activity of aspirin. The results, demonstrate that some NSAIDs do not interfere with the antiplatelet action of aspirin while many others do and provide a basis for understanding the observed differences among individual non-aspirin NSAIDs. PMID:24075938

  10. Drug-drug interactions between rosuvastatin and oral antidiabetic drugs occurring at the level of OATP1B1.

    PubMed

    van de Steeg, E; Greupink, R; Schreurs, M; Nooijen, I H G; Verhoeckx, K C M; Hanemaaijer, R; Ripken, D; Monshouwer, M; Vlaming, M L H; DeGroot, J; Verwei, M; Russel, F G M; Huisman, M T; Wortelboer, H M

    2013-03-01

    Organic anion-transporting polypeptide 1B1 (OATP1B1) is an important hepatic uptake transporter, of which the polymorphic variant OATP1B1*15 (Asn130Asp and Val174Ala) has been associated with decreased transport activity. Rosuvastatin is an OATP1B1 substrate and often concomitantly prescribed with oral antidiabetics in the clinic. The aim of this study was to investigate possible drug-drug interactions between these drugs at the level of OATP1B1 and OATP1B1*15. We generated human embryonic kidney (HEK)293 cells stably overexpressing OATP1B1 or OATP1B1*15 that showed similar protein expression levels of OATP1B1 and OATP1B1*15 at the cell membrane as measured by liquid chromatography-tandem mass spectrometry. In HEK-OATP1B1*15 cells, the V(max) for OATP1B1-mediated transport of E(2)17β-G (estradiol 17β-d-glucuronide) was decreased >60%, whereas K(m) values (Michaelis constant) were comparable. Uptake of rosuvastatin in HEK-OATP1B1 cells (K(m) 13.1 ± 0.43 μM) was nearly absent in HEK-OATP1B1*15 cells. Interestingly, several oral antidiabetics (glyburide, glimepiride, troglitazone, pioglitazone, glipizide, gliclazide, and tolbutamide), but not metformin, were identified as significant inhibitors of the OATP1B1-mediated transport of rosuvastatin. The IC(50) values for inhibition of E(2)17β-G uptake were similar between OATP1B1 and OATP1B1*15. In conclusion, these studies indicate that several oral antidiabetic drugs affect the OATP1B1-mediated uptake of rosuvastatin in vitro. The next step will be to translate these data to the clinical situation, as it remains to be established whether the studied oral antidiabetics indeed affect the clinical pharmacokinetic profile of rosuvastatin in patients. PMID:23248200

  11. A novel algorithm for analyzing drug-drug interactions from MEDLINE literature

    PubMed Central

    Lu, Yin; Shen, Dan; Pietsch, Maxwell; Nagar, Chetan; Fadli, Zayd; Huang, Hong; Tu, Yi-Cheng; Cheng, Feng

    2015-01-01

    Drug–drug interaction (DDI) is becoming a serious clinical safety issue as the use of multiple medications becomes more common. Searching the MEDLINE database for journal articles related to DDI produces over 330,000 results. It is impossible to read and summarize these references manually. As the volume of biomedical reference in the MEDLINE database continues to expand at a rapid pace, automatic identification of DDIs from literature is becoming increasingly important. In this article, we present a random-sampling-based statistical algorithm to identify possible DDIs and the underlying mechanism from the substances field of MEDLINE records. The substances terms are essentially carriers of compound (including protein) information in a MEDLINE record. Four case studies on warfarin, ibuprofen, furosemide and sertraline implied that our method was able to rank possible DDIs with high accuracy (90.0% for warfarin, 83.3% for ibuprofen, 70.0% for furosemide and 100% for sertraline in the top 10% of a list of compounds ranked by p-value). A social network analysis of substance terms was also performed to construct networks between proteins and drug pairs to elucidate how the two drugs could interact. PMID:26612138

  12. Potential for Drug-Drug Interactions between Antiretrovirals and HCV Direct Acting Antivirals in a Large Cohort of HIV/HCV Coinfected Patients

    PubMed Central

    Poizot-Martin, Isabelle; Naqvi, Alissa; Obry-Roguet, Véronique; Valantin, Marc-Antoine; Cuzin, Lise; Billaud, Eric; Cheret, Antoine; Rey, David; Jacomet, Christine; Duvivier, Claudine; Pugliese, Pascal; Pradat, Pierre; Cotte, Laurent

    2015-01-01

    Objectives Development of direct acting antivirals (DAA) offers new benefits for patients with chronic hepatitis C. The combination of these drugs with antiretroviral treatment (cART) is a real challenge in HIV/HCV coinfected patients. The aim of this study was to describe potential drug-drug interactions between DAAs and antiretroviral drugs in a cohort of HIV/HCV coinfected patients. Methods Cross-sectional study of all HIV/HCV coinfected patients attending at least one visit in 2012 in the multicenter French Dat’AIDS cohort. A simulation of drug-drug interactions between antiretroviral treatment and DAAs available in 2015 was performed. Results Of 16,634 HIV-infected patients, 2,511 had detectable anti-HCV antibodies, of whom 1,196 had a detectable HCV-RNA and were not receiving HCV treatment at the time of analysis. 97.1% of these patients were receiving cART and 81.2% had a plasma HIV RNA <50 copies/mL. cART included combinations of nucleoside reverse transcriptase inhibitors with a boosted protease inhibitor in 43.6%, a non-nucleoside reverse transcriptase inhibitor in 17.3%, an integrase inhibitor in 15.4% and various combinations or antiretroviral drugs in 23.7% of patients. A previous treatment against HCV had been administered in 64.4% of patients. Contraindicated associations/potential interactions were expected between cART and respectively sofosbuvir (0.2%/0%), sofosbuvir/ledipasvir (0.2%/67.6%), daclatasvir (0%/49.4%), ombitasvir/boosted paritaprevir (with or without dasabuvir) (34.4%/52.2%) and simeprevir (78.8%/0%). Conclusions Significant potential drug-drug interactions are expected between cART and the currently available DAAs in the majority of HIV/HCV coinfected patients. Sofosbuvir/ledipasvir and sofosbuvir/daclatasvir with or without ribavirin appeared the most suitable combinations in our population. A close collaboration between hepatologists and HIV/AIDS specialists appears necessary for the management of HCV treatment concomitantly to c

  13. Nonclinical Pharmacokinetics, Disposition, and Drug-Drug Interaction Potential of a Novel d-Amino Acid Peptide Agonist of the Calcium-Sensing Receptor AMG 416 (Etelcalcetide).

    PubMed

    Subramanian, Raju; Zhu, Xiaochun; Kerr, Savannah J; Esmay, Joel D; Louie, Steven W; Edson, Katheryne Z; Walter, Sarah; Fitzsimmons, Michael; Wagner, Mylo; Soto, Marcus; Pham, Roger; Wilson, Sarah F; Skiles, Gary L

    2016-08-01

    AMG 416 (etelcalcetide) is a novel synthetic peptide agonist of the calcium-sensing receptor composed of a linear chain of seven d-amino acids (referred to as the d-amino acid backbone) with a d-cysteine linked to an l-cysteine via a disulfide bond. AMG 416 contains four basic d-arginine residues and is a +4 charged peptide at physiologic pH with a mol. wt. of 1048.3 Da. The pharmacokinetics (PK), disposition, and potential of AMG 416 to cause drug-drug interaction were investigated in nonclinical studies with two single (14)C-labels placed either at a potentially metabolically labile acetyl position or on the d-alanine next to d-cysteine in the interior of the d-amino acid backbone. After i.v. dosing, the PK and disposition of AMG 416 were similar in male and female rats. Radioactivity rapidly distributed to most tissues in rats with intact kidneys, and renal elimination was the predominant clearance pathway. No strain-dependent differences were observed. In bilaterally nephrectomized rats, minimal radioactivity (1.2%) was excreted via nonrenal pathways. Biotransformation occurred primarily via disulfide exchange with endogenous thiol-containing molecules in whole blood rather than metabolism by enzymes, such as proteases or cytochrome P450s; the d-amino acid backbone remained unaltered. A substantial proportion of the plasma radioactivity was covalently conjugated to albumin. AMG 416 presents a low risk for P450 or transporter-mediated drug-drug interactions because it showed no interactions in vitro. These studies demonstrated a (14)C label on either the acetyl or the d-alanine in the d-amino acid backbone would be appropriate for clinical studies. PMID:26895981

  14. Drug-drug interactions with the use of psychotropic medications. Interview by Diane M. Sloan.

    PubMed

    Ereshefsky, Larry

    2009-08-01

    Drug interactions with psychotropics can result in poor tolerability or reduced efficacy, or both, which can negatively impact patient outcomes. Most drug interactions with psychotropics are pharmacokinetic and involve the CYP family of enzymes. Clinicians can improve outcomes for patients by considering the potential for DDIs when selecting a specific psychotropic, and when evaluating patient progress, compliance, and the incidence of AEs throughout the course of treatment. Resources for clinicians include internet databases, software programs, package inserts, and consultation with pharmacists. PMID:20085108

  15. Evaluation of Mutual Drug-Drug Interaction within Geneva Cocktail for Cytochrome P450 Phenotyping using Innovative Dried Blood Sampling Method.

    PubMed

    Bosilkovska, Marija; Samer, Caroline; Déglon, Julien; Thomas, Aurélien; Walder, Bernhard; Desmeules, Jules; Daali, Youssef

    2016-09-01

    Cytochrome P450 (CYP) activity can be assessed using a 'cocktail' phenotyping approach. Recently, we have developed a cocktail (Geneva cocktail) which combines the use of low-dose probes with a low-invasiveness dried blood spots (DBS) sampling technique and a single analytical method for the phenotyping of six major CYP isoforms. We have previously demonstrated that modulation of CYP activity after pre-treatment with CYP inhibitors/inducer could be reliably predicted using Geneva cocktail. To further validate this cocktail, in this study, we have verified whether probe drugs contained in the latter cause mutual drug-drug interactions. In a randomized, four-way, Latin-square crossover study, 30 healthy volunteers received low-dose caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam (a previously validated combination with no mutual drug-drug interactions); fexofenadine alone; bupropion alone; or all seven drugs simultaneously (Geneva cocktail). Pharmacokinetic profiles of the probe drugs and their metabolites were determined in DBS samples using both conventional micropipette sampling and new microfluidic device allowing for self-sampling. The 90% confidence intervals for the geometric mean ratios of AUC metabolite/AUC probe for CYP probes administered alone or within Geneva cocktail fell within the 0.8-1.25 bioequivalence range indicating the absence of pharmacokinetic interaction. The same result was observed for the chosen phenotyping indices, that is metabolic ratios at 2 hr (CYP1A2, CYP3A) or 3 hr (CYP2B6, CYP2C9, CYP2C19, CYP2D6) post-cocktail administration. DBS sampling could successfully be performed using a new microfluidic device. In conclusion, Geneva cocktail combined with an innovative DBS sampling device can be used routinely as a test for simultaneous CYP phenotyping. PMID:27009433

  16. Measuring Drug Metabolism Kinetics and Drug-Drug Interactions Using Self-Assembled Monolayers for Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry.

    PubMed

    Anderson, Lyndsey L; Berns, Eric J; Bugga, Pradeep; George, Alfred L; Mrksich, Milan

    2016-09-01

    The competition of two drugs for the same metabolizing enzyme is a common mechanism for drug-drug interactions that can lead to altered kinetics in drug metabolism and altered elimination rates in vivo. With the prevalence of multidrug therapy, there is great potential for serious drug-drug interactions and adverse drug reactions. In an effort to prevent adverse drug reactions, the FDA mandates the evaluation of the potential for metabolic inhibition by every new chemical entity. Conventional methods for assaying drug metabolism (e.g., those based on HPLC) have been established for measuring drug-drug interactions; however, they are low-throughput. Here we describe an approach to measure the catalytic activity of CYP2C9 using the high-throughput technique self-assembled monolayers for matrix-assisted laser desorption-ionization (SAMDI) mass spectrometry. We measured the kinetics of CYP450 metabolism of the substrate, screened a set of drugs for inhibition of CYP2C9 and determined the Ki values for inhibitors. The throughput of this platform may enable drug metabolism and drug-drug interactions to be interrogated at a scale that cannot be achieved with current methods. PMID:27467208

  17. Assessment of the mass balance recovery and metabolite profile of avibactam in humans and in vitro drug-drug interaction potential.

    PubMed

    Vishwanathan, Karthick; Mair, Stuart; Gupta, Anshul; Atherton, James; Clarkson-Jones, Jacqueline; Edeki, Timi; Das, Shampa

    2014-05-01

    Avibactam, a novel non-β-lactam β-lactamase inhibitor with activity against Ambler class A, class C, and some class D enzymes is being evaluated in combination with various β-lactam antibiotics to treat serious bacterial infections. The in vivo mass balance recovery and metabolite profile of [(14)C] avibactam (500 mg/1-h infusion) was assessed in six healthy male subjects, and a series of in vitro experiments evaluated the metabolism and drug-drug interaction potential of avibactam. In the mass balance study, measurement of plasma avibactam (using a validated liquid chromatography-tandem mass spectrometry method) and total radioactivity in plasma, whole blood, urine, and feces (using liquid scintillation counting) indicated that most of the avibactam was excreted unchanged in urine within 12 hours, with recovery complete (>97% of the administered dose) within 96 hours. Geometric mean avibactam renal clearance (158 ml/min) was greater than the product of unbound fraction of drug and glomerular filtration rate (109.5 ml/min), suggesting that active tubular secretion accounted for some renal elimination. There was no evidence of metabolism in plasma and urine, with unchanged avibactam the major component in both matrices. Avibactam demonstrated in vitro substrate potential for organic anion transporters 1 and 3 (OAT1 and OAT3) proteins expressed in human embryonic kidney 293 cells (Km > 1000 μM; >10-fold the Cmax of a therapeutic dose), which could account for the active tubular secretion observed in vivo. Avibactam uptake by OAT1 and OAT3 was inhibited by probenecid, a potent OAT1/OAT3 inhibitor. Avibactam did not interact with various other membrane transport proteins or cytochrome P450 enzymes in vitro, suggesting it has limited propensity for drug-drug interactions involving cytochrome P450 enzymes. PMID:24616266

  18. CLINICALLY SIGNIFICANT PSYCHOTROPIC DRUG-DRUG INTERACTIONS IN THE PRIMARY CARE SETTING

    PubMed Central

    English, Brett A.; Dortch, Marcus; Ereshefsky, Larry; Jhee, Stanford

    2014-01-01

    In recent years, the growing numbers of patients seeking care for a wide range of psychiatric illnesses in the primary care setting has resulted in an increase in the number of psychotropic medications prescribed. Along with the increased utilization of psychotropic medications, considerable variability is noted in the prescribing patterns of primary care providers and psychiatrists. Because psychiatric patients also suffer from a number of additional medical comorbidities, the increased utilization of psychotropic medications presents an elevated risk of clinically significant drug interactions in these patients. While life-threatening drug interactions are rare, clinically significant drug interactions impacting drug response or appearance of serious adverse drug reactions have been documented and can impact long-term outcomes. Additionally, the impact of genetic variability on the psychotropic drug’s pharmacodynamics and/or pharmacokinetics may further complicate drug therapy. Increased awareness of clinically relevant psychotropic drug interactions can aid clinicians to achieve optimal therapeutic outcomes in patients in the primary care setting. PMID:22707017

  19. Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2

    PubMed Central

    Kido, Yasuto; Matsson, Pär; Giacomini, Kathleen M.

    2011-01-01

    Drug-drug interactions (DDIs) are major causes of serious adverse drug reactions. Most DDIs have a pharmacokinetic basis in which one drug reduces the elimination of a second drug, leading to potentially toxic drug levels. As a major organ of drug elimination, the kidney represents an important site for DDIs. Here, we screened a prescription drug library against the renal organic cation transporter OCT2/SLC22A2, which mediates the first step in the renal secretion of many cationic drugs. Of the 910 compounds screened, 244 inhibited OCT2. Computational analyses revealed key properties of inhibitors versus non-inhibitors, which included overall molecular charge. Four of six potential clinical inhibitors were transporter-selective in follow-up screens against additional transporters: OCT1/SLC22A1, MATE1/SLC47A1 and MATE2-K/SLC47A2. Two compounds showed different kinetics of interaction with the common polymorphism OCT2-A270S, suggesting a role of genetics in modulating renal DDIs. PMID:21599003

  20. Text mining for pharmacovigilance: Using machine learning for drug name recognition and drug-drug interaction extraction and classification.

    PubMed

    Ben Abacha, Asma; Chowdhury, Md Faisal Mahbub; Karanasiou, Aikaterini; Mrabet, Yassine; Lavelli, Alberto; Zweigenbaum, Pierre

    2015-12-01

    Pharmacovigilance (PV) is defined by the World Health Organization as the science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. An essential aspect in PV is to acquire knowledge about Drug-Drug Interactions (DDIs). The shared tasks on DDI-Extraction organized in 2011 and 2013 have pointed out the importance of this issue and provided benchmarks for: Drug Name Recognition, DDI extraction and DDI classification. In this paper, we present our text mining systems for these tasks and evaluate their results on the DDI-Extraction benchmarks. Our systems rely on machine learning techniques using both feature-based and kernel-based methods. The obtained results for drug name recognition are encouraging. For DDI-Extraction, our hybrid system combining a feature-based method and a kernel-based method was ranked second in the DDI-Extraction-2011 challenge, and our two-step system for DDI detection and classification was ranked first in the DDI-Extraction-2013 task at SemEval. We discuss our methods and results and give pointers to future work. PMID:26432353

  1. Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone

    PubMed Central

    Wang, R.; Luo, W.-L.; Wastall, P.; Kandoussi, H.; DeMicco, M.; Bruce, R. D.; Hwang, C.; Bertz, R.; Bifano, M.

    2015-01-01

    Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (Cmax) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized Cmax for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. PMID:26124175

  2. Assessment of drug-drug interactions between daclatasvir and methadone or buprenorphine-naloxone.

    PubMed

    Garimella, T; Wang, R; Luo, W-L; Wastall, P; Kandoussi, H; DeMicco, M; Bruce, R D; Hwang, C; Bertz, R; Bifano, M

    2015-09-01

    Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (C max) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments. PMID:26124175

  3. Drug-drug interaction profile of components of a fixed combination of netupitant and palonosetron: Review of clinical data.

    PubMed

    Natale, James J; Spinelli, Tulla; Calcagnile, Selma; Lanzarotti, Corinna; Rossi, Giorgia; Cox, David; Kashef, Kimia

    2016-06-01

    Neurokinin-1 (NK1) receptor antagonists (RAs) are commonly coadministered with serotonin (5-HT3) RAs (e.g. palonosetron (PALO)) to prevent chemotherapy-induced nausea/vomiting. Netupitant/palonosetron (NEPA), an oral fixed combination of netupitant (NETU)-a new NK1 RA-and PALO, is currently under development. In vitro data suggest that NETU inhibits CYP3A4 and is a substrate for and weak inhibitor of P-glycoprotein (P-gp). This review evaluates potential drug-drug interactions between NETU or NEPA and CYP3A4 substrates/inducers/inhibitors or P-gp substrates in healthy subjects. Pharmacokinetic (PK) parameters were evaluated for each drug when NETU was coadministered with PALO (single doses) and when single doses of NETU or NEPA were coadministered with CYP3A4 substrates (erythromycin (ERY), midazolam (MID), dexamethasone (DEX), or oral contraceptives), inhibitors (ketoconazole (KETO)), or inducers (rifampicin (RIF)), or a P-gp substrate (digoxin (DIG)). Results showed no relevant PK interactions between NETU and PALO. Coadministration of NETU increased MID and ERY exposure and significantly increased DEX exposure in a dose-dependent manner; NETU exposure was unaffected. NEPA coadministration had no clinically significant effect on oral contraception, although levonorgestrel exposure increased. NETU exposure increased after coadministration of NEPA with KETO and decreased after coadministration with RIF; PALO exposure was unaffected. NETU coadministration did not influence DIG exposure. In conclusion, there were no clinically relevant interactions between NETU and PALO, or NEPA and oral contraceptives (based on levonorgestrel and ethinylestradiol exposure). Coadministration of NETU or NEPA with CYP3A4 inducers/inhibitors/substrates should be done with caution. Dose reduction is recommended for DEX. Dose adjustments are not needed for NETU coadministration with P-gp substrates. PMID:25998320

  4. Metformin and cimetidine: Physiologically based pharmacokinetic modelling to investigate transporter mediated drug-drug interactions.

    PubMed

    Burt, H J; Neuhoff, S; Almond, L; Gaohua, L; Harwood, M D; Jamei, M; Rostami-Hodjegan, A; Tucker, G T; Rowland-Yeo, K

    2016-06-10

    Metformin is used as a probe for OCT2 mediated transport when investigating possible DDIs with new chemical entities. The aim of the current study was to investigate the ability of physiologically-based pharmacokinetic (PBPK) models to simulate the effects of OCT and MATE inhibition by cimetidine on metformin kinetics. PBPK models were developed, incorporating mechanistic kidney and liver sub-models for metformin (OCT and MATE substrate) and a mechanistic kidney sub-model for cimetidine. The models were used to simulate inhibition of the MATE1, MATE2-K, OCT1 and OCT2 mediated transport of metformin by cimetidine. Assuming competitive inhibition and using cimetidine Ki values determined in vitro, the predicted metformin AUC ratio was 1.0 compared to an observed value of 1.46. The observed AUC ratio could only be recovered with this model when the cimetidine Ki for OCT2 was decreased 1000-fold or the Ki's for both OCT1 and OCT2 were decreased 500-fold. An alternative description of metformin renal transport by OCT1 and OCT2, incorporating electrochemical modulation of the rate of metformin uptake together with 8-18-fold decreases in cimetidine Ki's for OCTs and MATEs, allowed recovery of the extent of the observed effect of cimetidine on metformin AUC. While the final PBPK model has limitations, it demonstrates the benefit of allowing for the complexities of passive permeability combined with active cellular uptake modulated by an electrochemical gradient and active efflux. PMID:27019345

  5. Integrated in vitro analysis for the in vivo prediction of cytochrome P450-mediated drug-drug interactions.

    PubMed

    McGinnity, Dermot F; Waters, Nigel J; Tucker, James; Riley, Robert J

    2008-06-01

    Unbound IC(50) (IC(50,u)) values of 15 drugs were determined in eight recombinantly expressed human cytochromes P450 (P450s) and human hepatocytes, and the data were used to simulate clinical area under the plasma concentration-time curve changes (deltaAUC) on coadministration with prototypic CYP2D6 substrates. Significant differences in IC(50,u) values between enzyme sources were observed for quinidine (0.02 microM in recombinant CYP2D6 versus 0.5 microM in hepatocytes) and propafenone (0.02 versus 4.1 microM). The relative contribution of individual P450s toward the oxidative metabolism of clinical probes desipramine, imipramine, tolterodine, propranolol, and metoprolol was estimated via determinations of intrinsic clearance using recombinant P450s (rP450s). Simulated deltaAUC were compared with those observed in vivo via the ratios of unbound inhibitor concentration at the entrance to the liver to inhibition constants determined against rP450s ([I](in,u)/K(i)) and incorporating parallel substrate elimination pathways. For this dataset, there were 20% false negatives (observed deltaAUC >or= 2, predicted deltaAUC < 2), 77% correct predictions, and 3% false positives. Thus, the [I](in,u)/K(i) approach appears relatively successful at estimating the degree of clinical interactions and can be incorporated into drug discovery strategies. Using a Simcyp ADME (absorption, metabolism, distribution, elimination) simulator (Simcyp Ltd., Sheffield, UK), there were 3% false negatives, 94% correct simulations, and 3% false positives. False-negative predictions were rationalized as a result of mechanism-based inhibition, production of inhibitory metabolites, and/or hepatic uptake. Integrating inhibition and reaction phenotyping data from automated rP450 screens have shown applicability to predict the occurrence and degree of in vivo drug-drug interactions, and such data may identify the clinical consequences for candidate drugs as both "perpetrators" and "victims" of P450

  6. Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males.

    PubMed

    Wang, Liupeng; Wu, Chunyong; Shen, Lu; Liu, Haiyan; Chen, Ying; Liu, Fang; Wang, Youqun; Yang, Jin

    2016-08-01

    1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin-independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two-period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co-administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0-24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0-24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin Cmax (GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co-administered with metformin without dose adjustment of either drug. PMID:26608671

  7. Interaction of Ethambutol with human organic cation transporters of the SLC22 family indicates potential for drug-drug interactions during antituberculosis therapy.

    PubMed

    Pan, Xiaolei; Wang, Li; Gründemann, Dirk; Sweet, Douglas H

    2013-10-01

    According to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ∼9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2'-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 ± 10.9 and 253.8 ± 90.8 μM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50 = 4.1 ± 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting that in vivo pharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin). PMID:23917312

  8. Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy

    PubMed Central

    Pan, Xiaolei; Gründemann, Dirk

    2013-01-01

    According to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ∼9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2′-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 ± 10.9 and 253.8 ± 90.8 μM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50 = 4.1 ± 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting that in vivo pharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin). PMID:23917312

  9. Assessment of Disease-Related Therapeutic Protein Drug-Drug Interaction for Etrolizumab in Patients With Moderately to Severely Active Ulcerative Colitis.

    PubMed

    Wei, Xiaohui; Kenny, Jane R; Dickmann, Leslie; Maciuca, Romeo; Looney, Caroline; Tang, Meina T

    2016-06-01

    The efficacy and safety of etrolizumab, a humanized IgG1 mAb, were evaluated in patients with ulcerative colitis (UC) in a phase 2 study (EUCALYPTUS). The current study assessed the risk of therapeutic protein drug-drug interaction (TP-DDI) of etrolizumab on CYP3A activity in patients with UC. Literature review was performed to compare serum proinflammatory cytokine levels and pharmacokinetic (PK) parameters of CYP3A substrate drugs between patients with inflammatory bowel disease (IBD) and healthy subjects. Treatment effect of etrolizumab on CYP3A activity was evaluated by measuring colonic CYP3A4 mRNA expression and serum C-reactive protein (CRP) in EUCALYPTUS patients. Literature data suggested similar levels between IBD patients and healthy subjects for serum proinflammatory cytokines and PK parameters of CYP3A substrate drugs. Additionally, treatment with etrolizumab did not change colonic CYP3A4 mRNA expression or serum CRP levels in UC patients. In conclusion, our results indicate a low TP-DDI risk for etrolizumab in UC patients, particularly on medications metabolized by CYP3A. PMID:26412221

  10. Underlying mechanism of drug-drug interaction between pioglitazone and gemfibrozil: Gemfibrozil acyl-glucuronide is a mechanism-based inhibitor of CYP2C8.

    PubMed

    Takagi, Motoi; Sakamoto, Masaya; Itoh, Tomoo; Fujiwara, Ryoichi

    2015-08-01

    While co-administered gemfibrozil can increase the area under the concentration/time curve (AUC) of pioglitazone more than 3-fold, the underlying mechanism of the drug-drug interaction between gemfibrozil and pioglitazone has not been fully understood. In the present study, gemfibrozil preincubation time-dependently inhibited the metabolism of pioglitazone in the cytochrome P450 (CYP)- and UDP-glucuronosyltransferase (UGT)-activated human liver microsomes. We estimated the kinact and K'app values, which are the maximum inactivation rate constant and the apparent dissociation constant, of gemfibrozil to be 0.071 min(-1) and 57.3 μM, respectively. In this study, the kobs, in vivo value was defined as a parameter that indicates the potency of the mechanism-based inhibitory effect at the blood drug concentration in vivo. The kobs, in vivo values of potent mechanism-based inhibitors, clarithromycin and erythromycin, were estimated to be 0.0096 min(-1) and 0.0051 min(-1), respectively. The kobs, in vivo value of gemfibrozil was 0.0060 min(-1), which was comparable to those of clarithromycin and erythromycin, suggesting that gemfibrozil could be a mechanism-based inhibitor as potent as clarithromycin and erythromycin in vivo. PMID:26195223

  11. A Strategy for assessing potential drug-drug interactions of a concomitant agent against a drug absorbed via an intestinal transporter in humans.

    PubMed

    Mizuno-Yasuhira, Akiko; Nakai, Yasuhiro; Gunji, Emi; Uchida, Saeko; Takahashi, Teisuke; Kinoshita, Kohnosuke; Jingu, Shigeji; Sakai, Soichi; Samukawa, Yoshishige; Yamaguchi, Jun-Ichi

    2014-09-01

    A strategy for assessing potential drug-drug interactions (DDIs) based on a simulated intestinal concentration is described. The proposed prediction method was applied to the DDI assessment of luseogliflozin, a novel antidiabetic drug, against miglitol absorbed via the intestinal sodium-glucose cotransporter 1 (SGLT1). The method involves four steps: collection of physicochemical and pharmacokinetic parameters of luseogliflozin for use in a computer simulation; evaluation of the validity of these parameters by verifying the goodness of fit between simulated and observed plasma profiles; simulation of the intestinal luseogliflozin concentration-time profile using the Advanced Compartment Absorption and Transit (ACAT) model in a computer program and estimation of the time spent above a value 10-fold higher than the IC50 value (TAIC) for SGLT1; and evaluation of the DDI potential of luseogliflozin by considering the percentage of TAIC against the miglitol Tmax (time for Cmax) value (TAIC/Tmax). An initial attempt to prove the validity of this method was performed in rats. The resulting TAIC/Tmax in rats was 32%, suggesting a low DDI potential of luseogliflozin against miglitol absorption. The validity was then confirmed using an in vivo interaction study in rats. In humans, luseogliflozin was expected to have no DDI potential against miglitol absorption, since the TAIC/Tmax in humans was lower than that in rats. This prediction was proven, as expected, in a clinical interaction study. In conclusion, the present strategy based on a simulation of the intestinal concentration-time profile using dynamic modeling would be useful for assessing the clinical DDI potential of a concomitant agent against drugs absorbed via an intestinal transporter. PMID:25005603

  12. Statin-Induced Cardioprotection Against Ischemia-Reperfusion Injury: Potential Drug-Drug Interactions. Lesson to be Learnt by Translating Results from Animal Models to the Clinical Settings.

    PubMed

    Birnbaum, Gilad D; Birnbaum, Itamar; Ye, Yumei; Birnbaum, Yochai

    2015-10-01

    Numerous interventions have been shown to limit myocardial infarct size in animal models; however, most of these interventions have failed to have a significant effect in clinical trials. One potential explanation for the lack of efficacy in the clinical setting is that in bench models, a single intervention is studied without the background of other interventions or modalities. This is in contrast to the clinical setting in which new medications are added to the "standard of care" treatment that by now includes a growing number of medications. Drug-drug interaction may lead to alteration, dampening, augmenting or masking the effects of the intended intervention. We use the well described model of statin-induced myocardial protection to demonstrate potential interactions with agents which are commonly concomitantly used in patients with stable coronary artery disease and/or acute coronary syndromes. These interactions could potentially explain the reduced efficacy of statins in the clinical trials compared to the animal models. In particular, caffeine and aspirin could attenuate the infarct size limiting effects of statins; morphine could delay the onset of protection or mask the protective effect in patients with ST elevation myocardial infarction, whereas other anti-platelet agents (dipyridamole, cilostazol and ticagrelor) may augment (or mask) the effect due to their favorable effects on adenosine cell reuptake and intracellular cAMP levels. We recommend that after characterizing the effects of new modalities in single intervention bench research, studies should be repeated in the background of standard-of-care medications to assure that the magnitude of the effect is not altered before proceeding with clinical trials. PMID:26303765

  13. Incidence rate and pattern of clinically relevant potential drug-drug interactions in a large outpatient population of a developing country

    PubMed Central

    Nabovati, Ehsan; Vakili-Arki, Hasan; Taherzadeh, Zhila; Saberi, Mohammad Reza; Abu-Hanna, Ameen; Eslami, Saeid

    2016-01-01

    The objective of this study was to determine incidence rate, type, and pattern of clinically relevant potential drug-drug interactions (pDDIs) in a large outpatient population of a developing country. A retrospective, descriptive cross-sectional study was conducted on outpatients’ prescriptions in Khorasan Razavi province, Iran, over 12 months. A list of 25 clinically relevant DDIs, which are likely to occur in the outpatient setting, was used as the reference. Most frequent clinically relevant pDDIs, most common drugs contributing to the pDDIs, and the pattern of pDDIs for each medical specialty were determined. Descriptive statistics were used to report the results. In total, out of 8,169,142 prescriptions, 6,096 clinically relevant pDDIs were identified. The most common identified pDDIs were theophyllines-quinolones, warfarin-nonsteroidal anti-inflammatory drugs, benzodiazepines-azole antifungal agents, and anticoagulants-thyroid hormones. The most common drugs contributing to the identified pDDIs were ciprofloxacin, theophylline, warfarin, aminophylline, alprazolam, levothyroxine, and selegiline. While the incidence rate of clinically relevant pDDIs in prescriptions of general practitioners, internists, and cardiologists was the highest, the average pDDI incidence per 10,000 prescriptions of pulmonologists, infectious disease specialists, and cardiologists was highest. Although a small proportion of the analyzed prescriptions contained drug pairs with potential for clinically relevant DDIs, a significant number of outpatients have been exposed to the adverse effects associated with these interactions. It is recommended that in addition to training physicians and pharmacists, other effective interventions such as computerized alerting systems and electronic prescribing systems be designed and implemented. PMID:27499793

  14. Incidence rate and pattern of clinically relevant potential drug-drug interactions in a large outpatient population of a developing country.

    PubMed

    Nabovati, Ehsan; Vakili-Arki, Hasan; Taherzadeh, Zhila; Saberi, Mohammad Reza; Abu-Hanna, Ameen; Eslami, Saeid

    2016-01-01

    The objective of this study was to determine incidence rate, type, and pattern of clinically relevant potential drug-drug interactions (pDDIs) in a large outpatient population of a developing country. A retrospective, descriptive cross-sectional study was conducted on outpatients' prescriptions in Khorasan Razavi province, Iran, over 12 months. A list of 25 clinically relevant DDIs, which are likely to occur in the outpatient setting, was used as the reference. Most frequent clinically relevant pDDIs, most common drugs contributing to the pDDIs, and the pattern of pDDIs for each medical specialty were determined. Descriptive statistics were used to report the results. In total, out of 8,169,142 prescriptions, 6,096 clinically relevant pDDIs were identified. The most common identified pDDIs were theophyllines-quinolones, warfarin-nonsteroidal anti-inflammatory drugs, benzodiazepines-azole antifungal agents, and anticoagulants-thyroid hormones. The most common drugs contributing to the identified pDDIs were ciprofloxacin, theophylline, warfarin, aminophylline, alprazolam, levothyroxine, and selegiline. While the incidence rate of clinically relevant pDDIs in prescriptions of general practitioners, internists, and cardiologists was the highest, the average pDDI incidence per 10,000 prescriptions of pulmonologists, infectious disease specialists, and cardiologists was highest. Although a small proportion of the analyzed prescriptions contained drug pairs with potential for clinically relevant DDIs, a significant number of outpatients have been exposed to the adverse effects associated with these interactions. It is recommended that in addition to training physicians and pharmacists, other effective interventions such as computerized alerting systems and electronic prescribing systems be designed and implemented. PMID:27499793

  15. Suspicion of drug-drug interaction between high-dose methotrexate and proton pump inhibitors: a case report - should the practice be changed?

    PubMed

    Ranchon, F; Vantard, N; Gouraud, A; Schwiertz, V; Franchon, E; Pham, B N; Vial, T; You, B; Bouafia, F; Salles, G; Rioufol, C

    2011-01-01

    We report a case of a potential drug-drug interaction in a woman treated by a first injection of high-dose methotrexate for a T-lymphoblastic lymphoma. Valaciclovir, fluoxetine and pantoprazole were given concomitantly. A methotrexate overdosage was shown at 36 h after infusion associated with a severe renal failure. Alkaline hyperhydration, folinic acid and carboxypeptidase G2 were given. Prescription analyses by pharmacists and literature research have permitted us to suggest that a drug-drug interaction between methotrexate and proton pump inhibitors (PPI) was responsible for this renal failure. Several mechanisms of interaction were suggested and might be related to the inhibition of renal methotrexate transporters by PPI, an increase in the methotrexate efflux to the blood by an upregulation of multidrug resistance protein 3 by PPI or genetic polymorphisms. This case shows that pharmacists can help physicians to optimize patient treatment: they consensually decided on the systematic discontinuation of PPI or a switch to ranitidine when patients were treated by high-dose methotrexate. PMID:21597286

  16. Pharmacokinetic drug-drug interaction assessment of LCZ696 (an angiotensin receptor neprilysin inhibitor) with omeprazole, metformin or levonorgestrel-ethinyl estradiol in healthy subjects.

    PubMed

    Gan, Lu; Jiang, Xuemin; Mendonza, Anisha; Swan, Therese; Reynolds, Christine; Nguyen, Joanne; Pal, Parasar; Neelakantham, Srikanth; Dahlke, Marion; Langenickel, Thomas; Rajman, Iris; Akahori, Mizuki; Zhou, Wei; Rebello, Sam; Sunkara, Gangadhar

    2016-01-01

    LCZ696 is a novel angiotensin receptor neprilysin inhibitor in development for the treatment of cardiovascular diseases. Here, we assessed the potential for pharmacokinetic drug-drug interaction of LCZ696 (400 mg, single dose or once daily [q.d.]) when co-administered with omeprazole 40 mg q.d. (n = 28) or metformin 1000 mg q.d. (n = 27) or levonorgestrel-ethinyl estradiol 150/30 μg single dose (n = 24) in three separate open-label, single-sequence studies in healthy subjects. Pharmacokinetic parameters of LCZ696 analytes (sacubitril, LBQ657, and valsartan), metformin, and levonorgestrel-ethinyl estradiol were assessed. Omeprazole did not alter the AUCinf of sacubitril and pharmacokinetics of LBQ657; however, 7% decrease in the Cmax of sacubitril, and 11% and 13% decreases in AUCinf and Cmax of valsartan were observed. Co-administration of LCZ696 with metformin had no significant effect on the pharmacokinetics of LBQ657 and valsartan; however, AUCtau,ss and Cmax,ss of metformin were decreased by 23%. Co-administration of LCZ696 with levonorgestrel-ethinyl estradiol had no effect on the pharmacokinetics of ethinyl estradiol and LBQ657 or AUCinf of levonorgestrel. The Cmax of levonorgestrel decreased by 15%, and AUCtau,ss and Cmax,ss of valsartan decreased by 14% and 16%, respectively. Co-administration of LCZ696 with omeprazole, metformin, or levonorgestrel-ethinyl estradiol was not associated with any clinically relevant pharmacokinetic drug interactions. PMID:27119576

  17. VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions.

    PubMed

    Zetterberg, Craig; Maltais, Francois; Laitinen, Leena; Liao, Shengkai; Tsao, Hong; Chakilam, Ananthsrinivas; Hariparsad, Niresh

    2016-08-01

    (R)-2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide (VX-509, decernotinib) is an oral Janus kinase 3 inhibitor that has been studied in patients with rheumatoid arthritis. Patients with rheumatoid arthritis often receive multiple medications, such as statins and steroids, to manage the signs and symptoms of comorbidities, which increases the chances of drug-drug interactions (DDIs). Mechanism-based inhibition is a subset of time-dependent inhibition (TDI) and occurs when a molecule forms a reactive metabolite which irreversibly binds and inactivates drug-metabolizing enzymes, potentially increasing the systemic load to toxic concentrations. Traditionally, perpetrating compounds are screened using human liver microsomes (HLMs); however, this system may be inadequate when the precipitant is activated by a non-cytochrome P450 (P450)-mediated pathway. Even though studies assessing competitive inhibition and TDI using HLM suggested a low risk for CYP3A4-mediated DDI in the clinic, VX-509 increased the area under the curve of midazolam, atorvastatin, and methyl-prednisolone by approximately 12.0-, 2.7-, and 4.3-fold, respectively. Metabolite identification studies using human liver cytosol indicated that VX-509 is converted to an oxidative metabolite, which is the perpetrator of the DDIs observed in the clinic. As opposed to HLM, hepatocytes contain the full complement of drug-metabolizing enzymes and transporters and can be used to assess TDI arising from non-P450-mediated metabolic pathways. In the current study, we highlight the role of aldehyde oxidase in the formation of the hydroxyl-metabolite of VX-509, which is involved in clinically significant TDI-based DDIs and represents an additional example in which a system-dependent prediction of TDI would be evident. PMID:27298338

  18. How the Probability and Potential Clinical Significance of Pharmacokinetically Mediated Drug-Drug Interactions Are Assessed in Drug Development: Desvenlafaxine as an Example

    PubMed Central

    Nichols, Alice I.; Preskorn, Sheldon H.

    2015-01-01

    Objective: The avoidance of adverse drug-drug interactions (DDIs) is a high priority in terms of both the US Food and Drug Administration (FDA) and the individual prescriber. With this perspective in mind, this article illustrates the process for assessing the risk of a drug (example here being desvenlafaxine) causing or being the victim of DDIs, in accordance with FDA guidance. Data Sources/Study Selection: DDI studies for the serotonin-norepinephrine reuptake inhibitor desvenlafaxine conducted by the sponsor and published since 2009 are used as examples of the systematic way that the FDA requires drug developers to assess whether their new drug is either capable of causing clinically meaningful DDIs or being the victim of such DDIs. In total, 8 open-label studies tested the effects of steady-state treatment with desvenlafaxine (50–400 mg/d) on the pharmacokinetics of cytochrome (CYP) 2D6 and/or CYP 3A4 substrate drugs, or the effect of CYP 3A4 inhibition on desvenlafaxine pharmacokinetics. The potential for DDIs mediated by the P-glycoprotein (P-gp) transporter was assessed in in vitro studies using Caco-2 monolayers. Data Extraction: Changes in area under the plasma concentration-time curve (AUC; CYP studies) and efflux (P-gp studies) were reviewed for potential DDIs in accordance with FDA criteria. Results: Desvenlafaxine coadministration had minimal effect on CYP 2D6 and/or 3A4 substrates per FDA criteria. Changes in AUC indicated either no interaction (90% confidence intervals for the ratio of AUC geometric least-squares means [GM] within 80%–125%) or weak inhibition (AUC GM ratio 125% to < 200%). Coadministration with ketoconazole resulted in a weak interaction with desvenlafaxine (AUC GM ratio of 143%). Desvenlafaxine was not a substrate (efflux ratio < 2) or inhibitor (50% inhibitory drug concentration values > 250 μM) of P-gp. Conclusions: A 2-step process based on FDA guidance can be used first to determine whether a pharmacokinetically mediated

  19. Assessment of intestinal availability (FG) of substrate drugs of cytochrome p450s by analyzing changes in pharmacokinetic properties caused by drug-drug interactions.

    PubMed

    Hisaka, Akihiro; Nakamura, Mikiko; Tsukihashi, Ayako; Koh, Saori; Suzuki, Hiroshi

    2014-10-01

    In this study, we developed the drug-drug interaction (DDI) method as a new assessment technique of intestinal availability (F(G), the fraction of drug transferred from the intestinal enterocytes into the liver, escaping from intestinal metabolism) based on the clearance theory. This method evaluates F(G) from changes caused by DDIs in the area under the blood concentration-time curve and in the elimination half-life of victim drugs. Application of the DDI method to data from the literature revealed that the mean and S.D. of F(G) values for 20 substrate drugs of CYP3A was 0.56 ± 0.29, whereas that for 8 substrate drugs of CYP2C9, CYP2C19, and CYP2D6 was 0.86 ± 0.11. These results were consistent with the fact that intestinal metabolism is mediated predominantly by CYP3A. The DDI method showed reasonable correlations with the conventional i.v./p.o. method and the grape fruit juice (GFJ) method (coefficients of determination of 0.41 and 0.81, respectively). The i.v./p.o. method was more susceptible to fluctuations in the hepatic blood flow rate compared with the DDI and GFJ methods. The DDI method evaluates F(G) separating from the absorption ratio (F(A)) although it requires approximation of F(A). Since preciseness of approximation of F(A) does not greatly affect the evaluation of F(G) by the DDI method, we proposed a reasonable approximation method of F(A) for the evaluation of F(G) in the DDI method. The DDI method would be applicable to a broad range of situations in which various DDI data are utilizable. PMID:25061161

  20. Investigation of the impact of substrate selection on in vitro organic anion transporting polypeptide 1B1 inhibition profiles for the prediction of drug-drug interactions.

    PubMed

    Izumi, Saki; Nozaki, Yoshitane; Maeda, Kazuya; Komori, Takafumi; Takenaka, Osamu; Kusuhara, Hiroyuki; Sugiyama, Yuichi

    2015-02-01

    The risk assessment of organic anion transporting polypeptide (OATP) 1B1-mediated drug-drug interactions (DDIs) is an indispensable part of drug development. We previously reported that in vitro inhibitory potencies of several inhibitors on OATP1B1 depend on the substrates when prototypical substrates, estradiol-17β-glucuronide (E₂G), estrone-3-sulfate, and sulfobromophthalein were used as test substrates. The purpose of this study was to comprehensively investigate this substrate-dependent inhibition of OATP1B1 using clinically relevant OATP1B1 inhibitors and substrate drugs. Effects of cyclosporine A (CsA), rifampin, and gemfibrozil on OATP1B1-mediated uptake of 12 substrate drugs were examined in OATP1B1-expressing human embryonic kidney 293 cells. The Ki values (μM) for CsA varied from 0.0771 to 0.486 (6.3-fold), for rifampin from 0.358 to 1.23 (3.4-fold), and for gemfibrozil from 9.65 to 252 (26-fold). Except for the inhibition of torasemide uptake by CsA and that of nateglinide uptake by gemfibrozil, the Ki values were within 2.8-fold of those obtained using E₂G as a substrate. Preincubation potentiated the inhibitory effect of CsA on OATP1B1 with similar magnitude regardless of the substrates. R values calculated based on a static model showed some variation depending on the Ki values determined with various substrates, and such variability could have an impact on the DDI predictions particularly for a weak-to-moderate inhibitor (gemfibrozil). OATP1B1 substrate drugs except for torasemide and nateglinide, or E₂G as a surrogate, is recommended as an in vitro probe in the inhibition experiments, which will help mitigate the risk of false-negative DDI predictions potentially caused by substrate-dependent Ki variation. PMID:25414411

  1. Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects.

    PubMed

    Kasserra, Claudia; Assaf, Mahmoud; Hoffmann, Matthew; Li, Yan; Liu, Liangang; Wang, Xiaomin; Kumar, Gondi; Palmisano, Maria

    2015-02-01

    Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors. PMID:25159194

  2. Importance of multi-P450 inhibition in drug-drug interactions: evaluation of incidence, inhibition magnitude and prediction from in vitro data

    PubMed Central

    Isoherranen, Nina; Lutz, Justin D; Chung, Sophie P; Hachad, Houda; Levy, Rene H; Ragueneau-Majlessi, Isabelle

    2012-01-01

    Drugs that are mainly cleared by a single enzyme are considered more sensitive to drug-drug interactions (DDIs) than drugs cleared by multiple pathways. However, whether this is true when a drug cleared by multiple pathways is co-administered with an inhibitor of multiple P450 enzymes (multi-P450 inhibition) is not known. Mathematically, simultaneous equipotent inhibition of two elimination pathways that each contributes half of the drug clearance is equal to equipotent inhibition of a single pathway that clears the drug. However, simultaneous strong or moderate inhibition of two pathways by a single inhibitor is perceived as an unlikely scenario. The aim of this study was (i) to identify P450 inhibitors currently in clinical use that can inhibit more than one clearance pathway of an object drug in vivo, and (ii) to evaluate the magnitude and predictability of DDIs caused by these multi-P450 inhibitors. Multi-P450 inhibitors were identified using the Metabolism and Transport Drug Interaction Database™. A total of 38 multi-P450 inhibitors, defined as inhibitors that increased the AUC or decreased the clearance of probes of two or more P450’s, were identified. Seventeen (45 %) multi-P450 inhibitors were strong inhibitors of at least one P450 and an additional 12 (32 %) were moderate inhibitors of one or more P450s. Only one inhibitor (fluvoxamine) was a strong inhibitor of more than one enzyme. Fifteen of the multi-P450 inhibitors also inhibit drug transporters in vivo, but such data are lacking on many of the inhibitors. Inhibition of multiple P450 enzymes by a single inhibitor resulted in significant (>2-fold) clinical DDIs with drugs that are cleared by multiple pathways such as imipramine and diazepam while strong P450 inhibitors resulted in only weak DDIs with these object drugs. The magnitude of the DDIs between multi-P450 inhibitors and diazepam, imipramine and omeprazole could be predicted using in vitro data with similar accuracy as probe substrate

  3. Prevalence of drug-drug interactions upon addition of simeprevir- or sofosbuvir-containing treatment to medication profiles of patients with HIV and hepatitis C coinfection.

    PubMed

    Patel, Nimish; Nasiri, Mona; Koroglu, Arden; Amin, Ronish; McGuey, Liam; McNutt, Louise-Anne; Roman, Martha; Miller, Christopher

    2015-02-01

    The objectives were to (1) compare the frequency of contraindicated drug-drug interactions (XDDI) when simeprevir (SIM)- and sofosbuvir (SOF)-containing regimens are theoretically added to a patient's medication profile; (2) identify which hepatitis C (HCV) regimen is associated with the lowest frequency of XDDIs within different types of antiretroviral treatment (ART) regimens; and (3) determine the risk factors for XDDIs with each regimen. A cross-sectional study was performed among adult HIV/HCV-coinfected patients. Demographics, comorbidities, and medication lists were collected from medical records. Medication lists were entered into Lexi-Interact drug interaction software and XDDI before/after the addition of SIM- and SOF-containing therapy was documented. Classification and regression tree (CART) analyses identified breakpoints in continuous variables. Before the addition of any HCV therapy, XDDIs were present in 20% of the 335 included patients. After the addition of SIM-containing therapy, the frequency of XDDIs significantly increased to 88.4% (p<0.001). After adding SOF-containing therapy, the prevalence of XDDIs increased to 24.5% (p<0.001). The prevalence of XDDIs was significantly lower for SOF-containing HCV therapy within various types of ART regimens. Use of ≥7 non-HIV medications (CART breakpoint) was the only variable to predict XDDIs before the addition of any HCV therapy. Similarly, this was the only variable to predict XDDIs after the addition of SOF-containing therapy (PR: 4.80; 95% CI: 2.57-8.96, p<0.001). Variables independently associated with XDDIs after the addition of SIM-containing therapy were NNRTI regimen (prevalence ratio, PR: 1.62; 95% confidence interval, CI: 1.38-1.91, p<0.001), PI regimen (PR: 1.64; 95% CI: 1.40-1.93, p<0.001), and ≥7 non-HIV medications (PR: 1.06; 95% CI: 1.00-1.14, p=0.09). The addition of SOF-containing therapy was associated with a lower prevalence of XDDI than SIM-containing therapy. PMID:25432275

  4. Coproporphyrins in Plasma and Urine Can Be Appropriate Clinical Biomarkers to Recapitulate Drug-Drug Interactions Mediated by Organic Anion Transporting Polypeptide Inhibition.

    PubMed

    Lai, Yurong; Mandlekar, Sandhya; Shen, Hong; Holenarsipur, Vinay K; Langish, Robert; Rajanna, Prabhakar; Murugesan, Senthilkumar; Gaud, Nilesh; Selvam, Sabariya; Date, Onkar; Cheng, Yaofeng; Shipkova, Petia; Dai, Jun; Humphreys, William G; Marathe, Punit

    2016-09-01

    In the present study, an open-label, three-treatment, three-period clinical study of rosuvastatin (RSV) and rifampicin (RIF) when administered alone and in combination was conducted in 12 male healthy subjects to determine if coproporphyrin I (CP-I) and coproporphyrin III (CP-III) could serve as clinical biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) and 1B3 that belong to the solute carrier organic anion gene subfamily. Genotyping of the human OATP1B1 gene was performed in all 12 subjects and confirmed absence of OATP1B1*5 and OATP1B1*15 mutations. Average plasma concentrations of CP-I and CP-III prior to drug administration were 0.91 ± 0.21 and 0.15 ± 0.04 nM, respectively, with minimum fluctuation over the three periods. CP-I was passively eliminated, whereas CP-III was actively secreted from urine. Administration of RSV caused no significant changes in the plasma and urinary profiles of CP-I and CP-III. RIF markedly increased the maximum plasma concentration (Cmax) of CP-I and CP-III by 5.7- and 5.4-fold (RIF) or 5.7- and 6.5-fold (RIF+RSV), respectively, as compared with the predose values. The area under the plasma concentration curves from time 0 to 24 h (AUC0-24h) of CP-I and CP-III with RIF and RSV increased by 4.0- and 3.3-fold, respectively, when compared with RSV alone. In agreement with this finding, Cmax and AUC0-24h of RSV increased by 13.2- and 5.0-fold, respectively, when RIF was coadministered. Collectively, we conclude that CP-I and CP-III in plasma and urine can be appropriate endogenous biomarkers specifically and reliably reflecting OATP inhibition, and thus the measurement of these molecules can serve as a useful tool to assess OATP drug-drug interaction liabilities in early clinical studies. PMID:27317801

  5. Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation.

    PubMed

    Lu, Chuang; Suri, Ajit; Shyu, Wen Chyi; Prakash, Shimoga

    2014-12-01

    Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50  > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively. PMID:25264242

  6. An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome.

    PubMed

    Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Mathy, Francois-Xavier; Braun, Marina

    2015-04-01

    This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D₃/D₂/D₁ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile

  7. P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate.

    PubMed

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

    2016-09-01

    The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1 and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity. PMID:27377006

  8. In Vitro Metabolism and Drug-Drug Interaction Potential of UTL-5g, a Novel Chemo- and Radioprotective Agent

    PubMed Central

    Wu, Jianmei; Shaw, Jiajiu; Dubaisi, Sarah; Valeriote, Frederick

    2014-01-01

    N-(2,4-dichlorophenyl)-5-methyl-1,2-oxazole-3-carboxamide (UTL-5g), a potential chemo- and radioprotective agent, acts as a prodrug requiring bioactivation to the active metabolite 5-methylisoxazole-3-carboxylic acid (ISOX). UTL-5g hydrolysis to ISOX and 2,4-dichloroaniline (DCA) has been identified in porcine and rabbit liver esterases. The purpose of this study was to provide insights on the metabolism and drug interaction potential of UTL-5g in humans. The kinetics of UTL-5g hydrolysis was determined in human liver microsomes (HLM) and recombinant human carboxylesterases (hCE1b and hCE2). The potential of UTL-5g and its metabolites for competitive inhibition and time-dependent inhibition of microsomal cytochrome P450 (P450) was examined in HLM. UTL-5g hydrolysis to ISOX and DCA in HLM were NADPH-independent, with a maximum rate of reaction (Vmax) of 11.1 nmol/min per mg and substrate affinity (Km) of 41.6 µM. Both hCE1b and hCE2 effectively catalyzed UTL-5g hydrolysis, but hCE2 exhibited ∼30-fold higher catalytic efficiency (Vmax/Km) than hCE1b. UTL-5g and DCA competitively inhibited microsomal CYP1A2, CYP2B6, and CYP2C19 (IC50 values <50 µM), and exhibited time-dependent inhibition of microsomal CYP1A2 with the inactivation efficiency (kinact/KI) of 0.68 and 0.51 minute−1·mM−1, respectively. ISOX did not inhibit or inactivate any tested microsomal P450. In conclusion, hCE1b and hCE2 play a key role in the bioactivation of UTL-5g. Factors influencing carboxylesterase activities may have a significant impact on the pharmacological and therapeutic effects of UTL-5g. UTL-5g has the potential to inhibit P450-mediated metabolism through competitive inhibition or time-dependent inhibition. Caution is particularly needed for potential drug interactions involving competitive inhibition or time-dependent inhibition of CYP1A2 in the future clinical development of UTL-5g. PMID:25249693

  9. Metabolic Drug-Drug Interaction Potential of Macrolactin A and 7-O-Succinyl Macrolactin A Assessed by Evaluating Cytochrome P450 Inhibition and Induction and UDP-Glucuronosyltransferase Inhibition In Vitro

    PubMed Central

    Bae, Soo Hyeon; Kwon, Min Jo; Park, Jung Bae; Kim, Doyun; Kim, Dong-Hee; Kang, Jae-Seon; Kim, Chun-Gyu; Oh, Euichaul

    2014-01-01

    Macrolactin A (MA) and 7-O-succinyl macrolactin A (SMA), polyene macrolides containing a 24-membered lactone ring, show antibiotic effects superior to those of teicoplanin against vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. MA and SMA are currently being evaluated as antitumor agents in preclinical studies in Korea. We evaluated the potential of MA and SMA for the inhibition or induction of human liver cytochrome P450 (CYP) enzymes and UDP-glucuronosyltransferases (UGTs) in vitro to assess their safety as new molecular entities. We demonstrated that MA and SMA are potent competitive inhibitors of CYP2C9, with Ki values of 4.06 μM and 10.6 μM, respectively. MA and SMA also weakly inhibited UGT1A1 activity, with Ki values of 40.1 μM and 65.3 μM, respectively. However, these macrolactins showed no time-dependent inactivation of the nine CYPs studied. In addition, MA and SMA did not induce CYP1A2, CYP2B6, or CYP3A4/5. On the basis of an in vitro-in vivo extrapolation, our data strongly suggested that MA and SMA are unlikely to cause clinically significant drug-drug interactions mediated via inhibition or induction of most of the CYPs involved in drug metabolism in vivo, except for the inhibition of CYP2C9 by MA. Similarly, MA and SMA are unlikely to inhibit the activity of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 enzymes in vivo. Although further investigations will be required to clarify the in vivo interactions of MA with CYP2C9-targeted drugs, our findings offer a clearer understanding and prediction of drug-drug interactions for the safe use of MA and SMA in clinical practice. PMID:24890600

  10. Drug-drug interaction between oxycodone and adjuvant analgesics in blood-brain barrier transport and antinociceptive effect.

    PubMed

    Nakazawa, Yusuke; Okura, Takashi; Shimomura, Keita; Terasaki, Tetsuya; Deguchi, Yoshiharu

    2010-01-01

    To examine possible blood-brain barrier (BBB) transport interactions between oxycodone and adjuvant analgesics, we firstly screened various candidates in vitro using [(3)H]pyrilamine, a substrate of the oxycodone transporter, as a probe drug. The uptake of [(3)H]pyrilamine by conditionally immortalized rat brain capillary endothelial cells (TR-BBB13) was inhibited by antidepressants (amitriptyline, imipramine, clomipramine, amoxapine, and fluvoxamine), antiarrhythmics (mexiletine, lidocaine, and flecainide), and ketamine. On the other hand, antiepileptics (carbamazepine, phenytoin, and clonazepam) and corticosteroids (dexamethasone and prednisolone) did not inhibit [(3)H]pyrilamine uptake, with the exception of sodium valproate. The uptake of oxycodone was significantly inhibited in a concentration-dependent manner by amitriptyline, fluvoxamine and mexiletine with K(i) values of 13, 65, and 44 microM, respectively. These K(i) values are 5-300 times greater than the human therapeutic plasma concentrations. Finally, we evaluated in vivo interaction between oxycodone and amitriptyline in mice. Antinociceptive effects of oxycodone were increased by coadministration of amitriptyline. The oxycodone concentrations in plasma and brain were not changed by coadministration of amitriptyline. Overall, the results suggest that several adjuvant analgesics may interact with the BBB transport of oxycodone at relatively high concentrations. However, it is unlikely that there would be any significant interaction at therapeutically or pharmacologically relevant concentrations. PMID:19499573

  11. Downregulation of Organic Anion Transporting Polypeptide (OATP) 1B1 Transport Function by Lysosomotropic Drug Chloroquine: Implication in OATP-Mediated Drug-Drug Interactions.

    PubMed

    Alam, Khondoker; Pahwa, Sonia; Wang, Xueying; Zhang, Pengyue; Ding, Kai; Abuznait, Alaa H; Li, Lang; Yue, Wei

    2016-03-01

    and Drug Administration Adverse Event Reporting System indicated that CQ plus pitavastatin, rosuvastatin, and pravastatin, which are minimally metabolized by the cytochrome P450 enzymes, led to higher myopathy risk than these statins alone. In summary, the present studies report novel findings that lysosome is involved in degradation of OATP1B1 protein and that pre-incubation with lysosomotropic drug CQ downregulates OATP1B1 transport activity. Our in vitro data in combination with pharmacoepidemiologic studies support that CQ has potential to cause OATP-mediated drug-drug interactions. PMID:26750564

  12. Drug-Drug Interaction of Omeprazole With the HCV Direct-Acting Antiviral Agents Paritaprevir/Ritonavir and Ombitasvir With and Without Dasabuvir.

    PubMed

    Polepally, Akshanth R; Dutta, Sandeep; Hu, Beibei; Podsadecki, Thomas J; Awni, Walid M; Menon, Rajeev M

    2016-07-01

    Paritaprevir (administered with low-dose ritonavir), ombitasvir, and dasabuvir are direct-acting antiviral agents administered as combination regimens for the treatment of chronic hepatitis C virus infection. Drug-drug interactions between 2D (ombitasvir/paritaprevir/ritonavir) or 3D (ombitasvir/paritaprevir/ritonavir and dasabuvir) regimens and omeprazole, a CYP2C19 substrate and acid-reducing agent, were evaluated in 24 healthy volunteers. Subjects received omeprazole (40 mg once daily) on day 1 and days 20-24 and the 2D or 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily) on days 6-24. Compared with omeprazole alone, coadministration with the 2D or 3D regimen decreased omeprazole geometric mean Cmax and AUCt values by 40% to 50%. Ombitasvir, dasabuvir, and ritonavir mean exposures showed <10% change, and paritaprevir mean exposures showed <20% change when the 2D or 3D regimen was administered with omeprazole compared with administration without omeprazole. Although no a priori dose adjustment is needed, a higher omeprazole dose should be considered if clinically indicated when coadministered with the 2D or 3D regimen. No dose adjustment is required for the 2D or 3D regimen when administered with omeprazole, other acid-reducing agents, or CYP2C19 inhibitors. PMID:27310328

  13. Modeling of Rifampicin-Induced CYP3A4 Activation Dynamics for the Prediction of Clinical Drug-Drug Interactions from In Vitro Data

    PubMed Central

    Yamashita, Fumiyoshi; Sasa, Yukako; Yoshida, Shuya; Hisaka, Akihiro; Asai, Yoshiyuki; Kitano, Hiroaki; Hashida, Mitsuru; Suzuki, Hiroshi

    2013-01-01

    Induction of cytochrome P450 3A4 (CYP3A4) expression is often implicated in clinically relevant drug-drug interactions (DDI), as metabolism catalyzed by this enzyme is the dominant route of elimination for many drugs. Although several DDI models have been proposed, none have comprehensively considered the effects of enzyme transcription/translation dynamics on induction-based DDI. Rifampicin is a well-known CYP3A4 inducer, and is commonly used as a positive control for evaluating the CYP3A4 induction potential of test compounds. Herein, we report the compilation of in vitro induction data for CYP3A4 by rifampicin in human hepatocytes, and the transcription/translation model developed for this enzyme using an extended least squares method that can account for inherent inter-individual variability. We also developed physiologically based pharmacokinetic (PBPK) models for the CYP3A4 inducer and CYP3A4 substrates. Finally, we demonstrated that rifampicin-induced DDI can be predicted with reasonable accuracy, and that a static model can be used to simulate DDI once the blood concentration of the inducer reaches a steady state following repeated dosing. This dynamic PBPK-based DDI model was implemented on a new multi-hierarchical physiology simulation platform named PhysioDesigner. PMID:24086247

  14. Use of three-compartment physiologically based pharmacokinetic modeling to predict hepatic blood levels of fluvoxamine relevant for drug-drug interactions.

    PubMed

    Iga, Katsumi

    2015-04-01

    Using a three-compartment physiologically based pharmacokinetic (PBPK) model and a tube model for hepatic extraction kinetics, equations for calculating blood drug levels (Cb s) and hepatic blood drug levels (Chb s, proportional to actual hepatic drug levels), were derived mathematically. Assuming the actual values for total body clearance (CLtot ), oral bioavailability (F), and steady-state distribution volume (Vdss ), Cb s, and Chb s after intravenous and oral administration of fluvoxamine (strong perpetrator in drug-drug interactions, DDIs), propranolol, imipramine, and tacrine were simulated. Values for Cb s corresponded to the actual values for all tested drugs, and mean Chb and maximal Chb -to-maximal Cb ratio predicted for oral fluvoxamine administration (50 mg twice-a-day administration) were nearly 100 nM and 2.3, respectively, which would be useful for the predictions of the DDIs caused by fluvoxamine. Fluvoxamine and tacrine are known to exhibit relatively large F values despite having CLtot similar to or larger than hepatic blood flow, which may be because of the high liver uptake (almost 0.6) upon intravenous administration. The present method is thus considered to be more predictive of the Chb for perpetrators of DDIs than other methods. PMID:25558834

  15. Pattern and associated factors of potential drug-drug interactions in both pre- and early post-hematopoietic stem cell transplantation stages at a referral center in the Middle East.

    PubMed

    Gholaminezhad, Safoora; Hadjibabaie, Molouk; Gholami, Kheirollah; Javadi, Mohammad Reza; Radfar, Mania; Karimzadeh, Iman; Ghavamzadeh, Ardeshir

    2014-11-01

    The aim of this study was to determine the pattern as well as associated factors of moderate and major potential drug-drug interactions (PDDIs) in both the pre- and early post-transplantation stages at a referral hematopoietic stem cell transplantation (HSCT) center. All adolescents and adults undergone HSCT within a 3-year period were screened retrospectively for potential moderate or severe PDDIs by the Lexi-Interact On-Desktop software. Among 384 patients, a total of 13,600 PDDIs were detected. The median (interquartile range) cumulative PDDIs burden was 41 (28). All (100 %) individuals experienced at least one PDDI. More than four fifths (81.8 %) of detected PDDIs were moderate. The predominant mechanism of PDDIs was pharmacokinetics (54.3 %). Interaction between sulfamethoxazole-trimethoprim and fluconazole was the most common PDDIs involving 95.3 % of the study population. More than three fifths (61.5 %) of detected PDDIs were caused by HSCT-related medications. No interaction was identified between two anticancer agents. Interactions of cyclophosphamide with phenytoin, busulfan with metronidazole, dexamethasone, or clarithromycin were the only detected PDDI between anticancer and non-anticancer medications. Type of HSCT and the numbers of administered medications were significantly associated with major PDDIs. The epidemiology, real clinical consequence, and economic burden of DDIs on patients undergone HSCT particularly around the transplantation period should be assessed further by prospective, multicenter studies. PMID:24906215

  16. Cobicistat versus ritonavir boosting and differences in the drug-drug interaction profiles with co-medications.

    PubMed

    Marzolini, Catia; Gibbons, Sara; Khoo, Saye; Back, David

    2016-07-01

    Nearly all HIV PIs and the integrase inhibitor elvitegravir require a pharmacokinetic enhancer in order to achieve therapeutic plasma concentrations at the desired dose and frequency. Whereas ritonavir has been the only available pharmacokinetic enhancer for more than a decade, cobicistat has recently emerged as an alternative boosting agent. Cobicistat and ritonavir are equally strong inhibitors of cytochrome P450 (CYP) 3A4 and consequently were shown to be equivalent pharmacokinetic enhancers for elvitegravir and for the PIs atazanavir and darunavir. Since cobicistat is a more selective CYP inhibitor than ritonavir and is devoid of enzyme-inducing properties, differences are expected in their interaction profiles with some co-medications. Drugs whose exposure might be altered by ritonavir but unaltered by cobicistat are drugs primarily metabolized by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP2C19 or drugs undergoing mainly glucuronidation. Thus, co-medications should be systematically reviewed when switching the pharmacokinetic enhancer to anticipate potential dosage adjustments. PMID:26945713

  17. Clinical Pharmacokinetic, Pharmacodynamic, and Drug-Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor.

    PubMed

    Devineni, Damayanthi; Polidori, David

    2015-10-01

    The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1-2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50-1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose

  18. Oral epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: comparative pharmacokinetics and drug-drug interactions.

    PubMed

    Peters, Solange; Zimmermann, Stefan; Adjei, Alex A

    2014-09-01

    The development of orally active small molecule inhibitors of the epidermal growth factor receptor (EGFR) has led to new treatment options for non-small cell lung cancer (NSCLC). Patients with activating mutations of the EGFR gene show sensitivity to, and clinical benefit from, treatment with EGFR tyrosine kinase inhibitors (EGFR-TKls). First generation reversible ATP-competitive EGFR-TKls, gefitinib and erlotinib, are effective as first, second-line or maintenance therapy. Despite initial benefit, most patients develop resistance within a year, 50-60% of cases being related to the appearance of a T790M gatekeeper mutation. Newer, irreversible EGFR-TKls - afatinib and dacomitinib - covalently bind to and inhibit multiple receptors in the ErbB family (EGFR, HER2 and HER4). These agents have been mainly evaluated for first-line treatment but also in the setting of acquired resistance to first-generation EGFR-TKls. Afatinib is the first ErbB family blocker approved for patients with NSCLC with activating EGFR mutations; dacomitinib is in late stage clinical development. Mutant-selective EGFR inhibitors (AZD9291, CO-1686, HM61713) that specifically target the T790M resistance mutation are in early development. The EGFR-TKIs differ in their spectrum of target kinases, reversibility of binding to EGFR receptor, pharmacokinetics and potential for drug-drug interactions, as discussed in this review. For the clinician, these differences are relevant in the setting of polymedicated patients with NSCLC, as well as from the perspective of innovative anticancer drug combination strategies. PMID:25027951

  19. Substrate-dependent drug-drug interactions between gemfibrozil, fluvastatin and other organic anion-transporting peptide (OATP) substrates on OATP1B1, OATP2B1, and OATP1B3.

    PubMed

    Noé, Johannes; Portmann, Renée; Brun, Marie-Elise; Funk, Christoph

    2007-08-01

    Hepatic uptake carriers of the organic anion-transporting peptide (OATP) family of solute carriers are more and more recognized as being involved in hepatic elimination of many drugs and potentially associated drug-drug interactions. The gemfibrozil-statin interaction was studied at the level of active hepatic uptake as a model for such drug-drug interactions. Active, temperature-dependent uptake of fluvastatin into primary human hepatocytes was shown. Multiple transporters are involved in this uptake as Chinese hamster ovary or HEK293 cells expressing either OATP1B1 (K(m) = 1.4-3.5 microM), OATP2B1 (K(m) = 0.7-0.8 microM), or OATP1B3 showed significant fluvastatin uptake relative to control cells. For OATP1B1 the inhibition by gemfibrozil was substrate-dependent as the transport of fluvastatin (IC(50) of 63 microM), pravastatin, simvastatin, and taurocholate was inhibited by gemfibrozil, whereas the transport of estrone-3-sulfate and troglitazone sulfate (both used at 3 microM) was not affected. The OATP1B1- but not OATP2B1-mediated transport of estrone-3-sulfate displayed biphasic saturation kinetics, with two distinct affinity components for estrone-3-sulfate (0.23 and 45 microM). Only the high-affinity component was inhibited by gemfibrozil. Recombinant OATP1B1-, OATP2B1-, and OATP1B3-mediated fluvastatin transport was inhibited to 97, 70, and 62% by gemfibrozil (200 microM), respectively, whereas only a small inhibitory effect by gemfibrozil (200 microM) on fluvastatin uptake into primary human hepatocytes was observed (27% inhibition). The results indicate that the in vitro engineered systems can not always predict the behavior in more complex systems such as freshly isolated primary hepatocytes. Therefore, selection of substrate, substrate concentration, and in vitro transport system are critical for the conduct of in vitro interaction studies involving individual liver OATP carriers. PMID:17470528

  20. Treatment optimization in patients co-infected with HIV and Mycobacterium tuberculosis infections: focus on drug-drug interactions with rifamycins.

    PubMed

    Regazzi, Mario; Carvalho, Anna Cristina; Villani, Paola; Matteelli, Alberto

    2014-06-01

    Tuberculosis (TB) and HIV continue to be two of the major causes of morbidity and mortality in the world, and together are responsible for the death of millions of people every year. There is overwhelming evidence to recommend that patients with TB and HIV co-infection should receive concomitant therapy of both conditions regardless of the CD4 cell count level. The principles for treatment of active TB disease in HIV-infected patients are the same as in HIV-uninfected patients. However, concomitant treatment of both conditions is complex, mainly due to significant drug-drug interactions between TB and HIV drugs. Rifamycins are potent inducers of the cytochrome P450 (CYP) pathway, leading to reduced (frequently sub-therapeutic) plasma concentrations of some classes of antiretrovirals. Rifampicin is also an inducer of the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes and interferes with drugs, such as integrase inhibitors, that are metabolized by this metabolic pathway. Rifampicin is also an inducer of the adenosine triphosphate (ATP) binding cassette transporter P-glycoprotein, which may also lead to decreased bioavailability of concomitantly administered antiretrovirals. On the other side, rifabutin concentrations are affected by the antiretrovirals that induce or inhibit CYP enzymes. In this review, the pharmacokinetic interactions, and the relevant clinical consequences, of the rifamycins-rifampicin, rifabutin, and rifapentine-with antiretroviral drugs are reviewed and discussed. A rifampicin-based antitubercular regimen and an efavirenz-based antiretroviral regimen is the first choice for treatment of TB/HIV co-infected patients. Rifabutin is the preferred rifamycin to use in HIV-infected patients on a protease inhibitor-based regimen; however, the dose of rifabutin needs to be reduced to 150 mg daily. More information is required to select optimal treatment regimens for TB/HIV co-infected patients whenever efavirenz cannot be used and rifabutin

  1. Multidrug PLA-PEG filomicelles for concurrent delivery of anticancer drugs-The influence of drug-drug and drug-polymer interactions on drug loading and release properties.

    PubMed

    Jelonek, Katarzyna; Li, Suming; Kaczmarczyk, Bożena; Marcinkowski, Andrzej; Orchel, Arkadiusz; Musiał-Kulik, Monika; Kasperczyk, Janusz

    2016-08-20

    This study aimed to analyze the influence of drug-drug and drug-polymer interactions on drug loading and release properties of multidrug micelles. Three hydrophobic drugs-paclitaxel (Ptx), 17-AAG and rapamycin (Rap) were incorporated in poly(l-lactide)-poly(ethylene glycol) (PLA-PEG) filomicelles. Double loaded micelles containing Ptx and 17-AAG were used for the sake of comparison. (1)H NMR confirmed the effective incorporation of the various drugs in micelles, and HPLC allowed to determine the drug loading contents. FTIR was used to evaluate interactions between particular drugs and between drugs and copolymer. Ptx and 17-AAG present similar loading efficiencies in double loaded micelles probably due to interactions of drugs with each other and also with the copolymer. In contrast, unequal drug loading properties are observed for triple loaded micelles. Rapamycin shows very weak interactions with the copolymer, and displays the lowest loading efficiency. In vitro release of drugs from micelles was realized in pH 7.4 phosphate buffered saline at 37°C, and monitored by HPLC. Similar release profiles are observed for the three drugs: a strong burst followed by slower release. Nevertheless, Ptx release from micelles is significantly slower as compared to 17-AAG and Rap, probably due to interactions of NH and OH groups of Ptx with the carbonyl group of PLA. In vitro cytotoxicity of Ptx/17-AAG/Rap loaded micelles and a mixture of free drugs was determined. Drug loaded micelles exhibit advantageous effect of prolonged drug release and cytotoxic activity against Caco-2 cells, which makes them a promising solution for simultaneous drug delivery to solid tumors. Therefore, understanding of interactions within multidrug micelles should be a valuable approach for the development of concurrent delivery systems of anticancer drugs with tailored properties. PMID:27346726

  2. Inhibition of hepatic organic anion-transporting polypeptide by RNA interference in sandwich-cultured human hepatocytes: an in vitro model to assess transporter-mediated drug-drug interactions.

    PubMed

    Liao, Mingxiang; Raczynski, Arek R; Chen, Michael; Chuang, Bei-Ching; Zhu, Qing; Shipman, Rob; Morrison, Jodi; Lee, David; Lee, Frank W; Balani, Suresh K; Xia, Cindy Q

    2010-09-01

    Organic anion-transporting polypeptides (OATPs), members of the SLCO/SLC21 family, mediate the transport of various endo- and xenobiotics. In human liver, OATP1B1, 1B3, and 2B1 are located at the basolateral membrane of hepatocytes and are involved in hepatic drug uptake and biliary elimination. Clinically significant drug-drug interactions (DDIs) mediated by hepatic OATPs have drawn great attention from clinical practitioners and researchers. However, there are considerable challenges to prospectively understanding the extent of OATP-mediated DDIs because of the lack of specific OATP inhibitors or substrates and the limitations of in vitro tools. In the present study, a novel RNA interference knockdown sandwich-cultured human hepatocyte model was developed and validated. Quantitative polymerase chain reaction, microarray and immunoblotting analyses, along with uptake assays, illustrated that the expression and transport activity of hepatic OATPs were reduced by small interfering (siRNA) efficiently and specifically in this model. Although OATP siRNA decreased only 20 to 30% of the total uptake of cerivastatin into human hepatocytes, it caused a 50% reduction in cerivastatin metabolism, which was observed by monitoring the formation of the two major metabolites of cerivastatin. The results suggest that coadministration of a drug that is a hepatic OATP inhibitor could significantly alter the pharmacokinetic profile of cerivastatin in clinical studies. Further studies with this novel model demonstrated that OATP and cytochrome P450 have a synergistic effect on cerivastatin-gemfibrozil interactions. The siRNA knockdown sandwich-cultured human hepatocytes may provide a new powerful model for evaluating DDIs. PMID:20516252

  3. Solitary Inhibition of the Breast Cancer Resistance Protein Efflux Transporter Results in a Clinically Significant Drug-Drug Interaction with Rosuvastatin by Causing up to a 2-Fold Increase in Statin Exposure.

    PubMed

    Elsby, Robert; Martin, Paul; Surry, Dominic; Sharma, Pradeep; Fenner, Katherine

    2016-03-01

    The intestinal efflux transporter breast cancer resistance protein (BCRP) restricts the absorption of rosuvastatin. Of the transporters important to rosuvastatin disposition, fostamatinib inhibited BCRP (IC50 = 50 nM) and organic anion-transporting polypeptide 1B1 (OATP1B1; IC50 > 10 μM), but not organic anion transporter 3, in vitro, predicting a drug-drug interaction (DDI) in vivo through inhibition of BCRP only. Consequently, a clinical interaction study between fostamatinib and rosuvastatin was performed (and reported elsewhere). This confirmed the critical role BCRP plays in statin absorption, as inhibition by fostamatinib resulted in a significant 1.96-fold and 1.88-fold increase in rosuvastatin area under the plasma concentration-time curve (AUC) and Cmax, respectively. An in vitro BCRP inhibition assay, using polarized Caco-2 cells and rosuvastatin as probe substrate, was subsequently validated with literature inhibitors and used to determine BCRP inhibitory potencies (IC50) of the perpetrator drugs eltrombopag, darunavir, lopinavir, clopidogrel, ezetimibe, fenofibrate, and fluconazole. OATP1B1 inhibition was also determined using human embryonic kidney 293-OATP1B1 cells versus estradiol 17β-glucuronide. Calculated parameters of maximum enterocyte concentration [Igut max], maximum unbound hepatic inlet concentration, transporter fraction excreted value, and determined IC50 value were incorporated into mechanistic static equations to compute theoretical increases in rosuvastatin AUC due to inhibition of BCRP and/or OATP1B1. Calculated theoretical increases in exposure correctly predicted the clinically observed changes in rosuvastatin exposure and suggested intestinal BCRP inhibition (not OATP1B1) to be the mechanism underlying the DDIs with these drugs. In conclusion, solitary inhibition of the intestinal BCRP transporter can result in clinically significant DDIs with rosuvastatin, causing up to a maximum 2-fold increase in exposure, which may warrant

  4. Investigation of drug-drug interactions caused by human pregnane X receptor-mediated induction of CYP3A4 and CYP2C subfamilies in chimeric mice with a humanized liver.

    PubMed

    Hasegawa, Maki; Tahara, Harunobu; Inoue, Ryo; Kakuni, Masakazu; Tateno, Chise; Ushiki, Junko

    2012-03-01

    The induction of cytochrome P450 (P450) enzymes is one of the risk factors for drug-drug interactions (DDIs). To date, the human pregnane X receptor (PXR)-mediated CYP3A4 induction has been well studied. In addition to CYP3A4, the expression of CYP2C subfamily is also regulated by PXR, and the DDIs caused by the induction of CYP2C enzymes have been reported to have a major clinical impact. The purpose of the present study was to investigate whether chimeric mice with a humanized liver (PXB mice) can be a suitable animal model for investigating the PXR-mediated induction of CYP2C subfamily, together with CYP3A4. We evaluated the inductive effect of rifampicin (RIF), a typical human PXR ligand, on the plasma exposure to the four P450 substrate drugs (triazolam/CYP3A4, pioglitazone/CYP2C8, (S)-warfarin/CYP2C9, and (S)-(-)-mephenytoin/CYP2C19) by cassette dosing in PXB mice. The induction of several drug-metabolizing enzymes and transporters in the liver was also examined by measuring the enzyme activity and mRNA expression levels. Significant reductions in the exposure to triazolam, pioglitazone, and (S)-(-)-mephenytoin, but not to (S)-warfarin, were observed. In contrast to the in vivo results, all the four P450 isoforms, including CYP2C9, were elevated by RIF treatment. The discrepancy in the (S)-warfarin results between in vivo and in vitro studies may be attributed to the relatively small contribution of CYP2C9 to (S)-warfarin elimination in the PXB mice used in this study. In summary, PXB mice are a useful animal model to examine DDIs caused by PXR-mediated induction of CYP2C and CYP3A4. PMID:22126990

  5. Synthesis of stable isotope labelled internal standards for drug-drug interaction (DDI) studies.

    PubMed

    Atzrodt, J; Blankenstein, J; Brasseur, D; Calvo-Vicente, S; Denoux, M; Derdau, V; Lavisse, M; Perard, S; Roy, S; Sandvoss, M; Schofield, J; Zimmermann, J

    2012-09-15

    The syntheses of stable isotope labelled internal standards of important CYP-isoform selective probes, like testosterone 1, diclofenac 3, midazolam 5, and dextromethorphan 7, as well as their corresponding hydroxylated metabolites 6β-hydroxytestosterone 2, 4'-hydroxydiclofenac 4, 1'-hydroxymidazolam 6 and dextrorphan 8 are reported. Microwave-enhanced H/D-exchange reactions applying either acid, base, or homogeneous and heterogeneous transition metal catalysis, or combinations thereof proved to be highly efficient for direct deuterium labelling of the above mentioned probes. Compared to conventional stepwise synthetic approaches, the combination of H/D exchange and biotransformation provides the potential for considerable time- and cost savings, in particular for the synthesis of the stable isotope labelled internal standards of 4'-hydroxydiclofenac 4 and 1'-hydroxymidazolam 6. PMID:22890009

  6. Development of an enantioselective assay for simultaneous separation of venlafaxine and O-desmethylvenlafaxine by micellar electrokinetic chromatography-tandem mass spectrometry: Application to the analysis of drug-drug interaction.

    PubMed

    Liu, Yijin; Jann, Michael; Vandenberg, Chad; Eap, Chin B; Shamsi, Shahab A

    2015-11-13

    To-date, there has been no effective chiral capillary electrophoresis-mass spectrometry (CE-MS) method reported for the simultaneous enantioseparation of the antidepressant drug, venlafaxine (VX) and its structurally-similar major metabolite, O-desmethylvenlafaxine (O-DVX). This is mainly due to the difficulty of identifying MS compatible chiral selector, which could provide both high enantioselectivity and sensitive MS detection. In this work, poly-sodium N-undecenoyl-L,L-leucylalaninate (poly-L,L-SULA) was employed as a chiral selector after screening several dipeptide polymeric chiral surfactants. Baseline separation of both O-DVX and VX enantiomers was achieved in 15 min after optimizing the buffer pH, poly-L,L-SULA concentration, nebulizer pressure and separation voltage. Calibration curves in spiked plasma (recoveries higher than 80%) were linear over the concentration range 150-5000 ng/mL for both VX and O-DVX. The limit of detection (LOD) was found to be as low as 30 ng/mL and 21 ng/mL for O-DVX and VX, respectively. This method was successfully applied to measure the plasma concentrations of human volunteers receiving VX or O-DVX orally when co-administered without and with indinivar therapy. The results suggest that micellar electrokinetic chromatography electrospray ionization-tandem mass spectrometry (MEKC-ESI-MS/MS) is an effective low cost alternative technique for the pharmacokinetics and pharmacodynamics studies of both O-DVX and VX enantiomers. The technique has potential to identify drug-drug interaction involving VX and O-DVX enantiomers while administering indinivar therapy. PMID:26460073

  7. CYP3A4-based drug-drug interaction: CYP3A4 substrates' pharmacokinetic properties and ketoconazole dose regimen effect.

    PubMed

    Boulenc, Xavier; Nicolas, Olivier; Hermabessière, Stéphanie; Zobouyan, Isabelle; Martin, Valérie; Donazzolo, Yves; Ollier, Céline

    2016-02-01

    The aim of the study was to assess the magnitude of the CYP3A4 inhibitory effect of 2 dosing regimens of ketoconazole and the influence of the pharmacokinetic properties of the CYP3A4 substrate on the extent of the substrate exposure increase. For this purpose, a clinical study was conducted and PBPK modeling simulations were performed. A crossover study was conducted in healthy subjects. The study was designed to compare the effects of different regimens of reversible CYP3A4 inhibitors, i.e., ketoconazole 400 mg OD, ketoconazole 200 mg BID, on two CYP3A4 substrates, alprazolam and midazolam, reflecting different pharmacokinetic properties in terms of first-pass effect and elimination. In parallel, time-based simulations were performed using the Simcyp population-based Simulator to address the usefulness of modeling to assess interaction clinical study design with CYP3A4 substrates. Comparison of the OD versus BID regimens for ketoconazole showed an opposite trend for the 2 substrates: BID (200 mg) dosing regimen provided the maximal clearance inhibition for alprazolam, while it was OD (400 mg) dosing regimen for midazolam. However, these effects are moderate despite the well-known pharmacokinetic differences between these substrates, suggesting that these differences are not enough. In the other way round, these investigations show how two CYP3A4 substrates can be different without leading to a major impact of the ketoconazole dosing regimen. The clinical findings are consistent with the Simcyp predictions, in particular the opposite trend observed with midazolam and alprazolam and the ketoconazole dosing regimen. These clinical investigations showed the influence of the CYP3A4 substrates' pharmacokinetic properties and the relevance of ketoconazole dose regimen on the magnitude of the interaction ratios. In addition, PBPK Simcyp simulations demonstrated how they can be used to help clinical study design assessment to capture the maximum effect. PMID:25374256

  8. Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions.

    PubMed

    Tornio, A; Filppula, A M; Kailari, O; Neuvonen, M; Nyrönen, T H; Tapaninen, T; Neuvonen, P J; Niemi, M; Backman, J T

    2014-10-01

    Cerivastatin and repaglinide are substrates of cytochrome P450 (CYP)2C8, CYP3A4, and organic anion-transporting polypeptide (OATP)1B1. A recent study revealed an increased risk of rhabdomyolysis in patients using cerivastatin with clopidogrel, warranting further studies on clopidogrel interactions. In healthy volunteers, repaglinide area under the concentration-time curve (AUC(0-∞)) was increased 5.1-fold by a 300-mg loading dose of clopidogrel and 3.9-fold by continued administration of 75 mg clopidogrel daily. In vitro, we identified clopidogrel acyl-β-D-glucuronide as a potent time-dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel acyl-β-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl-β-D-glucuronide at the CYP2C8 active site with its thiophene moiety close to heme. The results indicate that clopidogrel is a strong CYP2C8 inhibitor via its acyl-β-D-glucuronide and imply that glucuronide metabolites should be considered potential inhibitors of CYP enzymes. PMID:24971633

  9. Drug-drug interactions in inmates treated for human immunodeficiency virus and Mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak.

    PubMed

    Spradling, P; Drociuk, D; McLaughlin, S; Lee, L M; Peloquin, C A; Gallicano, K; Pozsik, C; Onorato, I; Castro, K G; Ridzon, R

    2002-11-01

    The use of rifamycins is limited by drug interactions in human immunodeficiency virus (HIV)-infected persons who are receiving highly active antiretroviral therapy (HAART). During a tuberculosis (TB) outbreak at a prison housing HIV-infected inmates, rifabutin was used to treat 238 men (13 case patients and 225 contacts). Steady-state peak plasma rifabutin concentrations were obtained after rifabutin dosages were adjusted for men receiving single-interacting HAART (with either 1 protease inhibitor [PI] or efavirenz), multi-interacting HAART (with either 2 PIs or > or =1 PI with efavirenz), and for noninteracting HAART (>1 nucleoside reverse-transcriptase inhibitor or no HAART) without rifabutin dose adjustments. Low rifabutin concentrations occurred in 9% of those receiving noninteracting HAART, compared with 19% of those receiving single-interacting and 29% of those receiving multi-interacting HAART (chi2, 3.76; P=.05). Of 225 contacts treated with rifabutin-pyrazinamide, 158 (70%) completed treatment while incarcerated. Rifabutin-pyrazinamide therapy was difficult to implement, because of the need for dosage adjustments and expert clinical management. PMID:12384845

  10. Drug-drug interactions in older patients with cancer: a report from the 15th Conference of the International Society of Geriatric Oncology, Prague, Czech Republic, November 2015

    PubMed Central

    Stepney, Rob; Lichtman, Stuart M; Danesi, Romano

    2016-01-01

    Drugs taken for cancer can interact with each other, with agents taken as part of supportive care, with drugs taken for comorbid conditions (which are particularly common in the elderly patients), and with herbal supplements and complementary medicines. We tend to focus on the narrow therapeutic window of cytotoxics, but the metabolism of tyrosine kinase inhibitors by the cytochrome P450 3A4 enzyme (CYP3A4) makes some TKIs particularly prone to interference with or from other agents sharing this pathway. There is also potential for adverse pharmacokinetic interactions with new hormonal agents used in advanced prostate cancer. PMID:26823680

  11. Utilizing structures of CYP2D6 and BACE1 complexes to reduce risk of drug-drug interactions with a novel series of centrally efficacious BACE1 inhibitors.

    PubMed

    Brodney, Michael A; Beck, Elizabeth M; Butler, Christopher R; Barreiro, Gabriela; Johnson, Eric F; Riddell, David; Parris, Kevin; Nolan, Charles E; Fan, Ying; Atchison, Kevin; Gonzales, Cathleen; Robshaw, Ashley E; Doran, Shawn D; Bundesmann, Mark W; Buzon, Leanne; Dutra, Jason; Henegar, Kevin; LaChapelle, Erik; Hou, Xinjun; Rogers, Bruce N; Pandit, Jayvardhan; Lira, Ricardo; Martinez-Alsina, Luis; Mikochik, Peter; Murray, John C; Ogilvie, Kevin; Price, Loren; Sakya, Subas M; Yu, Aijia; Zhang, Yong; O'Neill, Brian T

    2015-04-01

    In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug-drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins. PMID:25781223

  12. The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug-Drug Interactions in a Clinical Setting-Proposal of a Four Component Transporter Cocktail.

    PubMed

    Ebner, Thomas; Ishiguro, Naoki; Taub, Mitchell E

    2015-09-01

    Probe drug cocktails are used clinically to assess the potential for drug-drug interactions (DDIs), and in particular, DDIs resulting from coadministration of substrates and inhibitors of cytochrome P450 enzymes. However, a probe drug cocktail has not been identified to assess DDIs involving inhibition of drug transporters. We propose a cocktail consisting of the following substrates to explore the potential for DDIs caused by inhibition of key transporters: digoxin (P-glycoprotein, P-gp), rosuvastatin (breast cancer resistance protein, BCRP; organic anion transporting polypeptides, OATP), metformin (organic cation transporter, OCT; multidrug and toxin extrusion transporters, MATE), and furosemide (organic anion transporter, OAT). Furosemide was evaluated in vitro, and is a substrate of OAT1 and OAT3, with Km values of 38.9 and 21.5 μM, respectively. Furosemide was also identified as a substrate of BCRP, OATP1B1, and OATP1B3. Furosemide inhibited BCRP (50% inhibition of drug transport: 170 μM), but did not inhibit OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K at concentrations below 300 μM, and P-gp at concentrations below 2000 μM. Conservative approaches for the estimation of the likelihood of in vivo DDIs indicate a remote chance of in vivo transporter inhibition by these probe drugs when administered at low single oral doses. This four component probe drug cocktail is therefore proposed for clinical evaluation. PMID:25981193

  13. Dynamic and Static Simulations of Fluvoxamine-Perpetrated Drug-Drug Interactions Using Multiple Cytochrome P450 Inhibition Modeling, and Determination of Perpetrator-Specific CYP Isoform Inhibition Constants and Fractional CYP Isoform Contributions to Victim Clearance.

    PubMed

    Iga, Katsumi

    2016-03-01

    Fluvoxamine-perpetrated drug-drug interactions (DDIs) of victims metabolized by multiple cytochrome P450 isoforms (CYP1A2, CYP2C19, and CYP3A4) were simulated using 2 compartment-based tube modeling, assuming a multiple inhibition-constant (Ki) model, as well as a previously reported single Ki model. Good fittings were obtained for all DDIs using consistent perpetrator-specific CYP isoform Kis and fractional CYP isoform contributions to victim clearance in concordance with literature information. Through these simulations, the following rules to predict DDI were derived. Overall enzymatic inhibitory activity calculated from static DDI data determines entirely dynamic DDIs. DDI-relevant time-dependent hepatic blood unbound perpetrator levels can be approximated to mean hepatic blood unbound perpetrator levels in any victim DDIs when a perpetrator is supplied consistently. Static and dynamic multiple CYP model-based simulations agree with one another. Fluvoxamine-perpetrated DDIs can be bridged to other perpetrator DDIs. The derived rules will allow simpler prediction of DDIs from in vivo DDI databases. Tens or hundreds of Ki gaps between in vitro and in vivo data could be reduced to within severalfold using the liver-microsome contamination model, thus suggesting that microsomes qualified with contamination would greatly improve prediction of DDIs from in vitro data. PMID:26886336

  14. Methods and strategies for assessing uncontrolled drug-drug interactions in population pharmacokinetic analyses: results from the International Society of Pharmacometrics (ISOP) Working Group.

    PubMed

    Bonate, Peter L; Ahamadi, Malidi; Budha, Nageshwar; de la Peña, Amparo; Earp, Justin C; Hong, Ying; Karlsson, Mats O; Ravva, Patanjali; Ruiz-Garcia, Ana; Struemper, Herbert; Wade, Janet R

    2016-04-01

    The purpose of this work was to present a consolidated set of guidelines for the analysis of uncontrolled concomitant medications (ConMed) as a covariate and potential perpetrator in population pharmacokinetic (PopPK) analyses. This white paper is the result of an industry-academia-regulatory collaboration. It is the recommendation of the working group that greater focus be given to the analysis of uncontrolled ConMeds as part of a PopPK analysis of Phase 2/3 data to ensure that the resulting outcome in the PopPK analysis can be viewed as reliable. Other recommendations include: (1) collection of start and stop date and clock time, as well as dose and frequency, in Case Report Forms regarding ConMed administration schedule; (2) prespecification of goals and the methods of analysis, (3) consideration of alternate models, other than the binary covariate model, that might more fully characterize the interaction between perpetrator and victim drug, (4) analysts should consider whether the sample size, not the percent of subjects taking a ConMed, is sufficient to detect a ConMed effect if one is present and to consider the correlation with other covariates when the analysis is conducted, (5) grouping of ConMeds should be based on mechanism (e.g., PGP-inhibitor) and not drug class (e.g., beta-blocker), and (6) when reporting the results in a publication, all details related to the ConMed analysis should be presented allowing the reader to understand the methods and be able to appropriately interpret the results. PMID:26837775

  15. Evaluation of Drug-Drug Interactions between Direct-Acting Anti-Hepatitis C Virus Combination Regimens and the HIV-1 Antiretroviral Agents Raltegravir, Tenofovir, Emtricitabine, Efavirenz, and Rilpivirine.

    PubMed

    Khatri, Amit; Dutta, Sandeep; Dunbar, Martin; Podsadecki, Thomas; Trinh, Roger; Awni, Walid; Menon, Rajeev

    2016-05-01

    The three direct-acting antiviral agent (3D) regimen is a novel combination of direct-acting antiviral agents (DAAs) that has proven effective for the treatment of hepatitis C virus (HCV) infection. Given the potential for coadministration in patients with human immunodeficiency virus infection, possible drug interactions with antiretroviral drugs must be carefully considered. Four phase 1, multiple-dose pharmacokinetic studies were conducted in healthy volunteers (n = 66). The 3D regimen of 150/100 mg daily paritaprevir/ritonavir, 25 mg daily ombitasvir, and 400 mg twice-daily dasabuvir was administered alone or in combination with 200 mg daily of emtricitabine and 300 mg daily of tenofovir disoproxil fumarate (tenofovir DF), 25 mg daily of rilpivirine, or 400 mg of raltegravir twice daily. A 2-DAA regimen of 150/100 mg daily paritaprevir/ritonavir and 400 mg of dasabuvir twice daily was also studied in combination with efavirenz/emtricitabine/tenofovir DF at 600/200/300 mg daily, respectively (Atripla; Bristol-Myers Squibb). Pharmacokinetic parameters were determined from plasma drug concentrations. No clinically significant drug interactions were observed (≤32% change in exposure) between the 3D regimen and that of emtricitabine plus tenofovir DF. Raltegravir exposure was increased up to 134% when the drug was coadministered with the 3D regimen. Although coadministration with rilpivirine was well tolerated in healthy volunteers, observed elevations in rilpivirine exposures may increase the potential for adverse drug reactions. Concomitant use of the 2-DAA regimen and efavirenz/emtricitabine/tenofovir DF was discontinued owing to poor tolerability and adverse events. No dose adjustment is required during coadministration of raltegravir, tenofovir DF, or emtricitabine with the 3D regimen. Rilpivirine is not recommended and efavirenz is contraindicated for coadministration with the 3D regimen. PMID:26953200

  16. Simulation of Metabolic Drug-Drug Interactions Perpetrated by Fluvoxamine Using Hybridized Two-Compartment Hepatic Drug-Pool-Based Tube Modeling and Estimation of In Vivo Inhibition Constants.

    PubMed

    Iga, Katsumi

    2015-10-01

    Co-administration of fluvoxamine (FLV) (perpetrator) and ramelteon (victim, high-clearance CYP1A2 substrate) reportedly showed a 130-fold increase in the area under blood-ramelteon-levels curve (AUCR), which is unpredictable by any method assuming the traditional well-stirred hepatic extraction (Eh ) model. Thus, in order to predict this drug interaction (DDI), a mathematical method that allows simulation of dynamic changes in blood victim levels in response to metabolic inhibition by a perpetrator, without the use of any specialized tools, was derived using hybridized two-compartment hepatic drug-pool-based tube modeling. Using this method, the ramelteon-victimized DDI could be simulated in comparison with other victim DDIs, assuming a consistent FLV dosing regimen. Despite large differences in AUCRs, CYP1A2 or CYP2C19 substrate-victimized DDIs resulted in equivalent inhibition constants (Ki , around 3 nM) and net enzymatic inhibitory activities calculated by eliminating hepatic availability increases for victims. Thus, the unusually large ramelteon DDI could be attributed to the Eh of ramelteon itself. This DDI risk could also be accurately predicted from Ki s estimated in the other CYP1A2 or CYP2C19-substrate interactions. Meanwhile, dynamic changes in blood perpetrator levels were demonstrated to have a small effect on DDI, thus suggesting the usefulness of a tube-based static method for DDI prediction. PMID:26099559

  17. In Silico Predictions and In Vivo Results of Drug-Drug Interactions by Ketoconazole and Verapamil on AZD1305, a Combined Ion Channel Blocker and a Sensitive CYP3A4 Substrate.

    PubMed

    Johansson, Susanne; Löfberg, Boel; Aunes, Maria; Lunde, Helen; Frison, Lars; Edvardsson, Nils; Cullberg, Marie

    2016-09-01

    The objectives were to estimate and compare, in silico and in vivo, the effects of a strong and a moderate CYP3A4 inhibitor on AZD1305 pharmacokinetics. In silico, simulations were performed with the computer software Simcyp, and the predicted outcome was compared with the results observed in healthy male subjects. In silico, the geometric mean plasma exposure of AZD1305 + ketoconazole showed a 7.1-fold higher AUC and a 4.4-fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 1.9-fold higher AUC and a 1.7-fold higher Cmax compared with AZD1305 alone. In vivo, the plasma exposure of AZD1305 + ketoconazole showed a 7.7-fold higher AUC and a 4.8 -fold higher Cmax compared with AZD1305 alone. Coadministration with verapamil gave a 2.2-fold higher AUC and a 2.0-fold higher Cmax compared with AZD1305 alone. The mean maximum QTcF increase from baseline was 407, 487, and 437 milliseconds for AZD1305, alone and in combination with verapamil or ketoconazole, respectively. Simcyp predicted the effects of ketoconazole and verapamil on the sensitive CYP3A4 substrate AZD1305 pharmacokinetics well. Both the in vivo study and the Simcyp predictions suggest a contraindication for strong CYP3A4 inhibitors and AZD1305 when given in combination. PMID:27627192

  18. Design, Characterization, and Optimization of Controlled Drug Delivery System Containing Antibiotic Drug/s.

    PubMed

    Patel, Apurv; Dodiya, Hitesh; Shelate, Pragna; Shastri, Divyesh; Dave, Divyang

    2016-01-01

    The objective of this work was design, characterization, and optimization of controlled drug delivery system containing antibiotic drug/s. Osmotic drug delivery system was chosen as controlled drug delivery system. The porous osmotic pump tablets were designed using Plackett-Burman and Box-Behnken factorial design to find out the best formulation. For screening of three categories of polymers, six independent variables were chosen for Plackett-Burman design. Osmotic agent sodium chloride and microcrystalline cellulose, pore forming agent sodium lauryl sulphate and sucrose, and coating agent ethyl cellulose and cellulose acetate were chosen as independent variables. Optimization of osmotic tablets was done by Box-Behnken design by selecting three independent variables. Osmotic agent sodium chloride, pore forming agent sodium lauryl sulphate, and coating agent cellulose acetate were chosen as independent variables. The result of Plackett-Burman and Box-Behnken design and ANOVA studies revealed that osmotic agent and pore former had significant effect on the drug release up to 12 hr. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of the optimization procedure in successful development of porous osmotic pump tablets containing antibiotic drug/s by using sodium chloride, sodium lauryl sulphate, and cellulose acetate as key excipients. PMID:27610247

  19. Design, Characterization, and Optimization of Controlled Drug Delivery System Containing Antibiotic Drug/s

    PubMed Central

    Shelate, Pragna; Dave, Divyang

    2016-01-01

    The objective of this work was design, characterization, and optimization of controlled drug delivery system containing antibiotic drug/s. Osmotic drug delivery system was chosen as controlled drug delivery system. The porous osmotic pump tablets were designed using Plackett-Burman and Box-Behnken factorial design to find out the best formulation. For screening of three categories of polymers, six independent variables were chosen for Plackett-Burman design. Osmotic agent sodium chloride and microcrystalline cellulose, pore forming agent sodium lauryl sulphate and sucrose, and coating agent ethyl cellulose and cellulose acetate were chosen as independent variables. Optimization of osmotic tablets was done by Box-Behnken design by selecting three independent variables. Osmotic agent sodium chloride, pore forming agent sodium lauryl sulphate, and coating agent cellulose acetate were chosen as independent variables. The result of Plackett-Burman and Box-Behnken design and ANOVA studies revealed that osmotic agent and pore former had significant effect on the drug release up to 12 hr. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of the optimization procedure in successful development of porous osmotic pump tablets containing antibiotic drug/s by using sodium chloride, sodium lauryl sulphate, and cellulose acetate as key excipients. PMID:27610247

  20. Application of Caco-2 Cell Line in Herb-Drug Interaction Studies: Current Approaches and Challenges

    PubMed Central

    Awortwe, C.; Fasinu, P.S.; Rosenkranz, B.

    2015-01-01

    The Caco-2 model is employed in pre-clinical investigations to predict the likely gastrointestinal permeability of drugs because it expresses cytochrome P450 enzymes, transporters, microvilli and enterocytes of identical characteristics to the human small intestine. The FDA recommends this model as integral component of the Biopharmaceutics Classification System (BCS). Most dedicated laboratories use the Caco-2 cell line to screen new chemical entities through prediction of its solubility, bioavailability and the possibility of drug-drug or herb-drug interactions in the gut lumen. However, challenges in the inherent characteristics of Caco-2 cell and inter-laboratory protocol variations have resulted to generation of irreproducible data. These limitations affect the extrapolation of data from pre-clinical research to clinical studies involving drug-drug and herb-drug interactions. This review addresses some of these caveats and enumerates the plausible current and future approaches to reduce the anomalies associated with Caco-2 cell line investigations focusing on its application in herb-drug interactions. PMID:24735758

  1. Critical Density Interaction Studies

    SciTech Connect

    Young, P; Baldis, H A; Cheung, P; Rozmus, W; Kruer, W; Wilks, S; Crowley, S; Mori, W; Hansen, C

    2001-02-14

    Experiments have been performed to study the propagation of intense laser pulses to high plasma densities. The issue of self-focusing and filamentation of the laser pulse as well as developing predictive capability of absorption processes and x-ray conversion efficiencies is important for numerous programs at the Laboratory, particularly Laser Program (Fast Ignitor and direct-drive ICF) and D&NT (radiography, high energy backlighters and laser cutting). Processes such as resonance absorption, profile modification, linear mode conversion, filamentation and stimulated Brillouin scattering can occur near the critical density and can have important effects on the coupling of laser light to solid targets. A combination of experiments have been used to study the propagation of laser light to high plasma densities and the interaction physics of intense laser pulses with solid targets. Nonparaxial fluid codes to study nonstationary behavior of filamentation and stimulated Brillouin scattering at high densities have also been developed as part of this project.

  2. Arc electrode interaction study

    NASA Technical Reports Server (NTRS)

    Zhou, X.; Berns, D.; Heberlein, J.

    1994-01-01

    The project consisted of two parts: (1) the cathode interaction studies which were a continuation of previous work and had the objective of increasing our understanding of the microscopic phenomena controlling cathode erosion in arc jet thrusters, and (2) the studies of the anode attachment in arc jet thrusters. The cathode interaction studies consisted of (1) a continuation of some modeling work in which the previously derived model for the cathode heating was applied to some specific gases and electrode materials, and (2) experimental work in which various diagnostics was applied to the cathode. The specific diagnostics used were observation of the cathode tip during arcing using a Laser Strobe Video system in conjunction with a tele-microscope, a monochromator with an optical multichannel analyzer for the determination of the cathode temperature distribution, and various ex situ materials analysis methods. The emphasis of our effort was shifted to the cathode materials analysis because a parallel project was in place during the second half of 1993 with a visiting scientist pursuing arc electrode materials studies. As a consequence, the diagnostic investigations of the arc in front of the cathode had to be postponed to the first half of 1994, and we are presently preparing these measurements. The results of last year's study showed some unexpected effects influencing the cathode erosion behavior, such as increased erosion away from the cathode tip, and our understanding of these effects should improve our ability to control cathode erosion. The arc jet anode attachment studies concentrated on diagnostics of the instabilities in subsonic anode attachment arc jet thrusters, and were supplemental measurements to work which was performed by one of the authors who spent the summer as an intern at NASA Lewis Research Center. A summary of the results obtained during the internship are included because they formed an integral part of the study. Two tasks for 1994, the

  3. Review of pharmacokinetic and pharmacodynamic interaction studies with citalopram.

    PubMed

    Brøsen, K; Naranjo, C A

    2001-08-01

    Citalopram is a selective serotonin reuptake inhibitor that is N-demethylated to N-desmethylcitalopram partially by CYP2C19 and partially by CYP3A4 and N-desmethylcitalopram is further N-demethylated by CYP2D6 to the likewise inactive metabolite di-desmethylcitalopram. The two metabolites are not active. The fact that citalopram is metabolised by more than one CYP means that inhibition of its biotransformation by other drugs is less likely. Besides citalopram has a wide margin of safety, so even if there was a considerable change in serum concentration then this would most likely not be of clinical importance. In vitro citalopram does not inhibit CYP or does so only very moderately. A number of studies in healthy subjects and patients have confirmed, that this also holds true in vivo. Thus no change in pharmacokinetics or only very small changes were observed when citalopram was given with CYP1A2 substrates (clozapine and therophylline), CYP2C9 (warfarin), CYP2C19 (imipramine and mephenytoin), CYP2D6 (sparteine, imipramine and amitriptyline) and CYP3A4 (carbamazepine and triazolam). At the pharmacodynamic level there have been a few documented cases of serotonin syndrome with citalopram and moclobemide and buspirone. It is concluded that citalopram is neither the source nor the cause of clinically important drug-drug interactions. PMID:11532381

  4. Sandwich-Cultured Hepatocytes: An In Vitro Model to Evaluate Hepatobiliary Transporter-Based Drug Interactions and Hepatotoxicity

    PubMed Central

    Swift, Brandon; Pfeifer, Nathan D.; Brouwer, Kim L.R.

    2011-01-01

    Sandwich-cultured hepatocytes (SCH) are a powerful in vitro tool that can be utilized to study hepatobiliary drug transport, species differences in drug transport, transport protein regulation, drug-drug interactions, and hepatotoxicity. This review provides an up-to-date summary of the SCH model, including a brief history of, and introduction to, the use of SCH, as well as methodology to evaluate hepatobiliary drug disposition. A summary of the literature that has utilized this model to examine the interplay between drug metabolizing enzymes and transport proteins, drug-drug interactions at the transport level, and hepatotoxicity as a result of altered hepatic transport also is provided. PMID:20109035

  5. Studies of food drug interactions.

    PubMed

    Aman, Syed Faisal; Hassan, Fouzia; Naqvi, Baqar S; Hasan, Syed Muhammmad Farid

    2010-07-01

    Medicines can treat and alleviate many diseases provided that they must be taken properly to ensure that they are safe and useful. One issue related with the medicines is that whether to take on empty stomach or with food. The present work gives information regarding food-drug interactions that were studied by collecting seventy five prescriptions from various hospitals. In most of the collected prescriptions, food-drug interactions were detected using the literature available. It was also found that only few studies have been carried out so far on the effect of food on drug disposition in the Asian population. Thus more studies on food-drug interactions particularly in the local population is recommended in order to determine the effect of food and food components on drug disposition and to the kinetics of the drugs which has not yet well highlighted in this part of the world. PMID:20566446

  6. Teratogenic drugs and their drug interactions with hormonal contraceptives.

    PubMed

    Ahn, M R; Li, L; Shon, J; Bashaw, E D; Kim, M-J

    2016-09-01

    The US Food and Drug Administration (FDA) Guidance for Industry-Drug Interaction Studies, recommends that a potential human teratogen needs to be studied in vivo for effects on contraceptive steroids.(1) This article highlights the need to evaluate the drug-drug interactions (DDIs) between drugs with teratogenic potential and hormonal contraceptives (HCs) during drug development. It also addresses the FDA's effort of communicating DDI findings in product labels to mitigate the risk of unintended pregnancy. PMID:27090193

  7. Co-Prescribing of Potentially Interacting Drugs during Warfarin Therapy - A Population-Based Register Study.

    PubMed

    Rikala, Maria; Hauta-Aho, Milka; Helin-Salmivaara, Arja; Lassila, Riitta; Korhonen, Maarit Jaana; Huupponen, Risto

    2015-08-01

    We analysed the occurrence of co-prescribing of potentially interacting drugs during warfarin therapy in the community-dwelling population of Finland. We identified drugs having interaction potential with warfarin using the Swedish Finnish INteraction X-referencing drug-drug interaction database (SFINX) and obtained data on drug purchases from the nationwide Prescription Register. We defined warfarin users as persons purchasing warfarin in 2010 (n = 148,536) and followed them from their first prescription in 2010 until the end of the calendar year. Co-prescribing was defined as at least 1-day overlap between warfarin and interacting drug episodes. In addition, we identified persons who initiated warfarin therapy between 1 January 2007 and 30 September 2010 (n = 110,299) and followed these incident users for a 3-month period since warfarin initiation. Overall, 74.4% of warfarin users were co-prescribed interacting drugs. Co-prescribing covered 46.4% of the total person-years of warfarin exposure. Interacting drugs that should be avoided with warfarin were co-prescribed for 13.4% of warfarin users. The majority of the co-prescriptions were for drugs that are not contraindicated during warfarin therapy but require special consideration. Among incident users, 57.1% purchased potentially interacting drugs during the 3-month period after initiation, while 9.0% purchased interacting drugs that should be avoided with warfarin. To conclude, the occurrence of co-prescribing of potentially interacting drugs was high during warfarin therapy. Our findings highlight the importance of close monitoring of warfarin therapy and the need for further studies on the clinical consequences of co-prescribing of interacting drugs with warfarin. PMID:25537751

  8. 77 FR 9946 - Draft Guidance for Industry on Drug Interaction Studies-Study Design, Data Analysis, Implications...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-02-21

    ... Federal Register of September 12, 2006 (71 FR 53696), FDA announced the availability of a draft guidance... in vivo studies of drug metabolism, drug transport, and drug-drug, or drug-therapeutic protein... metabolism and/or drug transport abruptly in individuals who previously had been receiving and tolerating...

  9. Extraterrestrial Studies Using Nuclear Interactions

    NASA Technical Reports Server (NTRS)

    Reedy, Robert C.

    2003-01-01

    Cosmogenic nuclides were used to study the recent histories of the aubrite Norton County and the pallasite Brenham using calculated production rates. Calculations were done of the rates for making cosmogenic noble-gas isotopes in the Jovian satellite Europa by the interactions of galactic cosmic rays and especially trapped Jovian protons. Cross sections for the production of cosmogenic nuclides were reported and plans made to measure additional cross sections. A new code, MCNPX, was used to numerically simulate the interactions of cosmic rays with matter and the subsequent production of cosmogenic nuclides. A review was written about studies of extraterrestrial matter using cosmogenic radionuclides. Several other projects were done. Results are reviewed here with references to my recent publications for details.

  10. Water-module interaction studies

    NASA Technical Reports Server (NTRS)

    Mon, G.; Wen, L.; Ross, R., Jr.

    1988-01-01

    Mechanisms by which moisture enters photovoltaic modules and techniques for reducing such interactions are reported. Results from a study of the effectiveness of various module sealants are given. Techniques for measuring the rate and quantity of moisture ingress are discussed. It is shown that scribe lines and porous frit bridging conductors provide preferential paths for moisture ingress and that moisture diffusion by surface/interfacial paths is considerably more rapid than diffusion by bulk paths, which implies that thin-film substrate and supersubstrate modules are much more vulnerable to moist environments than are bulk-encapsulated crystalline-silicon modules. Design approaches that reduce moisture entry are discussed.

  11. Water-module interaction studies

    NASA Astrophysics Data System (ADS)

    Mon, G.; Wen, L.; Ross, R., Jr.

    Mechanisms by which moisture enters photovoltaic modules and techniques for reducing such interactions are reported. Results from a study of the effectiveness of various module sealants are given. Techniques for measuring the rate and quantity of moisture ingress are discussed. It is shown that scribe lines and porous frit bridging conductors provide preferential paths for moisture ingress and that moisture diffusion by surface/interfacial paths is considerably more rapid than diffusion by bulk paths, which implies that thin-film substrate and supersubstrate modules are much more vulnerable to moist environments than are bulk-encapsulated crystalline-silicon modules. Design approaches that reduce moisture entry are discussed.

  12. Influence of gold(I) complexes involving adenine derivatives on major drug-drug interaction pathway.

    PubMed

    Dvořák, Zdeněk; Novotná, Aneta; Vančo, Ján; Trávníček, Zdeněk

    2013-12-01

    A series of considerably anti-inflammatory active gold(I) mixed-ligand complexes, involving the benzyl-substituted derivatives of N6-benzyladenine (HLn) and triphenylphosphine (PPh3) as ligands and having the general formula [Au(Ln)(PPh3)]·xH2O (1-4; n=1-4 and x=0-1), was evaluated for the ability to influence the expression of CYP1A1/2 and CYP3A4 and transcriptional activity of glucocorticoid (GR) and aryl hydrocarbon (AhR) receptors in primary human hepatocytes and HepG2 cells. In both tests, evaluating the ability of the complexes to modulate the expression of CYP1A1, CYP1A2 and CYP3A4 in primary human hepatocytes and influence the transcriptional activity of AhR and GR in the reporter cell lines, no negative influence on the major drug-metabolizing cytochrome P450 isoenzymes and their signaling pathway (through GR and AhR receptors) was observed. These positive findings revealed another substantial evidence that could lead to utilization of the complexes as effective and relatively safe drugs for the treatment of hard-to-treat inflammation-related diseases, such as rheumatoid arthritis, comparable or even better than clinically used gold-containing drug Auranofin. PMID:24157406

  13. Arc-cathode interaction study

    NASA Technical Reports Server (NTRS)

    Zhou, X.; Heberlein, J.

    1992-01-01

    Insufficient electrode life and uncertainties in that life are major problems hampering the development in many plasma application areas which make use of plasma torches, arc heaters, and arc jet thrusters. In spite of a considerable amount of work published dealing with arc-cathode phenomena, our present understanding is still incomplete because different physical phenomena dominate for different combinations of experimental parameters. The objective of our present research project is to gain a better understanding of the behavior of arc-cathode surface interaction over a wide range of parameters, and furthermore to develop guidelines for better thermal design of the electrode and the selection of materials. This report will present the research results and progress obtained on the arc-cathode interaction studies at the University of Minnesota. It includes results which have been obtained under programs other than the NASA funded program. Some of the results have been submitted in an informal interim progress report, and all of the results have been presented in a seminar during a visit to the NASA Lewis Research Center on October 16, 1992.

  14. Theoretical studies of molecular interactions

    SciTech Connect

    Lester, W.A. Jr.

    1993-12-01

    This research program is directed at extending fundamental knowledge of atoms and molecules including their electronic structure, mutual interaction, collision dynamics, and interaction with radiation. The approach combines the use of ab initio methods--Hartree-Fock (HF) multiconfiguration HF, configuration interaction, and the recently developed quantum Monte Carlo (MC)--to describe electronic structure, intermolecular interactions, and other properties, with various methods of characterizing inelastic and reaction collision processes, and photodissociation dynamics. Present activity is focused on the development and application of the QMC method, surface catalyzed reactions, and reorientation cross sections.

  15. Airframe noise component interaction studies

    NASA Technical Reports Server (NTRS)

    Fink, M. R.; Schlinker, R. H.

    1979-01-01

    Acoustic wind tunnel tests were conducted to examine the noise-generating processes of an airframe during approach flight. The airframe model was a two-dimensional wing section, to which highlift leading and trailing edge devices and landing gear could be added. Far field conventional microphones were utilized to determine component spectrum levels. An acoustic mirror directional microphone was utilized to examine noise source distributions on airframe components extended separately and in combination. Measured quantities are compared with predictions inferred from aircraft flyover data. Aeroacoustic mechanisms for each airframe component are identified. Component interaction effects on total radiated noise generally were small (within about 2 dB). However, some interactions significantly redistributed the local noise source strengths by changing local flow velocities and turbulence levels. Possibilities for noise reduction exist if trailing edge flaps could be modified to decrease their noise radiation caused by incident turbulent flow.

  16. Drug-Drug Molecular Salt Hydrate of an Anticancer Drug Gefitinib and a Loop Diuretic Drug Furosemide: An Alternative for Multidrug Treatment.

    PubMed

    Thorat, Shridhar H; Sahu, Sanjay Kumar; Patwadkar, Manjusha V; Badiger, Manohar V; Gonnade, Rajesh G

    2015-12-01

    A 1:1 monohydrate salt containing gefitinib, an orally administrated chemotherapy treatment for lung and breast cancers and furosemide, a loop diuretic drug, commonly used in the treatment of hypertension and edema, has been prepared. The molecular salt crystallized in triclinic P-1 space group. The C-O bond lengths (~1.26 Å) in the COOH group show that proton transfer has occurred from furosemide to morpholine moiety of the gefitinib suggesting cocrystal to be ionic. The morpholine moiety of the gefitinib showed significant conformational change because of its involvement in conformation dictating the strong N-H···O hydrogen bonding interaction. The strong hydrogen bonding interaction between gefitinib and furosemide places their benzene rings in stacking mode to facilitate the generation of π-stack dimers. The neighboring dimers are bridged to each other via water molecule through N-H···O, C-H···O, O-H···N, and O-H···O interactions. The remarkable stability of the salt hydrate could be attributed to the strong hydrogen bonding interactions in the crystal structure. Interestingly, release of water from the lattice at 140°C produced new anhydrous salt that has better solubility and dissolution rate than salt hydrate. The drug-drug molecular salt may have some bearing on the treatment of patient suffering from anticancer and hypertension. PMID:26413799

  17. Study of Compton vs. Photoelectric Interactions

    SciTech Connect

    Gronberg, J B; Johnson, S C; Lange, D J; Wright, D M; Beiersdorfer, P

    2004-07-09

    We have studied how often incoming photons interact via a Compton interaction and/or a photoelectric interaction as a function of energy and detector material Results are using a 1m{sup 3} detector, and discrete energy photons from 0.1 MeV up to 10 MeV. Essentially all of the lower energy photons interact at least once in a detector of this size. This is not the case at higher energies. Each detector, photon energy combination was simulated with 2000 photons.

  18. Interactive Videodisc Case Studies for Medical Education

    PubMed Central

    Harless, William G.; Zier, Marcia A.; Duncan, Robert C.

    1986-01-01

    The TIME Project of the Lister Hill National Center for Biomedical Communications is using interactive videodisc, microprocessor and voice recognition technology to create patient simulations for use in the training of medical students. These interactive case studies embody dramatic, lifelike portrayals of the social and medical conditions of a patient and allow uncued, verbal intervention by the student for independent clinical decisions.

  19. Why study gene-environment interactions?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    PURPOSE OF REVIEW: We examine the reasons for investigating gene-environment interactions and address recent reports evaluating interactions between genes and environmental modulators in relation to cardiovascular disease and its common risk factors. RECENT FINDINGS: Studies focusing on smoking, phy...

  20. Nephrotoxicity of vancomycin and drug interaction study with cilastatin in rabbits.

    PubMed Central

    Toyoguchi, T; Takahashi, S; Hosoya, J; Nakagawa, Y; Watanabe, H

    1997-01-01

    The nephrotoxic effects of vancomycin hydrochloride (VCM) and the potential drug-drug interaction with cilastatin sodium (CS) were examined in rabbits. The aim of the study was to measure the possible dose-related suppressive effects or elimination by cilastatin of the adverse reactions generated by vancomycin in the kidneys of rabbits. To clarify the interactions of these two drugs, we examined the nephrotoxicity and pharmacokinetics of VCM in the rabbit when administered alone and when coadministered with CS. VCM administered alone (300 mg/kg of body weight as an intravenous bolus; n = 5) caused typical symptoms of nephrotoxicity, such as increases in serum creatinine and blood urea nitrogen (BUN) levels, as well as morphological changes in the kidneys. A lack of such signs of nephrotoxicity was observed in the groups administered VCM plus CS (i.e., CS at 150 mg/kg plus VCM at 300 mg/kg or CS at 300 mg/kg plus VCM at 300 mg/kg, intravenous bolus; n = 5/group). At a reduced combination ratio of VCM plus CS (4:1 ratio, VCM at 300 mg/kg plus CS at 75 mg/kg, intravenous bolus; n = 5) some symptoms of nephrotoxicity induced by VCM were present, but the degree of this effect was much reduced and was significantly different from preadministration values by only modest increases of the BUN and N-acetyl-beta-D-glucosaminidase levels (P < 0.05). Overall clearance of VCM was accelerated by coadministration of CS and was found to be dose dependent upon CS. No changes in renal function values from the preadministration values were observed for animals receiving CS alone (300 mg/kg, intravenous bolus; n = 3). These results suggest that CS has the ability to reduce or eliminate in a dose-dependent manner the nephrotoxic effects caused by VCM administration in rabbits. PMID:9303398

  1. Pharmacokinetic drug interactions of the selective androgen receptor modulator GTx-024(Enobosarm) with itraconazole, rifampin, probenecid, celecoxib and rosuvastatin.

    PubMed

    Coss, Christopher C; Jones, Amanda; Dalton, James T

    2016-08-01

    GTx-024 (also known as enobosarm) is a first in class selective androgen receptor modulator being developed for diverse indications in oncology. Preclinical studies of GTx-024 supported the evaluation of several potential drug-drug interactions in a clinical setting. A series of open-label Phase I GTx-024 drug-drug interaction studies were designed to interrogate potential interactions with CYP3A4 inhibitor (itraconazole), a CYP3A4 inducer (rifampin), a pan-UGT inhibitor (probenecid), a CYP2C9 substrate (celecoxib) and a BCRP substrate (rosuvastatin). The plasma pharmacokinetics of GTx-024, its major metabolite (GTx-024 glucuronide), and each substrate were characterized in detail. Itraconazole administration had no effect on GTx-024 pharmacokinetics. Likewise, GTx-024 administration did not significantly change the pharmacokinetics of celecoxib or rosuvastatin. Rifampin administration had the largest impact on GTx-024 pharmacokinetics of any co-administered agent and reduced the maximal plasma concentration (Cmax) by 23 % and the area under the curve (AUC∞) by 43 %. Probenecid had a complex interaction with GTx-024 whereby both GTx-024 plasma levels and GTx-024 glucuronide plasma levels (AUC∞) were increased by co-administration of the UGT inhibitor (50 and 112 %, respectively). Overall, GTx-024 was well tolerated and poses very little risk of generating clinically relevant drug-drug interactions. PMID:27105861

  2. Enthalpic studies of xyloglucan-cellulose interactions.

    PubMed

    Lopez, Marie; Bizot, Hervé; Chambat, Gérard; Marais, Marie-France; Zykwinska, Agata; Ralet, Marie-Christine; Driguez, Hugues; Buléon, Alain

    2010-06-14

    We report a study of xyloglucan (XG)-cellulose interactions made possible by the preparation of various well-defined cellulosic and xyloglucosidic substrates. Bacterial microcrystalline cellulose (BMCC) as well as cellulose whiskers (CellWhisk) were used as cellulosic substrates. Xyloglucosidic substrates were obtained from Rubus cells and Tamarindus indica seeds. Different primary structure characteristics of XGs such as the backbone length and the nature of the side chains, as well as their repartition, were considered in order to examine the influence of the primary structure on their interaction capacity. Two complementary approaches were carried out: first, the determination of adsorption isotherms and its associated models, and second, an enthalpic study using isothermal titration calorimetry (ITC). This study highlighted that an increase of XG interaction capacity occurred with increasing XG molecular weight. Furthermore, we determined that a minimum of 12 glucosyl residues on the backbone is required to observe significant interactions. Moreover, both the presence of trisaccharidic side chains with fucosyl residues and an increase of unsubstituted glucosyl residues enhanced XG-cellulose interactions. The evolution of adsorption isotherms with temperature and ITC measurements showed that two different processes were occurring, one exothermic and one endothermic, respectively. Although the presence of an exothermic interaction mechanism has long been established, the presence of an endothermic interaction mechanism has never been reported. PMID:20433133

  3. Study of physical interaction mefenamic acid - isonicotinamide

    NASA Astrophysics Data System (ADS)

    Yuyun, Yonelian; Nugrahani, Ilma

    2015-09-01

    Solid-solid interaction in the form of physics and chemistry can occur in a combination of active ingredients with the active ingredient or active ingredients with excipients in a pharmaceutical preparation. Physical interactions can be classified into physical interaction system eutectic, peritectic, and molecular compounds based on the phase diagram of a mixture of two-component systems. The physical interaction between mefenamic acid and isonicotinamide not been reported previously. This study aims to examine the type of interaction of mefenamic acid (MA) with isonicotinamide (INA) and its interaction with the isolation methods by solvent drop grinding as the simplest method and easy to do. PXRD data showed the interaction of MA:INA mixture contained no new peaks, so the indicated MA:INA only form of eutectic interaction. There was founded new endothermic peak for DTA data at 149.5°C (SDG-Ethanol) and 148.4°C (SDG-EtAct). The results of infrared spectroscopy analysis indicated a shift in the NH stretch 3367 cm-1 to 3359 cm-1; and 3185 cm-1 to 3178 cm-1.

  4. Protein-Inhibitor Interaction Studies Using NMR

    PubMed Central

    Ishima, Rieko

    2015-01-01

    Solution-state NMR has been widely applied to determine the three-dimensional structure, dynamics, and molecular interactions of proteins. The designs of experiments used in protein NMR differ from those used for small-molecule NMR, primarily because the information available prior to an experiment, such as molecular mass and knowledge of the primary structure, is unique for proteins compared to small molecules. In this review article, protein NMR for structural biology is introduced with comparisons to small-molecule NMR, such as descriptions of labeling strategies and the effects of molecular dynamics on relaxation. Next, applications for protein NMR are reviewed, especially practical aspects for protein-observed ligand-protein interaction studies. Overall, the following topics are described: (1) characteristics of protein NMR, (2) methods to detect protein-ligand interactions by NMR, and (3) practical aspects of carrying out protein-observed inhibitor-protein interaction studies. PMID:26361636

  5. Space Operations Center: Shuttle interaction study

    NASA Technical Reports Server (NTRS)

    1981-01-01

    The implication of using the Shuttle with the Space Operation Center (SOC), including constraints that the Shuttle will place upon the SOC design. The study identifies the considerations involved in the use of the Shuttle as a part of the SOC concept, and also identifies the constraints to the SOC imposed by the Shuttle in its interactions with the SOC, and on the design or technical solutions which allow satisfactory accomplishment of the interactions.

  6. SPIV study of two interactive fire whirls

    NASA Astrophysics Data System (ADS)

    Hartl, Katherine; Smits, Alexander

    2015-11-01

    Fire whirls are buoyancy-driven standing vortex structures that often form in forest fires. Capable of lifting and ejecting flaming debris, fire whirls can hasten the spread of fire lines and start fires in new places. Here we study the interaction of two jets in an externally applied circulation as an introduction to the study of two interacting fire whirls. To study this interaction we use two burner flames supplied with DME and induce swirl by entraining air through a split cylinder that surrounds both burners. Three components of velocity are measured using Stereo Particle Image Velocimetry both inside and outside the fire whirl core, at the base, midsection, and above the top of the fire whirls. The effects on the height and circulation on the distance between the burners, the rate of fuel supplied to the burners, and the gap size, are examined.

  7. Drug Interactions

    PubMed Central

    Tong Logan, Angela; Silverman, Andrew

    2012-01-01

    One of the most clinically significant complications related to the use of pharmacotherapy is the potential for drug-drug or drug-disease interactions. The gastrointestinal system plays a large role in the pharmacokinetic profile of most medications, and many medications utilized in gastroenterology have clinically significant drug interactions. This review will discuss the impact of alterations of intestinal pH, interactions mediated by phase I hepatic metabolism enzymes and P-glycoprotein, the impact of liver disease on drug metabolism, and interactions seen with commonly utilized gastrointestinal medications. PMID:22933873

  8. A Study of Leadership as Interaction.

    ERIC Educational Resources Information Center

    Krueger, Jo Ann

    The study examined leadership in schools as interaction between principals and teachers. The leadership process was conceptualized as the exercise of influence. The concept of ascriptive status was utilized to describe women as atypical and men as typical principals. Teachers responded to protocols depicting leader influence and cultural status.…

  9. NACASETAC BAY: AN INTERACTIVE CASE STUDY

    EPA Science Inventory

    This interactive case study or "game" was created to provide a "hands on" experience in the application of a weight of evidence approach to sediment assessment. The game proceeds in two phases. In each phase the players work together as a group. A scenario is presented, and the g...

  10. Hadronic Weak Interaction Studies at the SNS

    NASA Astrophysics Data System (ADS)

    Fomin, Nadia

    2016-03-01

    Neutrons have been a useful probe in many fields of science, as well as an important physical system for study in themselves. Modern neutron sources provide extraordinary opportunities to study a wide variety of physics topics. Among them is a detailed study of the weak interaction. An overview of studies of the hadronic weak (quark-quark) as well as semi-leptonic (quark-lepton) interactions at the Spallation Neutron Source (SNS) is presented. These measurements, done in few-nucleon systems, are finally letting us gain knowledge of the hadronic weak interaction without the contributions from nuclear effects. Forthcoming results from the NPDGamma experiment will, due to the simplicity of the neutron, provide an unambiguous measurement of the long range pion-nucleon weak coupling (often referred to as hπ), which will finally test the theoretical predictions. Results from NPDGamma and future results from the n +3 He experiment will need to be complemented by additional measurements to completely describe the hadronic weak interaction.