Drug-Metabolizing Enzymes, Transporters, and Drug-Drug Interactions

2011 ◽  
pp. 83-149 ◽  
Author(s):  
Steven W. Louie ◽  
Magang Shou
Keyword(s):  
Drug Interactions ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes

scholarly journals In Vitro Evaluation of the Drug Interaction Potential of Doravirine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Kelly Bleasby ◽  
Kerry L. Fillgrove ◽  
Robert Houle ◽  
Bing Lu ◽  
Jairam Palamanda ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Organic Anion Transporter ◽  
Reversible Inhibitor ◽  
Drug Metabolizing Enzymes ◽  
Cancer Resistance ◽  
Metabolizing Enzymes ◽  
Anion Transporter ◽  
Major Drug

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus type 1 infection. In vitro studies were conducted to assess the potential for drug interactions with doravirine via major drug-metabolizing enzymes and transporters. Kinetic studies confirmed that cytochrome P450 3A (CYP3A) plays a major role in the metabolism of doravirine, with ∼20-fold-higher catalytic efficiency for CYP3A4 versus CYP3A5. Doravirine was not a substrate of breast cancer resistance protein (BCRP) and likely not a substrate of organic anion transporting polypeptide 1B1 (OATP1B1) or OATP1B3. Doravirine was not a reversible inhibitor of major CYP enzymes (CYP1A2, -2B6, -2C8, -2C9, -2C19, -2D6, and -3A4) or of UGT1A1, nor was it a time-dependent inhibitor of CYP3A4. No induction of CYP1A2 or -2B6 was observed in cultured human hepatocytes; small increases in CYP3A4 mRNA (≤20%) were reported at doravirine concentrations of ≥10 μM but with no corresponding increase in enzyme activity. In vitro transport studies indicated a low potential for interactions with substrates of BCRP, P-glycoprotein, OATP1B1 and OATP1B3, the bile salt extrusion pump (BSEP), organic anion transporter 1 (OAT1) and OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion 1 (MATE1) and MATE2K proteins. In summary, these in vitro findings indicate that CYP3A4 and CYP3A5 mediate the metabolism of doravirine, although with different catalytic efficiencies. Clinical trials reported elsewhere confirm that doravirine is subject to drug-drug interactions (DDIs) via CYP3A inhibitors and inducers, but they support the notion that DDIs (either direction) are unlikely via other major drug-metabolizing enzymes and transporters.

scholarly journals How Can Drug Metabolism and Transporter Genetics Inform Psychotropic Prescribing?

2020 ◽  
Vol 11 ◽  
Author(s):  
Beatriz Carvalho Henriques ◽  
Esther H. Yang ◽  
Diego Lapetina ◽  
Michael S. Carr ◽  
Vasyl Yavorskyy ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Drug Interactions ◽  
Psychiatric Disorders ◽  
Genetic Variants ◽  
Clinical Utility ◽  
Future Research ◽  
Drug Metabolizing Enzymes ◽  
Research Focus ◽  
Metabolizing Enzymes ◽  
Clinical Associations

Many genetic variants in drug metabolizing enzymes and transporters have been shown to be relevant for treating psychiatric disorders. Associations are strong enough to feature on drug labels and for prescribing guidelines based on such data. A range of commercial tests are available; however, there is variability in included genetic variants, methodology, and interpretation. We herein provide relevant background for understanding clinical associations with specific variants, other factors that are relevant to consider when interpreting such data (such as age, gender, drug–drug interactions), and summarize the data relevant to clinical utility of pharmacogenetic testing in psychiatry and the available prescribing guidelines. We also highlight areas for future research focus in this field.

scholarly journals Molecular pharmacokinetic determinants of anticancer kinase inhibitors in humans

2011 ◽  
pp. 77-92
Author(s):  
Julie Scholler ◽  
Dominique Leveque
Keyword(s):  
Drug Interactions ◽  
Nuclear Receptors ◽  
Kinase Inhibitors ◽  
Drug Disposition ◽  
Clinical Impact ◽  
Published Data ◽  
Drug Metabolizing Enzymes ◽  
Orphan Nuclear Receptors ◽  
Metabolizing Enzymes ◽  
Molecular Determinants

This review presents the published data regarding the molecular determinants (drug metabolizing enzymes, drug transporters and orphan nuclear receptors) of approved anticancer kinase inhibitors pharmacokinetics in humans. The clinical impact of these determinants (drug disposition and drug–drug interactions) is also discussed.

scholarly journals Disease-drug and drug-drug interaction in COVID-19: risk and assessment

2020 ◽  
Author(s):  
Devendra Kumar ◽  
Neerja Trivedi
Keyword(s):  
Drug Interactions ◽  
Antiviral Agent ◽  
Morbidity Rate ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Safety And Efficacy ◽  
Mortality And Morbidity ◽  
Global Pandemic ◽  
Inflammatory State ◽  
Seriously Ill Patients

COVID-19 is announced as a global pandemic in 2020. The emergent outbreak of COVID-19 prompted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps spreading globally. Its mortality and morbidity rate are rapidly increasing, and medication options are still limited. A patient’s immune response plays a pivotal role in the pathogenesis of COVID-19. Hyperinflammatory state may sparks significant imbalances in transporters and drug metabolizing enzymes, and subsequent alteration of drug pharmacokinetics that may result in unexpected therapeutic response. The present scenario has accounted the requirement for therapeutic opportunities to relive and overcome this pandemic. Despite the fact, the diminishing developments of COVID-19, there is no drug still approved to have significant effects with no side effect. Based on the evidence, many antiviral and anti-inflammatory drugs have been authorized by the Food and Drug Administration (FDA) to treat the COVID-19 patients even though not knowing the possible drug-drug interactions. Hydroxychloroquine is the first medicine chosen for the treatment of disease. Remdesivir, favipiravir, and molnupiravir are deemed the most hopeful antiviral agent; by improving health of infected patients. The dexamethasone saved the lives of seriously ill patients. Many randomized and controlled clinical trials are taking place to further corroborate these agent’s safety and efficacy in handling COVID-19. The current review summarizes the involvement of drug transporters and drug metabolizing enzymes for the existing drugs and gives the opinion on the potential drug-drug interactions in an inflammatory state. This may permit the individualization of these drugs thereby enhancing the safety and efficacy.

Herb-Drug Interactions and Hepatotoxicity

2019 ◽  
Vol 20 (4) ◽  
pp. 275-282 ◽  
Author(s):  
Mohammad K. Parvez ◽  
Vikas Rishi
Keyword(s):  
Drug Interaction ◽  
Drug Interactions ◽  
Viral Hepatitis ◽  
Prescription Drugs ◽  
Herbal Remedies ◽  
Public Health Issue ◽  
Drug Metabolizing Enzymes ◽  
Metabolizing Enzymes ◽  
Pharmaceutical Industries ◽  
Underlying Mechanisms

Background: In recent times, herbals or phytomedicines have become very popular due to their global acceptance as a complementary and alternative remedy. While modern drugs are commercially available only after laboratory validations, clinical trials, as well as approval from drug regulatory authorities, majority of the marketed herbal products lack such scientific evidence of efficacy and safety. This results in herb or herb-drug interaction induced unfavorable clinical outcomes without crucial documentation on their temporal relations and concomitant use. Methods: An online literature search for peer-reviewed articles was conducted on the PubMed, Europe PMC, Medline and Google Scholar portals, using the phrases: complementary & alternative medicine, traditional Chinese medicine, herb-drug interaction, mechanisms of herb-drug interaction, herb-induced toxicity, herbal hepatotoxicity and causality, traditional medicine, viral hepatitis, etc. Results: The retrieved data showed that globally, patients are attracted to herbal remedies with the misconception that these are completely safe and therefore, use them simultaneously with prescription drugs. Notably, there exists a potential risk of herb-drug interactions leading to some adverse side effects, including hepatotoxicity. The toxicological effect of a drug or herb is due to the inhibition of drug metabolizing enzymes (e.g., cytochrome P450), including interactions with certain prescription drugs through various mechanisms. Several cases of hepatotoxicity due to use of herbals in viral hepatitis-related liver diseases have been recently reported. However, limited experimental data and clinical evidence on herbal pharmacokinetics hamper the evaluation and reporting of adverse reactions and the underlying mechanisms. Conclusion: Herb-drug interaction related morbidity is thus an emerging serious public health issue with broad implications for clinicians, pharmaceutical industries and health authorities. Nonetheless, despite increasing recognition of herb-drug interaction, a standard system for interaction prediction and evaluation is still nonexistent. This review article discusses the herb-drug interactions related hepatotoxicity and underlying mechanisms, including drug metabolizing enzymes and their regulation.

EVALUATION OF DRUG-DRUG INTERACTION IN THE HEPATOBILIARY AND RENAL TRANSPORT OF DRUGS

2005 ◽  
Vol 45 (1) ◽  
pp. 689-723 ◽  
Author(s):  
Yoshihisa Shitara ◽  
Hitoshi Sato ◽  
Yuichi Sugiyama
Keyword(s):  
Drug Interactions ◽  
Organic Anion ◽  
Renal Transport ◽  
Drug Metabolizing Enzymes ◽  
Organic Anion Transporters ◽  
Organic Anion Transporting Polypeptides ◽  
Metabolizing Enzymes ◽  
Anion Transporters ◽  
Degree Of Overlap

Recent studies have revealed the import role played by transporters in the renal and hepatobiliary excretion of many drugs. These transporters exhibit a broad substrate specificity with a degree of overlap, suggesting the possibility of transporter-mediated drug-drug interactions with other substrates. This review is an overview of the roles of transporters and the possibility of transporter-mediated drug-drug interactions. Among the large number of transporters, we compare the Ki values of inhibitors for organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs) and their therapeutic unbound concentrations. Among them, cephalosporins and probenecid have the potential to produce clinically relevant OAT-mediated drug-drug interactions, whereas cyclosporin A and rifampicin may trigger OATP-mediated ones. These drugs have been reported to cause drug-drug interactions in vivo with OATs or OATP substrates, suggesting the possibility of transporter-mediated drug-drug interactions. To avoid adverse consequences of such transporter-mediated drug-drug interactions, we need to be more aware of the role played by drug transporters as well as those caused by drug metabolizing enzymes.

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