ArticlePharmaceutical research2012
Drug-drug interaction potential of marketed oncology drugs: in vitro assessment of time-dependent cytochrome P450 inhibition, reactive metabolite formation and drug-drug interaction prediction.
Article in Pharmaceutical research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Evaluation of utility of pharmacokinetic studies in phase I trials of two oncology drugs.Clinical cancer research : an official journal of the American Association for Cancer Research · 2013Pooled it
- Erlotinib treatment induces cytochrome P450 3A activity in non-small cell lung cancer patients.British journal of clinical pharmacology · 2019Trial
- A multiparametric in vitro strategy for small molecule drug-induced liver injury risk mitigation in early drug development.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Prediction of Drug-Drug Interactions for Highly Plasma Protein Bound Compounds.The AAPS journal · 2024Article
- Stability Characterization of the Novel Anti-Cancer HM-10/10 HDL-Mimetic Peptide.International journal of molecular sciences · 2023Article
- The role of cytochrome P450 3A4-mediated metabolism in sorafenib and lapatinib hepatotoxicity.Livers · 2023Article
- Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib.Chemical research in toxicology · 2022Article
- Biotransformation novel advances - 2021 year in review.Drug metabolism reviews · 2022Review
- Bioactivation and reactivity research advances - 2021 year in review.Drug metabolism reviews · 2022Review
- Reversible Mechanisms of Enzyme Inhibition and Resulting Clinical Significance.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Case Study 11: Considerations for Enzyme Mapping Experiments-Interaction Between the Aldehyde Oxidase Inhibitor Hydralazine and Glutathione.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Irreversible Enzyme Inhibition Kinetics and Drug-Drug Interactions.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Potential role of drug metabolizing enzymes in chemotherapy-induced gastrointestinal toxicity and hepatotoxicity.Expert opinion on drug metabolism & toxicology · 2020Review
- Time-dependent enzyme inactivation: Numerical analyses of in vitro data and prediction of drug-drug interactions.Pharmacology & therapeutics · 2020Review
- Preincubation With Everolimus and Sirolimus Reduces Organic Anion-Transporting Polypeptide (OATP)1B1- and 1B3-Mediated Transport Independently of mTOR Kinase Inhibition: Implication in Assessing OATP1B1- and OATP1B3-Mediated Drug-Drug Interactions.Journal of pharmaceutical sciences · 2019Article
- Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity.British journal of pharmacology · 2019Article
- Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4.The AAPS journal · 2019Article
- Role of Cytochrome P450 Enzymes in the Metabolic Activation of Tyrosine Kinase Inhibitors.International journal of molecular sciences · 2018Review
- Cytochromes P450 1A2 and 3A4 Catalyze the Metabolic Activation of Sunitinib.Chemical research in toxicology · 2018Article
- Improved Predictions of Drug-Drug Interactions Mediated by Time-Dependent Inhibition of CYP3A.Molecular pharmaceutics · 2018Article
Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeTo evaluate 26 marketed oncology drugs for time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes. Evaluate TDI-positive drugs for potential to generate reactive intermediates. Assess clinical drug-drug interaction (DDI) risk using static mechanistic models.
methodsHuman liver microsomes and CYP-specific probes were used to assess TDI in a dilution shift assay followed by generation of K(I) and k(inact). Reactive metabolite trapping studies were performed with stable label probes. Static mechanistic model was used to predict DDI risk using a 1.25-fold AUC increase as a cut-off for positive DDI.
resultsNegative TDI across CYPs was observed for 13/26 drugs; the rest were time-dependent inhibitors of, predominantly, CYP3A. The k(inact)/K(I) ratios for 11 kinase inhibitors ranged from 0.7 to 42.2 ml/min/μmol. Stable label trapping agent-drug conjugates were observed for ten kinase inhibitors. DDI predictions gave no false negatives, one true negative, four false positives and three true positives. The magnitude of DDI was overestimated irrespective of the inhibitor concentration selected.
conclusions13/26 oncology drugs investigated showed TDI potential towards CYP3A, formation of reactive metabolites was also observed. An industry standard static mechanistic model gave no false negative predictions but did not capture the modest clinical DDI potential of kinase inhibitors.
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