ArticleBritish journal of pharmacology2012
Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates.
Article in British journal of pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 2 of them syntheses that pooled it.
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Who cites it
40 citing papers in PubMed, 2 syntheses or guidelines pooled it, 96 citations in OpenAlex.
- Evaluating the Safety of Combining Tyrosine Kinase Inhibitors with Anticoagulants in Chronic Myeloid Leukemia: A Systematic Review.Oncology · 2026Pooled 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
- Drug-drug interactions in targeted cancer therapies: a focus on tyrosine kinase inhibitors.Expert review of clinical pharmacology · 2025Review
- Influence of genetic variants of imatinib on pharmacokinetics and recurrence-free survival in postoperative patients with gastrointestinal stromal tumor.European journal of clinical pharmacology · 2025Article
- Interindividual variability in imatinib metabolism in human liver microsomes and primary human hepatocytes: Impact of CYP2C8 and CYP3A phenotypes.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- BCR::ABL1-positive chronic myeloid leukaemia in a scenario of a remote diagnosis of JAK2-V617F-mutated polycythemia vera: a single patient experience with imatinib and ruxolitinib combination therapy.Annals of hematology · 2025Article
- Phenoconversion andHepatology forum · 2025Review
- Influence of CYP2C8*3 and ABCG2 C421A genetic polymorphisms on trough concentration and molecular response of imatinib in Egyptian patients with chronic myeloid leukemia.Cancer chemotherapy and pharmacology · 2024Article
- Imatinib pharmacokinetics and creatine kinase levels in chronic myeloid leukemia patients: implications for therapeutic response and monitoring.European journal of clinical pharmacology · 2024Observational
- Physiologically based pharmacokinetic modeling of imatinib and N-desmethyl imatinib for drug-drug interaction predictions.CPT: pharmacometrics & systems pharmacology · 2024Article
- High-Risk Chronic Lymphocytic Leukemia Complicating the Course of Imatinib-Treated Chronic Myeloid Leukemia: Successful Disease Management With Dual Tyrosine Kinase Inhibition.Case reports in hematology · 2024Article
- Application of physiologically based pharmacokinetic modeling to understand real-world outcomes in patients receiving imatinib for chronic myeloid leukemia.Pharmacology research & perspectives · 2023Observational
- Article
- Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia.Handbook of experimental pharmacology · 2023Review
- Cytochromes P450 2C8 and 3A Catalyze the Metabolic Activation of the Tyrosine Kinase Inhibitor Masitinib.Chemical research in toxicology · 2022Article
- Bioactivation and reactivity research advances - 2021 year in review.Drug metabolism reviews · 2022Review
- Physiologically based pharmacokinetic model predictions of natural product-drug interactions between goldenseal, berberine, imatinib and bosutinib.European journal of clinical pharmacology · 2022Article
- Article
- Risk assessment and molecular mechanism study of drug-drug interactions between rivaroxaban and tyrosine kinase inhibitors mediated by CYP2J2/3A4 and BCRP/P-gp.Frontiers in pharmacology · 2022Article
- Genetic Polymorphisms in CYP2C19 Cause Changes in Plasma Levels and Adverse Reactions to Anlotinib in Chinese Patients With Lung Cancer.Frontiers in pharmacology · 2022Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
background and purposeImatinib, a cytochrome P450 2C8 (CYP2C8) and CYP3A4 substrate, markedly increases plasma concentrations of the CYP3A4/5 substrate simvastatin and reduces hepatic CYP3A4/5 activity in humans. Because competitive inhibition of CYP3A4/5 does not explain these in vivo interactions, we investigated the reversible and time-dependent inhibitory effects of imatinib and its main metabolite N-desmethylimatinib on CYP2C8 and CYP3A4/5 in vitro. EXPERIMENTAL APPROACH: Amodiaquine N-deethylation and midazolam 1'-hydroxylation were used as marker reactions for CYP2C8 and CYP3A4/5 activity. Direct, IC(50) -shift, and time-dependent inhibition were assessed with human liver microsomes. KEY
resultsInhibition of CYP3A4 activity by imatinib was pre-incubation time-, concentration- and NADPH-dependent, and the time-dependent inactivation variables K(I) and k(inact) were 14.3 µM and 0.072 in(-1) respectively. In direct inhibition experiments, imatinib and N-desmethylimatinib inhibited amodiaquine N-deethylation with a K(i) of 8.4 and 12.8 µM, respectively, and midazolam 1'-hydroxylation with a K(i) of 23.3 and 18.1 µM respectively. The time-dependent inhibition effect of imatinib was predicted to cause up to 90% inhibition of hepatic CYP3A4 activity with clinically relevant imatinib concentrations, whereas the direct inhibition was predicted to be negligible in vivo. CONCLUSIONS AND IMPLICATIONS: Imatinib is a potent mechanism-based inhibitor of CYP3A4 in vitro and this finding explains the imatinib-simvastatin interaction and suggests that imatinib could markedly increase plasma concentrations of other CYP3A4 substrates. Our results also suggest a possibility of autoinhibition of CYP3A4-mediated imatinib metabolism leading to a less significant role for CYP3A4 in imatinib biotransformation in vivo than previously proposed.
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