Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates.
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Filppula AM, Laitila J, Neuvonen PJ, Backman JT
Potent mechanism-based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates.
Br J Pharmacol. 2012 Apr;165(8):2787-98. doi: 10.1111/j.1476-5381.2011.01732.x.
- PubMed ID
- 22014153 [ View in PubMed]
- Abstract
BACKGROUND AND PURPOSE: Imatinib, 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 RESULTS: Inhibition 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 microM 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 microM, respectively, and midazolam 1'-hydroxylation with a K(i) of 23.3 and 18.1 microM 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.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Imatinib Cytochrome P450 3A4 Protein Humans NoSubstrateInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAcenocoumarolImatinib Imatinib may increase the anticoagulant activities of Acenocoumarol. ImatinibPhenytoin The metabolism of Imatinib can be increased when combined with Phenytoin. ImatinibPentobarbital The metabolism of Imatinib can be increased when combined with Pentobarbital. ImatinibCarbamazepine The metabolism of Imatinib can be increased when combined with Carbamazepine. ImatinibMitotane The metabolism of Imatinib can be increased when combined with Mitotane.