Potent mechanism‐based inhibition of CYP3A4 by imatinib explains its liability to interact with CYP3A4 substrates

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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 thesein vivointeractions, we investigated the reversible and time‐dependent inhibitory effects of imatinib and its main metabolite N‐desmethylimatinib on CYP2C8 and CYP3A4/5in vitro.EXPERIMENTAL APPROACH: Amodiaquine N‐deethylation and midazolam 1′‐hydroxylation were used as marker reactions for CYP2C8 and CYP3A4/5 activity. Direct, IC50‐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 variablesKIandkinactwere 14.3 µM and 0.072 min−1respectively. In direct inhibition experiments, imatinib and N‐desmethylimatinib inhibited amodiaquine N‐deethylation with aKiof 8.4 and 12.8 µM, respectively, and midazolam 1′‐hydroxylation with aKiof 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 negligiblein vivo.CONCLUSIONS AND IMPLICATIONS: Imatinib is a potent mechanism‐based inhibitor of CYP3A4in vitroand 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 biotransformationin vivothan previously proposed.

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