Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions.

Cerivastatin and repaglinide are substrates of cytochrome P450 (CYP)2C8, CYP3A4, and organic anion-transporting polypeptide (OATP)1B1. A recent study revealed an increased risk of rhabdomyolysis in patients using cerivastatin with clopidogrel, warranting further studies on clopidogrel interactions. In healthy volunteers, repaglinide area under the concentration-time curve (AUC(0-∞)) was increased 5.1-fold by a 300-mg loading dose of clopidogrel and 3.9-fold by continued administration of 75 mg clopidogrel daily. In vitro, we identified clopidogrel acyl-ß-D-glucuronide as a potent time-dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel acyl-ß-D-glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl-ß-D-glucuronide at the CYP2C8 active site with its thiophene moiety close to heme. The results indicate that clopidogrel is a strong CYP2C8 inhibitor via its acyl-ß-D-glucuronide and imply that glucuronide metabolites should be considered potential inhibitors of CYP enzymes.

Gemfibrozil impairs imatinib absorption and inhibits the CYP2C8-mediated formation of its main metabolite.

Cytochrome P450 (CYP) 3A4 is considered the most important enzyme in imatinib biotransformation. In a randomized, crossover study, 10 healthy subjects were administered gemfibrozil 600 mg or placebo twice daily for 6 days, and imatinib 200 mg on day 3, to study the significance of CYP2C8 in imatinib pharmacokinetics. Unexpectedly, gemfibrozil reduced the peak plasma concentration (Cmax) of imatinib by 35% (P < 0.001). Gemfibrozil also reduced the Cmax and area under the plasma concentration-time curve (AUC0-∞) of N-desmethylimatinib by 56 and 48% (P < 0.001), respectively, whereas the AUC0-∞ of imatinib was unaffected. Furthermore, gemfibrozil reduced the Cmax/plasma concentration at 24 h (C24 h) ratios of imatinib and N-desmethylimatinib by 44 and 17% (P < 0.05), suggesting diminished daily fluctuation of imatinib plasma concentrations during concomitant use with gemfibrozil. Our findings indicate significant participation of CYP2C8 in the metabolism of imatinib in humans, and support involvement of an intestinal influx transporter in imatinib absorption.

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

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 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.