A. Tornio, A. M. Filppula, O. Kailari, M. Neuvonen, T. H. Nyrönen, T. Tapaninen, P. J. Neuvonen, M. Niemi, J. T. Backman; University of Helsinki, Department of Clinical Pharmacology, Helsinki, Finland

BACKGROUND: Cerivastatin and repaglinide are substrates of CYP2C8, CYP3A4, and OATP1B1. An increased risk of rhabdomyolysis in patients using cerivastatin with clopidogrel has been reported, warranting further studies on clopidogrel interactions.
METHODS: Nine healthy volunteers received clopidogrel 300 mg on day 1, followed by 75 mg daily for two days or placebo in a cross-over study. Repaglinide was given 1 h after clopidogrel intake on days 1 and 3, and after placebo. The effects of clopidogrel and its metabolites on CYP2C8 and CYP3A4 were studied in vitro. A physiologically-based pharmacokinetic model was constructed in Simcyp and computational docking simulations were performed.
RESULTS: In humans, the AUC(0-∞) of repaglinide was increased 5.1- and 3.9-fold compared to control on days 1 and 3 of the clopidogrel treatment (P<0.001). In vitro, clopidogrel acyl-β-D-glucuronide was as a potent time-dependent inhibitor of CYP2C8. A physiologically based pharmacokinetic model indicated that inactivation of CYP2C8 by clopidogrel glucuronide leads to uninterrupted 60-85% inhibition of CYP2C8 during daily clopidogrel treatment. Computational modeling resulted in docking of clopidogrel acyl-β-D-glucuronide at the CYP2C8 active site with its thiophene moiety close to heme.
CONCLUSION: Clopidogrel markedly increases the plasma concentrations of repaglinide due to strong inhibition