Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations

Aims To determine the effects of mibefradil on the metabolism in human live r microsomal preparations of the HMG-CoA reductase inhibitors simvastatin, lovastatin. atorvastatin, cerivastatin and fluvastatin. Methods Metabolism of the above five statins (0.5, 5 or 10 mu M), as well a s of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in huma n liver microsomal preparations in the presence and absence of mibefradil ( 0.1-50 mu M) Results Mibefradil inhibited, in a concentration-dependent fashion, the met abolism of the four statins (simvastatin, lovastatin, atorvastatin and ceri vastatin) known to be substrates for CYP3A. The potency of inhibition was s uch that the IC50 values (<1 mu M) for inhibition of all of the CYP3A subst rates fell within the therapeutic plasma concentrations of mibefradil, and was comparable with that of ketoconazole. However, the inhibition by mibefr adil, unlike that of ketoconazole, was at least in part mechanism-based. Ba sed on the kinetics of its inhibition of hepatic testosterone 6 beta-hydrox ylase activity, mibefradil was judged to be a powerful mechanism-based inhi bitor of CYP3A4/5, with values for K-inactivation, K-i and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 mi n(-1), 2.3 mu M and 1.7, respectively. In contrast to the results with subs trates of CYP3A, metabolism of fluvastatin, a substrate of CYP2C8/9, and th e hydroxylation of tolbutamide, a functional probe for CYP2C8/9, were not i nhibited by mibefradil. Conclusions Mibefradil, at therapeutically relevant concentrations, strongl y sup pressed the metabolism in human liver microsomes of simvastatin, lova statin, atorvastatin and cerivastatin through its inhibitory effects on CYP 3A4/5, while the effects of mibefradil on fluvastatin, a substrate for CYP2 C8/9, were minimal in this system. Since mibefradil is a potent mechanism-b ased inhibitor of CYP3A4/5, it is anticipated that clinically significant d rug-drug interactions will likely ensue when mibefradil is coadministered w ith agents which are cleared primarily by CYP3A-mediated pathways.