Inhibitory effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes

Aims  To determine the effects of verapamil and diltiazem on simvastatin metabolism in human liver microsomes and to compare their inhibitory potencies and CYP3A4 inactivation parameters with those reported previously for mibefradil. Methods  Simvastatin metabolism was investigated in human liver microsomes in the presence and absence of verapamil or diltiazem (0.1–250 µ m ). Kinetics of CYP3A4 inactivation by verapamil and diltiazem were determined using testosterone as the substrate. Results  When verapamil was coincubated with simvastatin, I C 50 values ranged from 23 to 26 µ m for all major metabolites. The I C 50 values ranged from 4.8 to 5.6 µ m on preincubation of verapamil for 30 min in the presence of an NADPH‐generating system. Corresponding I C 50 values for diltiazem ranged from110–127 µ m and from 21–27 µ m , respectively. Verapamil and diltiazem inhibited testosterone 6β‐hydroxylation in a time‐ and concentration‐dependent manner, key features of mechanism‐based inactivation. Values for the inactivation parameters k inact and K I were 0.15 ± 0.04 min −1 (mean ± s.d.) and 2.9 ± 0.6 µ m , respectively, for verapamil and 0.07 ± 0.01 min −1 and 3.3 ± 1.5 µ m , respectively, for diltiazem. Conclusions  The I C 50 values for coincubation of verapamil and diltiazem were 46‐ and 220‐fold higher, respectively, than those reported previously for mibefradil, and 16‐ and 71‐fold higher, respectively, for preincubation. Thus, the results of this study suggest that verapamil and diltiazem are less likely than mibefradil to cause acute drug interactions with simvastatin in vivo . However, verapamil and diltiazem are moderate mechanism‐based inhibitors of CYP3A4 and therefore may still cause significant inhibition of simvastatin metabolism in vivo during chronic therapy.