A comparison of the effects of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors on the CYP3A4-dependent oxidation of mexazolam in vitro.

HMG-CoA reductase inhibitors can be divided into two groups: those administered as the prodrug, i.e., the lactone form (e.g., simvastatin and lovastatin), and those administered in the active form, i.e., the acid form (e.g., pravastatin, fluvastatin, atorvastatin, and cerivastatin). In this study, the influence of the lactone and acid forms of various HMG-CoA reductase inhibitors on metabolism by CYP3A4, a major cytochrome P450 isoform in human liver, was investigated by determining the in vitro inhibition constant (K(i) value) using an antianxiety agent, mexazolam, as a probe substrate. In human liver microsomes, all the lactone forms tested inhibited the oxidative metabolism of mexazolam more strongly than did the acid forms, which have lower partition coefficient (logD(7.0)) values. In addition, the degree of inhibition of mexazolam metabolism tended to increase with an increasing logD(7.0) value of the HMG-CoA reductase inhibitors among the lactone and acid forms. In particular, pravastatin (acid form), which has the lowest logD(7.0) value, failed to inhibit CYP3A4 activity. Taking account of the lipophilicity of the inhibitors, in conjunction with the CYP3A4-inhibitory activity, could be very useful in predicting drug interactions between substrates of CYP3A4 and HMG-CoA reductase inhibitors.