Abstract

The in vitro inhibitory effects of gemfibrozil on cytochrome P450 (CYP) 1A2 (phenacetin O-deethylation), CYP2A6 (coumarin 7-hydroxylation), CYP2C9 (tolbutamide hydroxylation), CYP2C19 (S-mephenytoin 4′-hydroxylation), CYP2D6 (dextromethorphan O-deethylation), CYP2E1 (chlorzoxazone 6-hydroxylation), and CYP3A4 (midazolam 1′-hydroxylation) activities were examined using pooled human liver microsomes. The in vivo drug interactions of gemfibrozil were predicted in vitro using the [I]/([I] + K_i) values. Gemfibrozil strongly and competitively inhibited CYP2C9 activity, with a K_i (IC₅₀) value of 5.8 (9.6) μM. In addition, gemfibrozil exhibited somewhat smaller inhibitory effects on CYP2C19 and CYP1A2 activities, withK_i (IC₅₀) values of 24 (47) μM and 82 (136) μM, respectively. With concentrations up to 250 μM, gemfibrozil showed no appreciable effect on CYP2A6, CYP2D6, CYP2E1, and CYP3A4 activities. Based on [I]/([I] +K_i) values calculated using peak total (or unbound) plasma concentration of gemfibrozil, 96% (56%), 86% (24%), and 64% (8%) inhibition of the clearance of CYP2C9, CYP2C19, and CYP1A2 substrates could be expected, respectively. In conclusion, gemfibrozil inhibits the activity of CYP2C9 at clinically relevant concentrations, and this is the likely mechanism by which gemfibrozil interacts with CYP2C9 substrate drugs, such as warfarin and glyburide. Gemfibrozil may also impair clearance of CYP2C19 and CYP1A2 substrates, but inhibition of other CYP isoforms is unlikely.