RT Journal Article
SR Electronic
T1 Gemfibrozil Is a Potent Inhibitor of Human Cytochrome P450 2C9
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1359
OP 1361
VO 29
IS 11
A1 Wen, Xia
A1 Wang, Jun-Sheng
A1 Backman, Janne T.
A1 Kivistö, Kari T.
A1 Neuvonen, Pertti J.
YR 2001
UL http://dmd.aspetjournals.org/content/29/11/1359.abstract
AB 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] + Ki) values. Gemfibrozil strongly and competitively inhibited CYP2C9 activity, with a Ki (IC50) value of 5.8 (9.6) μM. In addition, gemfibrozil exhibited somewhat smaller inhibitory effects on CYP2C19 and CYP1A2 activities, withKi (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] +Ki) 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. The American Society for Pharmacology and Experimental Therapeutics