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Vol. 29, Issue 11, 1359-1361, November 2001
Department of Clinical Pharmacology, 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, with
Ki (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.
University of Helsinki;
and Helsinki University Central Hospital,
Helsinki, Finland
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