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Drug Metabolism & Disposition

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Rapid CommunicationShort Communication

Gemfibrozil Is a Potent Inhibitor of Human Cytochrome P450 2C9

Xia Wen, Jun-Sheng Wang, Janne T. Backman, Kari T. Kivistö and Pertti J. Neuvonen
Drug Metabolism and Disposition November 2001, 29 (11) 1359-1361;
Xia Wen
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Jun-Sheng Wang
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Janne T. Backman
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Kari T. Kivistö
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Pertti J. Neuvonen
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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] + 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.

Footnotes

  • This study was supported by grants from the Helsinki University Central Hospital Research Fund and the National Technology Agency of Finland (Tekes).

  • Abbreviation used is::
    CYP
    cytochrome P450
    • Received May 1, 2001.
    • Accepted July 10, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 29 (11)
Drug Metabolism and Disposition
Vol. 29, Issue 11
1 Nov 2001
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Rapid CommunicationShort Communication

Gemfibrozil Is a Potent Inhibitor of Human Cytochrome P450 2C9

Xia Wen, Jun-Sheng Wang, Janne T. Backman, Kari T. Kivistö and Pertti J. Neuvonen
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1359-1361;

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Rapid CommunicationShort Communication

Gemfibrozil Is a Potent Inhibitor of Human Cytochrome P450 2C9

Xia Wen, Jun-Sheng Wang, Janne T. Backman, Kari T. Kivistö and Pertti J. Neuvonen
Drug Metabolism and Disposition November 1, 2001, 29 (11) 1359-1361;
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