Gemfibrozil is a strong inactivator of CYP2C8 in very small multiple doses

Clin Pharmacol Ther. 2012 May;91(5):846-55. doi: 10.1038/clpt.2011.313.


Therapeutic doses of gemfibrozil cause mechanism-based inactivation of CYP2C8 via formation of gemfibrozil 1-O-β-glucuronide. We investigated the extent of CYP2C8 inactivation caused by three different doses of gemfibrozil twice dailyfor 5 days, using repaglinide as a probe drug, in 10 healthy volunteers. At the end of this 5-day regimen, there were dose-dependent increases in the area under the plasma concentration–time curve from 0 to infinity (AUC0–∞) of repaglinide by3.4-, 5.5-, and 7.0-fold corresponding to 30, 100, and 600 mg of gemfibrozil, respectively, as compared with the control phase (P < 0.001). On the basis of a mechanism-based inactivation model involving gemfibrozil 1-O-β-glucuronide, a gemfibrozil dose of 30 mg twice daily was estimated to inhibit CYP2C8 by >70% and 100 mg twice daily was estimated to inhibit it by >90%. Hence, gemfibrozil is a strong inactivator of CYP2C8 even in very small, subtherapeutic, multiple doses. Administration of small gemfibrozil doses may be useful in optimizing the pharmacokinetics of CYP2C8 substrate drugs and in reducing the formation of their potentially toxic metabolites via CYP2C8.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Blood Glucose / analysis
  • Carbamates / metabolism
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Gemfibrozil / pharmacokinetics
  • Gemfibrozil / pharmacology*
  • Genotype
  • Glucuronides / metabolism
  • Humans
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters / genetics
  • Piperidines / metabolism


  • Blood Glucose
  • Carbamates
  • Enzyme Inhibitors
  • Glucuronides
  • Liver-Specific Organic Anion Transporter 1
  • Organic Anion Transporters
  • Piperidines
  • SLCO1B1 protein, human
  • repaglinide
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Gemfibrozil