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

J Honkalammi1, M Niemi, P J Neuvonen

  • 1Department of Clinical Pharmacology, University of Helsinki and HUSLAB, Helsinki University Central Hospital, Helsinki, Finland.

Clinical Pharmacology and Therapeutics
|April 5, 2012
PubMed

Insights

Gemfibrozil inactivates CYP2C8, an enzyme crucial for drug metabolism. Even small, subtherapeutic doses significantly inhibit this enzyme, impacting drug pharmacokinetics and metabolite formation.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Enzyme Kinetics

Background:

  • Therapeutic gemfibrozil doses cause mechanism-based inactivation of CYP2C8 through gemfibrozil 1-O-β-glucuronide formation.
  • CYP2C8 plays a vital role in metabolizing various drugs.

Purpose of the Study:

  • To investigate the extent of CYP2C8 inactivation by different doses of gemfibrozil.
  • To assess the impact of subtherapeutic gemfibrozil doses on CYP2C8 activity using repaglinide as a probe drug.

Main Methods:

  • Ten healthy volunteers received varying doses of gemfibrozil (30, 100, 600 mg twice daily for 5 days) or placebo.
  • Repaglinide pharmacokinetics, including area under the plasma concentration–time curve (AUC0–∞), were measured.
  • A mechanism-based inactivation model was employed to estimate CYP2C8 inhibition.

Main Results:

  • Dose-dependent increases in repaglinide AUC0–∞ were observed: 3.4-fold (30 mg), 5.5-fold (100 mg), and 7.0-fold (600 mg) compared to the control phase (P < 0.001).
  • Estimated CYP2C8 inhibition was >70% with 30 mg twice daily and >90% with 100 mg twice daily.
  • Gemfibrozil demonstrated potent CYP2C8 inactivation even at subtherapeutic doses.

Conclusions:

  • Gemfibrozil is a potent inactivator of CYP2C8, effective even at low, subtherapeutic, multiple doses.
  • Administering small gemfibrozil doses could optimize pharmacokinetics of CYP2C8 substrates and reduce toxic metabolite formation.

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