Abstract
Gemfibrozil 1-O-β-glucuronide inactivates CYP2C8 irreversibly. We investigated the effect of gemfibrozil dose on CYP2C8 activity in humans using repaglinide as a probe drug. In a randomized, five-phase crossover study, 10 healthy volunteers ingested 0.25 mg of repaglinide 1 h after different doses of gemfibrozil or placebo. Concentrations of plasma repaglinide, gemfibrozil, their metabolites, and blood glucose were measured. A single gemfibrozil dose of 30, 100, 300, and 900 mg increased the area under the concentration-time curve of repaglinide 1.8-, 4.5-, 6.7-, and 8.3-fold (P < 0.001), and its peak concentration 1.4-, 1.7-, 2.1-, and 2.4-fold (P < 0.05), compared with placebo, respectively. Gemfibrozil pharmacokinetics was characterized by a slightly more than dose-proportional increase in the area under the curve of gemfibrozil and its glucuronide. The gemfibrozil-repaglinide interaction could be mainly explained by gemfibrozil 1-O-β-glucuronide concentration-dependent, mechanism-based inhibition of CYP2C8, with a minor contribution by competitive inhibition of organic anion-transporting polypeptide 1B1 at the highest gemfibrozil dose. The findings are consistent with ∼50% inhibition of CYP2C8 already with a single 30-mg dose of gemfibrozil and >95% inhibition with 900 mg. In clinical drug-drug interaction studies, a single 900-mg dose of gemfibrozil can be used to achieve nearly complete inactivation of CYP2C8.
Footnotes
This work was supported by grants from the Helsinki University Central Hospital Research Fund and the Sigrid Jusélius Foundation, Finland.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040931.
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ABBREVIATIONS:
- P450
- cytochrome P450
- AUC
- area under the concentration-time curve
- Ch,u/Cp,tot
- the hepatocyte (unbound) to plasma (total) concentration ratio
- Cmax
- peak concentration
- fm,CYP2C8
- the fraction of repaglinide dose metabolized by CYP2C8
- ft,OATP1B1
- fraction of dose transported by OATP1B1
- ke
- the first-order degradation rate constant
- KI
- the inhibitor concentration that supports half the maximal rate of enzyme inactivation
- kinact
- maximal rate of inactivation
- SLCO1B1
- solute carrier organic anion transporter family, member 1B1 gene encoding for OATP1B1
- Tmax
- time to peak concentration
- CV
- coefficient of variation
- AUCi/AUCc
- fold change in total area under the concentration-time curve of repaglinide
- Cavg,10h
- average plasma concentration calculated from AUC0–10h
- kel
- elimination rate constant
- AUC0–3 h
- area under the plasma concentration-time curve from time 0 to 3 h
- AUC0–9 h
- area under the plasma concentration-time curve from time 0 to 9 h.
- Received May 29, 2011.
- Accepted July 21, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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