Abstract
Gemfibrozil 1-O-β-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after gemfibrozil and gemfibrozil 1-O-β-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of repaglinide metabolism continued up to 48 h after gemfibrozil administration. Based on the recovery of repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 ± 6 h (mean ± S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8.
Footnotes
This study was supported by 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.109.029728
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- P450
- cytochrome P450
- OATP
- organic anion transporting polypeptide
- AUC
- area under the concentration-time curve
- CV
- coefficient of variation
- Cmax
- peak concentration
- t1/2
- (elimination) half-life
- ke
- elimination rate constant
- CL/F
- oral clearance
- C0
- concentration at time 0
- tmax
- time to peak concentration
- FDCL
- fractional decrement in the oral clearance.
- Received July 30, 2009.
- Accepted September 21, 2009.
- Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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