Backman JT, Honkalammi J, Neuvonen M, Kurkinen KJ, Tornio A, Niemi M, Neuvonen PJ
CYP2C8 Activity Recovers Within 96 Hours After Gemfibrozil Dosing: Estimation of CYP2C8 Half-life Using Repaglinide as an In Vivo Probe. [JOURNAL ARTICLE]
Drug Metab Dispos 2009 Sep 22.
Gemfibrozil 1-O-beta-glucuronide is a mechanism-based inhibitor of cytochrome P450 (CYP) 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using repaglinide as a probe drug, in order to estimate the in vivo turn-over half-life of CYP2C8. In a randomized 5-phase crossover study, 9 healthy volunteers ingested 0.25 mg repaglinide alone or after different time intervals following a 3-day treatment with gemfibrozil 600 mg twice daily. The AUC(0-infinity) of repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared to the control phase when it was administered 1, 24, 48 or 96 h after 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-beta-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 turn-over half-life of CYP2C8 was estimated to average 22 +/- 6 h (mean +/- S.D.). In summary, CYP2C8 activity is recovered gradually during days 1-4 after gemfibrozil discontinuation, which should be considered when planning CYP2C8 substrate dosing. 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.
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