Dose-Dependent Interaction between Gemfibrozil and Repaglinide in Humans: Strong Inhibition of CYP2C8 with Subtherapeutic Gemfibrozil Doses

Abstract

ABSTRACT:Gemfibrozil 1-O-␤-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 doseproportional increase in the area under the curve of gemfibrozil and its glucuronide. The gemfibrozil-repaglinide interaction could be mainly explained by gemfibrozil 1-O-␤-glucuronide concentration-dependent, mechanism-based inhibition of CYP2C8, with a minor contribution by competitive inhibition of organic aniontransporting polypeptide 1B1 at the highest gemfibrozil dose. The findings are consistent with ϳ50% 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.

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…8-, 4.5-, 6.7-, and 8.3-fold compared with placebo, respectively (Fig. 8;Honkalammi et al, 2011a). Also after multiple doses of gemfibrozil (30, 100, or 600 mg twice daily for 5 days), the exposure to repaglinide increased dose dependently, but the greatest AUC increase did not exceed that observed after the single 900 mg gemfibrozil dose (Honkalammi et al, 2012).…”

Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

“…In vitro f m,CYP2C8 of pitavastatin, pioglitazone, and cerivastatin were reported to be 0.0, 0.68, and 0.61, respectively (Fujino et al, 2003;Shitara et al, 2004;Jaakkola et al, 2006). By contrast, f m,CYP2C8 for repaglinide are various: 0.41-0.71 from in vitro experiments (Kajosaari et al, 2005a;Säll et al, 2012) and 0.80-0.89 from in vivo data with modeling (Honkalammi et al, 2011b(Honkalammi et al, , 2012Kudo et al, 2013). We used in vitro f m,CYP2C8 for the prediction to apply a unified method for all the substrates.…”

Clopidogrel Markedly Increases Plasma Concentrations of CYP2C8 Substrate Pioglitazone

“…It should be noted that CYP2C8 inhibition by clopidogrel probably takes place quite rapidly, despite the timedependent mechanism . Also the inactivation of CYP2C8 by gemfibrozil (via formation of an acyl glucuronide metabolite) is a rapid process, as indicated by a 90% decrease in the AUC of a CYP2C8-dependent metabolite, and a nearly maximum increase in the AUC of the CYP2C8 substrate repaglinide when ingested 1 hour after 600 mg of gemfibrozil (Honkalammi et al, 2011). Theoretically, a prolonged absorption or an increased distribution volume of pioglitazone, together with its impaired metabolism, could also explain the unchanged C max despite the increased AUC 0-' .…”