Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide

Abstract

Background and aimsGemfibrozil, and particularly its combination with itraconazole, greatly increases the area under the plasma concentration-time curve [AUC(0, • )] and response to the cytochrome P450 (CYP) 2C8 and 3A4 substrate repaglinide. In vitro , gemfibrozil is a more potent inhibitor of CYP2C9 than of CYP2C8. Our aim was to investigate the effects of the gemfibrozil-itraconazole combination on the pharmacokinetics and pharmacodynamics of another meglitinide analogue, nateglinide, which is metabolized by CYP2C9 and CYP3A4. MethodsIn a randomized crossover study with two phases, nine healthy subjects took 600 mg gemfibrozil and 100 mg itraconazole (first dose 200 mg) twice daily or placebo for 3 days. On day 3, they ingested a single 30-mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 12 h. ResultsDuring the gemfibrozil-itraconazole phase, the AUC(0, • ) and C max of nateglinide were 47% (range 23-74%; P < 0.0001) and 30% (range -8% to 104%; P = 0.0146) higher than during the placebo phase, respectively, but the t max and t 1/2 of nateglinide remained unchanged. The combination of gemfibrozil and itraconazole had no effect on the formation of the M7 metabolite of nateglinide but impaired its elimination. The blood glucose response to nateglinide was not significantly changed by coadministration of gemfibrozil and itraconazole. ConclusionsThe combination of gemfibrozil and itraconazole has only a limited influence on the pharmacokinetics of nateglinide. This is in marked contrast to the substantial effect of this combination on the pharmacokinetics of repaglinide. The findings suggest that in vivo gemfibrozil, probably due to its metabolites, is a much more potent inhibitor of CYP2C8 than of CYP2C9.

Effect of fluvastatin, lovastatin, nifedipine and verapamil on the systemic exposure of nateglinide in rabbits

“…Rifampicin reduced nateglinide area under the plasma concentration-time curve (AUC) by 25% and decreased its half-life, but it did not significantly alter the blood glucose-lowering response to nateglinide administration [20]. Co-administration of gemfibrozil and itraconazole with nateglinide produced the same results [21]. In these studies, the pharmacokinetic alterations did not have pharmacodynamic consequences, probably because nateglinide, in a 'therapeutic window' of plasma concentrations, saturates the b-cell K ATP channels.…”

Effect of Gemfibrozil on the Metabolism of Brivaracetam In Vitro and in Human Subjects

“…In vitro/in vivo extrapolation would predict a maximal 34% decrease in a 2C9-mediated reaction [1/(1 ϩ I/K i )], with much less effect, if any, on the other isoforms. Consistent with these predictions, gemfibrozil increases the AUC of some CYP2C9 substrates such as nateglinide (ϩ47%; gemfibrozil coadministered with itraconazole) (Niemi et al, 2005), glimepiride (ϩ23%) (Niemi et al, 2001), and rosuvastatin (ϩ88%) (Schneck et al, 2004). The larger effect on rosuvastatin is thought to be due to additional non-P450-related mechanisms (i.e., inhibition of organic anion-transporting polypeptide 1B1-mediated hepatic uptake).…”

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…The AUC of nateglinide was increased only by 1.5-fold by 3 days' pretreatment with therapeutic doses of both gemfibrozil and itraconazole (Niemi et al, 2005a). Thus, neither CYP2C8 nor CYP3A4 has a substantial significance to the pharmacokinetics of nateglinide.…”