The impact of CYP2C8 polymorphism and grapefruit juice on the pharmacokinetics of repaglinide

Abstract

AimsThe primary aim of the study was to investigate the possible effect of the CYP2C8 * 3 allele and of grapefruit juice on the pharmacokinetics of repaglinide. Furthermore, the impact of a single dose of grapefruit juice on the pharmacokinetics of repaglinide in relation to dose. MethodsThirty-six healthy male subjects, genotyped for CYP2C8 * 3 (11 genotyped as CYP2C8 * 1/ * 3 , one as CYP2C8 * 3 /* 3 and 24 as CYP2C8 * 1/ * 1 ), participated in a randomized, cross-over trial. In the two phases, the subjects drank 300 mL water or 300 mL grapefruit juice, in randomized order, 2 h before administration of a single dose of either 0.25 mg or 2 mg repaglinide. ResultsNeither the mean AUC 0 −∞ (geometric mean ratio: 1.01; 95% CI: 0.93-1.1, P = 0.88) nor the mean C max (geometric mean ratio: 1.05; 95% CI: 0.94-1.2, P = 0.35) of repaglinide were statistically significantly different in the group carrying the CYP2C8 * 3 mutant allele compared with wild-types. Grapefruit juice caused a 19% decrease in the geometric mean ratio of the 3-hydroxyquinidine to quinidine ratio (difference: 0.81; 95% CI: 0.75-0.87, P < 0.0001), which was used as an index of CYP3A4 activity, and an increase in the mean AUC 0 −∞ of repaglinide (geometric mean ratio: 1.13; 95% CI: 1.04-1.2, P = 0.0048), but had no statistically significant effect on the t 1/2 . There was no statistically significant difference in blood glucose concentration in subjects who had or had not ingested grapefruit juice. The effect was more pronounced at the low dose of repaglinide (0.25 mg) than at the therapeutic dose of 2 mg. ConclusionsThe pharmacokinetics of repaglinide in subjects carrying the CYP2C8 * 3 mutant allele did not differ significantly from those in the wild-types. Grapefruit juice increased the bioavailability of repaglinide, suggesting significant intestinal elimination of the drug which was assumed to be primarily mediated by CYP3A4 in the gut.

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

“…It is noteworthy that the individual f m,CYP2C8 values of repaglinide and the extent of the interaction were greatest in the two carriers of the CYP2C8*3 allele. Although the number of subjects in the present study was too small to draw any definitive conclusions, this finding is consistent with previous studies in which CYP2C8*3 was associated with increased clearance of repaglinide (Niemi et al, 2003b(Niemi et al, , 2005 and argues against the lack of association reported in other studies (Bidstrup et al, 2006;Tomalik-Scharte et al, 2011). The estimated f t,OATP1B1 of repaglinide is also in line with previous pharmacogenetic studies.…”

“…The relative roles of CYP2C8 and CYP3A4 may be slightly different with higher 0.5-to 4-mg doses of repaglinide (Bidstrup et al, 2003(Bidstrup et al, , 2006Kajosaari et al, 2005a;Kalliokoski et al, 2008c). In any case, the consequences of CYP2C8 inhibition depend on the therapeutic index of the victim drug and the significance of CYP2C8 in its elimination.…”

Effect of theCYP2C8Genotype on the Pharmacokinetics and Pharmacodynamics of Repaglinide

“…Of note also is the fact that the repaglinide dose tested in both studies was clearly subclinical. Bidstrup et al (2006) also evaluated the role of the CYP2C8*3 polymorphism in the pharmacokinetics of repaglinide; however, they administered the drug in a clinically relevant dose of 2 mg. In this evaluation, the AUC and the maximal concentration of repaglinide did not differ significantly between 24 wild-type individuals and 12 carriers of the variant allele, one of whom was homozygous.…”

“…Niemi et al (2003bNiemi et al ( , 2005 found decreased (by 45-48%) AUC values of repaglinide in heterozygous carriers of the CYP2C8*3 variant allele, suggesting that it is related to a higher metabolic activity of the enzyme. On the other hand, the study by Bidstrup et al (2006) yielded no relevant differences in repaglinide pharmacokinetics with respect to this polymorphism.…”

CYP2C8 Activity Recovers within 96 Hours after Gemfibrozil Dosing: Estimation of CYP2C8 Half-Life Using Repaglinide as an in Vivo Probe

“…The formation of the main metabolite M2 and especially that of M4 is largely dependent on CYP2C8, whereas the less important M1 is mainly formed by CYP3A4 (Bidstrup et al, 2003;Kajosaari et al, 2005a,b). The plasma concentrations of repaglinide are considerably raised by inhibitors of CYP2C8 (Niemi et al, 2003;Kajosaari et al, 2005a;Bidstrup et al, 2006). Because of its sensitivity to CYP2C8 inhibition and its short half-life, repaglinide has been recommended as a probe drug for studying CYP2C8 activity (Huang et al, 2007).…”