Effect of theCYP2C8Genotype on the Pharmacokinetics and Pharmacodynamics of Repaglinide

Abstract

ABSTRACT:The pharmacokinetics of repaglinide shows pronounced interindividual variability, for which several reasons have been considered, including interactions with drugs inhibiting CYP2C8 and CYP2C8 genetic polymorphism. However, existing data on the role of genetic polymorphisms in repaglinide disposition are not fully consistent. We studied the effect of CYP2C8*3 on the pharmacokinetics and pharmacodynamics of repaglinide in 29 healthy whites carrying CYP2C8*3/*3 (n ‫؍‬ 4), CYP2C8*1/*3 (n ‫؍‬ 13), or CYP2C8*1/*1 (n ‫؍‬ 12). After administration of a single dose of 2 mg of repaglinide, blood was drawn for assessment of repaglinide pharmacokinetics and pharmacodynamics, and urine was collected to quantify the main repaglinide metabolites M1 and M4 up to 24 h postdose. Repaglinide and the metabolites were quantified by liquid chromatography-tandem mass spectrometry. Considering only the effect of CYP2C8*3, the mean (95% confidence interval) area under the time-concentration curve . In addition, for urinary metabolite excretion and pharmacodynamic parameters, i.e., mean and maximal changes in insulin and glucose concentration, no significant differences between CYP2C8 genotypes were observed. Likewise, no significant effects on the pharmacokinetics or pharmacodynamics were observed when AUC and C max of repaglinide were corrected for reported effects of the SLCO1B1 521T>C polymorphism or when both polymorphisms were tested in a two-way ANOVA. In conclusion, CYP2C8*3 does not seem to play an important role in the pharmacokinetics and pharmacodynamics of repaglinide given in a therapeutic dose.

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.…”

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…In this and later studies, individuals with the CYP2C8*1/*3 genotype have had an approximately 40-50% lower AUC of a subtherapeutic dose of repaglinide than individuals with the CYP2C8*1/*1 genotype (Niemi et al, 2005b,c). However, this finding has not been fully replicated in studies with higher repaglinide doses (Bidstrup et al, 2006;Tomalik-Scharte et al, 2011), suggesting that the effect of CYP2C8*3 allele on repaglinide pharmacokinetics may be dose dependent.…”

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

“…6(a)) and subsequently the blood glucose level was lower in subjects with c.521T>C or c.-11187G>A in SLCO1B1, whereas the plasma concentration was lower and the blood glucose level was higher in subjects with *1b allele. [53][54][55] Although the reason for the decreased function of OATP1B1 by c.-11187G>A is unknown, it is frequently linked to c.521T>C and c.521T>C may be a direct cause of functional change of OATP1B1. SLCO1B1 c.521T>C also increased the glucose lowering effect by nateglinide.…”