PT  - JOURNAL ARTICLE
AU  - Dorota Tomalik-Scharte
AU  - Uwe Fuhr
AU  - Martin Hellmich
AU  - Dorothee Frank
AU  - Oxana Doroshyenko
AU  - Alexander Jetter
AU  - Julia C. Stingl
TI  - Effect of the <em>CYP2C8</em> Genotype on the Pharmacokinetics and Pharmacodynamics of Repaglinide
AID  - 10.1124/dmd.110.036921
DP  - 2011 May 01
TA  - Drug Metabolism and Disposition
PG  - 927--932
VI  - 39
IP  - 5
4099  - http://dmd.aspetjournals.org/content/39/5/927.short
4100  - http://dmd.aspetjournals.org/content/39/5/927.full
SO  - Drug Metab Dispos2011 May 01; 39
AB  - 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 (AUC) from zero to infinity of repaglinide was 72.4 (6.7–138.0), 97.2 (59.2–135.2), and 105.9 (52.4–159.3) ng · ml−1 · h and the maximal concentration (Cmax) was 38.5 (3.8–73.2), 50.3 (37.5–63.0), and 60.3 (31.5–89.1) ng · ml−1, respectively, in carriers of CYP2C8*3/*3, CYP2C8*1/*3, and CYP2C8*1/*1 [p > 0.05, one-way analysis of variance (ANOVA)]. 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 Cmax 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.