Abstract
The pharmacokinetics of repaglinide is subject to a pronounced inter-individual 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 Caucasians carrying CYP2C8*3/*3 (n=4), CYP2C8*1/*3 (n=13) or CYP2C8*1/*1 (n=12). Following 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 24hours post-dose. Repaglinide and the metabolites were quantified by LC-MS/MS. Considering only the effect of CYP2C8*3, the mean (95%CI) AUC0-∞ of repaglinide was 72.4 (6.7-138.0), 97.2 (59.2-135.2), 105.9 (52.4-159.3) ng*mL-1*h and Cmax 38.5 (3.8-73.2), 50.3 (37.5-63.0), 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 ANOVA). Also 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 dynamics 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.
- Received October 27, 2010.
- Accepted January 18, 2011.
- The American Society for Pharmacology and Experimental Therapeutics