Association between Sex Differences and the Pharmacokinetics of Repaglinide among a Malaysian Population

This study was conducted to evaluate the effect of sex differences on the pharmacokinetics of repaglinide in healthy subjects. One hundred twenty one healthy volunteers (61 male and 60 female; aged 18 - 50 years) were included in the study. Subjects were administered a single 4-mg repaglinide oral dose. Blood samples were taken at 0, 30, 60, 120, 180 and 240 min. Serum repaglinide levels were determined by a high-performance liquid chromatography (HPLC) method. Subjects were also genotyped by polymerase chain reactions - restriction fragment length polymorphisms (PCR-RFLP) for CYP3A4*4, *5 and *18 alleles and by an allele-specific multiplex PCR for CYP2C8*2, *3, *4 and *5 alleles. The pharmacokinetics of repaglinide were comparable between male and female subjects. The mean clearance (CL) of repaglinide was 16.0% lower (p = 0.03), the mean area under the serum concentration-time curve (AUC) was 12.8% higher (p = 0.04) and the peak serum concentration (Cmax) was 13.2% higher (p = 0.03) in females compared to male subjects. The mean rate of elimination (kel) and mean CL of repaglinide were 47.67% (p = 0.03) higher and 29.25% (p = 0.03) higher, respectively, in male subjects having CYP2C8*5 allele compared to female subjects. We also found that the mean half-life (t1/2) of repaglinide was 42.43% higher (p = 0.03), and the mean AUC was 35.83% higher (p = 0.03) in female subjects when compared to the male subjects having CYP2C8*5 allele. Sex differences significantly influence the pharmacokinetics of repaglinide.