Effects of OCT2 c.602C > T genetic variant on the pharmacokinetics of lamivudine.

1. The renal excretion of organic cation drugs, including lamivudine, is mostly mediated by OCT2 in vitro. To date, three putatively relevant single nucleotide polymorphisms (SNPs), including c.596C > T (p.Thr199Ile), c.602C > T (p.Thr201Met), and c.808G > T (p.Ala270Ser) have been observed in Asians. The effects of the SLC22A2 c.602C > T genetic variant on the pharmacokinetics of lamivudine were studied with healthy Korean subjects. 2. Nineteen healthy subjects carrying either the SLC22A2 c.602CC (n = 12) or c.602CT (n = 7) genotype volunteered for this study. A single 100 mg dose of lamivudine was orally administered to each subject. Blood samples were collected for up to 24 h and the plasma concentrations of lamivudine were measured using liquid chromatography-tandem mass spectrometry. 3. The mean plasma concentration-time profiles of lamivudine in the c.602CC and c.602CT genotype groups were similar. There was no significant difference in the overall pharmacokinetic parameters of lamivudine between the c.602CC and c.602CT genotype groups. Differences in renal clearance and tubular secretion clearance were also not statistically significant between the two genotype groups. 4. The SLC22A2 c.602C > T genotype did not affect the pharmacokinetics of lamivudine in humans in vivo. Dose adjustment of lamivudine is not required between individuals with c.602CC and c.602CT genotypes.

Frequency of CYP2C9 alleles in Koreans and their effects on losartan pharmacokinetics.

AIM: CYP2C9 enzyme metabolizes numerous clinically important drugs. The aim of this study is to investigate the frequencies of CYP2C9 genotypes and the effects of selected alleles on losartan pharmacokinetics in a large sample of the Korean population. METHODS: The CYP2C9 gene was genotyped in 1796 healthy Korean subjects. CYP2C9 alleles (CYP2C9*1, *2, *3 and *13 alleles) were measured using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and direct sequencing assay. The enzymatic activity of each CYP2C9 genotype was evaluated using losartan as the substrate. RESULTS: The frequencies of CYP2C9*1, *3 and *13 allele were 0.952 (95% confidence interval 0.945-0.959), 0.044 (95% CI 0.037-0.051) and 0.005 (95% CI 0.003-0.007), respectively. The frequencies of the CYP2C9*1/*1, *1/*3, *1/*13 and *3/*3 genotypes were 0.904 (95% CI 0.890-0.918), 0.085 (95% CI 0.072-0.098), 0.009 (95% CI 0.005-0.013) and 0.001 (95% CI 0.000-0.002), respectively. In the pharmacokinetics studies, the AUC(0-∞) of losartan in CYP2C9*3/*3 subjects was 1.42-fold larger than that in CYP2C9*1/*1 subjects, and the AUC(0-∞) of E-3174, a more active metabolite of losartan, in CYP2C9*3/*3 subjects was only 12% of that in CYP2C9*1/*1 subjects. CONCLUSION: The results confirmed the frequencies of CYP2C9 genotypes in a large cohort of Koreans, and detected the CYP2C9*3/*3 genotype. CYP2C9*3/*3 subjects metabolized much less losartan into E-3174 than CYP2C9*1/*1 subjects.