Effects of cytochrome P450 oxidoreductase genotypes on the pharmacokinetics of amlodipine in healthy Korean subjects

Abstract

Background The aim of this study was to investigate the effects of P450 oxidoreductase (POR) genetic polymorphisms on the pharmacokinetic parameters of amlodipine. Methods After a single 10-mg dose of amlodipine administration, 25 healthy male subjects completed genotyping for 12 single nucleotide polymorphisms (SNPs) of the POR genes, cytochrome P450 (CYP)3A4 g.25343G>A (CYP3A4*1G), and CYP3A5 g.12083G>A (CYP3A5*3). Stratified analysis and in silico analysis to predict the possible effects of given variants on splicing were performed. Results The maximum blood concentration (C-max) of amlodipine in carriers of g.57332T>C and g.56551G>A SNPs of the POR gene was statistically significantly different. In addition, T-allele carriers of g.57332T>C had a 21% higher C-max than those with the CC genotype (p = .007). Subjects who carried the wild-type g.56551G>A allele also had a 1.12-fold significantly higher C-max than subjects with mutant-type homozygous carriers (p = .033). In stratified analyses, g.57332T>C was significantly associated with a 1.3-fold increase in C-max value in T-allele carriers compared with subjects with the CC genotype in CYP3A4 and CYP3A5 expressers. POR g.57332T>C increased the score above the threshold in both ESEfinder 3.0 and HSF 3.1. Conclusion This study identified a novel SNP of the POR gene, which affected amlodipine metabolism and may reduce interindividual variation in responses to amlodipine.