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 (Cmax ) 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 Cmax 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 Cmax 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 Cmax 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.