Effects of cytochrome P450 oxidoreductase genotypes on the pharmacokinetics of amlodipine in healthy Korean subjects. Issue 5 (5th March 2020)

• Record Type: Journal Article
• Authors: Han, Ji Min; Yee, Jeong; Chung, Jee Eun; Lee, Kyung Eun; Park, Kyungsoo; Gwak, Hye Sun
• Is Part Of: Molecular genetics & genomic medicine. Volume 8:Issue 5(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-03-05
• Subjects: amlodipine -- CYP3A -- pharmacokinetics -- POR polymorphism; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1201
• Languages: English
• ISSNs: 2324-9269

Abstract

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. Abstract : Our study identified a novel SNP of the POR gene, which affected amlodipine metabolism and may reduce interindividual variation in response to amlodipine. Rs4732511 and rs7796654 SNPs of the POR gene showed statistically significant difference in the Cmax of amlodipine. After adjusting for CYP3A effects, rs4732511 was significantly associated with the difference in Cmax value.