학술논문
Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene
Document Type
Academic Journal
Author
Source
Clinical Pharmacology & Therapeutics. Nov 01, 2002 72(5):584-594
Subject
Language
English
ISSN
0009-9236
Abstract
OBJECTIVE: We investigated the effect of polymorphisms in the P-glycoprotein (P-gp) MDR1 gene on steady-state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P-gp expression in the human intestine. METHODS: Eight healthy male homozygous carriers of the wild-type exon-26 3435C>T (CC), 8 heterozygous subjects (CT), and 8 homozygous mutant (TT) subjects were selected. Seven further MDR1 polymorphisms were determined. Digoxin was administered orally twice daily on the first two study days; on days 3 to 5, 0.25 mg was given in the morning. On day 5, kinetic parameters were analyzed for genotype-phenotype and haplotype-phenotype relationships. RESULTS: The area under the plasma concentration-time curve from time zero to 4 hours [AUC(0-4)] (P = .042) and Cmax (P = .043) values of digoxin were higher in subjects with the 3435TT genotype than in those with the 3435CC. No influence of other single nucleotide polymorphisms (SNPs) on digoxin parameters was detected. Comparison of genotypes deduced from SNPs 2677G>T (exon 21) and 3435C>T revealed significant differences for AUC(0-4) (P = .034) and Cmax (P = .039), which were substantiated by haplotype analysis. Haplotype 12 (2677G/3435T), which had a frequency of 13.3% in a randomly drawn Caucasian sample (n = 687), was associated (Mann-Whitney test) with higher AUC(0-4) values (P = .009) than were found in noncarriers (mean ± SD, 5.7 ± 0.9 μg · h/L [n = 7] versus 4.8 ± 0.9 μg · h/L [n = 17]). Haplotype 11 (2677G/3435C) had lower AUC(0-4) values (P = .013) compared with those of noncarriers (mean ± SD, 4.7 ± 0.9 μg · h/L [n = 16] versus 5.6 ± 0.9 μg · h/L [n = 8]). Results of haplotype analysis match data of other MDR1 studies. CONCLUSION: Haplotype 12 codes for high values of AUC(0-4) and Cmax of orally administered digoxin. Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1 phenotype. (Clin Pharmacol Ther 2002;72:584-94.)