Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene
Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene
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DOI：
10.1067/mcp.2002.129196
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发表时间：
2002-11-01
影响因子：
6.7
通讯作者：
Roots, I
中科院分区：
文献类型：
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作者：
Johne, A;Köpke, K;Roots, I
目的：我们研究了P-糖蛋白（P-gp）MDR 1基因多态性对高加索人地高辛稳态药代动力学的影响。根据早期的数据，外显子26互补脱氧核糖核酸（cDNA）3435 C>T多态性的纯合TT与人尿P-gp低表达相关。选择8名野生型外显子26 3435 C>T（CC）的健康男性纯合携带者、8名杂合受试者（CT）和8名纯合突变（TT）受试者。另外还确定了7种MDR 1多态性。在前两个研究日，地高辛口服给药，每日两次;在第3 - 5天，早晨给予0.25 mg。在第5天，分析基因型-表型和单倍型-表型关系的动力学参数。3435 TT基因型受试者中地高辛0 - 4小时血药浓度-时间曲线下面积[AUC（0-4）]（P = 0.042）和Cm（P =-0.043）值高于3435 CC基因型受试者。未检测到其他单核苷酸多态性（SNPs）对地高辛参数的影响。从SNPs 2677 G>T（外显子21）和3435 C>T推导的基因型的比较显示AUC（0-4）（P = 0.034）和C-max（P = 0.039）的显著差异，这通过单倍型分析得到证实。单体型12（2677 G/3435 T），在随机抽取的白人样本（n = 687）中的频率为13.3%，与（Mann-Whitney检验），AUC（0-4）值较高（P = 0.009）高于非携带者（平均值+/- SD，5.7 +/- 0.9 mug.h/L [n = 7] vs 4.8 +/- 0.9 mug.h/L [n = 17]）。单倍型11（2677 G/3435 C）的AUC（0-4）值（P = 0.013）低于非携带者（平均值：t SD，4.7 +/- 0.9 mug.h/L [n = 16] vs 5.6 +/- 0.9 mug.h/L [n = 8]）。结论：单倍型12编码地高辛口服给药的AUC（0-4）和Cmax值较高。MDR 1单倍型分析在预测MDR 1表型方面上级单核苷酸多态性分析。
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 Cm (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 C-max (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 mug.h/L [n = 7] versus 4.8 +/- 0.9 mug.h/L [n = 17]). Haplotype 11 (2677G/3435C) had lower AUC(0-4) values (P = .013) compared with those of noncarriers (mean:t SD, 4.7 +/- 0.9 mug.h/L [n = 16] versus 5.6 +/- 0.9 mug.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 C-max of orally administered digoxin. Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1 phenotype.