P-糖蛋白MDR1基因单倍型对洋地黄毒苷稳态动力学的调节作用。

Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene.

作者信息

Johne Andreas, Köpke Karla, Gerloff Thomas, Mai Ingrid, Rietbrock Stephan, Meisel Christian, Hoffmeyer Sven, Kerb Reinhold, Fromm Martin F, Brinkmann Ulrich, Eichelbaum Michel, Brockmöller Jürgen, Cascorbi Ingolf, Roots Ivar

机构信息

Institute of Clinical Pharmacology, University Medical Center Charité, Humboldt University of Berlin, Germany.

出版信息

Clin Pharmacol Ther. 2002 Nov;72(5):584-94. doi: 10.1067/mcp.2002.129196.

DOI:10.1067/mcp.2002.129196

PMID:12426522

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 C(max) (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 microg. h/L [n = 7] versus 4.8 +/- 0.9 microg. 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 microg. h/L [n = 16] versus 5.6 +/- 0.9 microg. 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.

摘要

目的

我们研究了P-糖蛋白（P-gp）MDR1基因多态性对高加索人地高辛稳态药代动力学的影响。根据早期数据，外显子26互补脱氧核糖核酸（cDNA）3435C>T多态性的纯合子TT与人类肠道中P-gp低表达相关。

方法

选择8名野生型外显子26 3435C>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。另外测定了7个MDR1多态性。在前两个研究日，地高辛每日口服两次；在第3至5天，早晨给予0.25mg。在第5天，分析动力学参数以研究基因型-表型和单倍型-表型关系。

结果

3435TT基因型受试者的地高辛血浆浓度-时间曲线下从零到4小时的面积[AUC(0-4)]（P = 0.042）和C(max)（P = 0.043）值高于3435CC基因型受试者。未检测到其他单核苷酸多态性（SNP）对地高辛参数的影响。对SNP 2677G>T（外显子21）和3435C>T推导的基因型进行比较，发现AUC(0-4)（P = 0.034）和C(max)（P = 0.039）存在显著差异，单倍型分析证实了这一点。单倍型12（2677G/3435T）在随机抽取的高加索人样本（n = 687）中的频率为13.3%，与非携带者相比，其AUC(0-4)值更高（曼-惠特尼检验，P = 0.009）（平均±标准差，5.7±0.9μg·h/L [n = 7] 对比4.8±0.9μg·h/L [n = 17]）。与非携带者相比，单倍型11（2677G/3435C）的AUC(0-4)值更低（P = 0.013）（平均±标准差，4.7±0.9μg·h/L [n = 16] 对比5.6±0.9μg·h/L [n = 8]）。单倍型分析结果与其他MDR1研究数据相符。