Pharmacogenetics of drug transporters and its impact on the pharmacotherapy.
Pharmacogenetics of drug transporters and its impact on the pharmacotherapy.
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DOI：
10.2174/1568026043387692
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发表时间：
2004-08
影响因子：
3.4
通讯作者：
T. Sakaeda;Tsutomu Nakamura;K. Okumura
中科院分区：
文献类型：
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作者：
T. Sakaeda;Tsutomu Nakamura;K. Okumura
大多数药物反应是由影响药代动力学和药效学的几种基因产物（即药物代谢酶、药物转运体和药物靶点）的相互作用决定的。随着人类基因组的测序，估计大约有500-1200个基因编码药物转运体。关于遗传多态性对药物治疗的影响，最具特征的药物转运体是多药耐药转运体p -糖蛋白/MDR1，即MDR1的基因产物。关于其他药物运输的这类信息很少。MDR1是一种糖基化膜蛋白，分子量为170 kDa，属于atp结合盒超家族，主要表达于肠、肝、肾和脑。许多不同类型的结构无关的药物都是MDR1的底物，它们的肠道吸收、肝胆分泌、肾脏分泌和脑运输都受MDR1的调控。2000年首次报道了MDR1基因型对药物治疗影响的研究：发现26号外显子C3435T的沉默单核苷酸多态性（silent single nucleotide polymorphism， SNP）与十二指肠MDR1的表达有关，从而与口服地高辛后的血浆浓度有关。目前，在MDR1基因的27个位点共发现28个snp。关于MDR1基因型与组织中MDR1表达、功能、药代动力学和药效学相关性的临床研究主要集中在C3435T；然而，结果仍然存在差异，这表明应该分析基因的单倍型而不是SNP。C3435T也被报道为炎性肠病、帕金森病和肾上皮肿瘤等一类疾病的危险因素，这也可能与对MDR1表达和功能的影响有关。本文综述了MDR1基因多态性对药物治疗影响的最新报道，并对其他转运体的药物遗传学研究进行了简要介绍。
Most drug responses are determined by the interplay of several gene products that influence pharmacokinetics and pharmacodynamics, i.e., drug metabolizing enzymes, drug transporters, and drug targets. With the sequencing of the human genome, it has been estimated that approximately 500-1200 genes code for drug transporters. Concerning the effects of genetic polymorphisms on pharmacotherapy, the best characterized drug transporter is the multidrug resistant transporter P-glycoprotein/MDR1, the gene product of MDR1. Little such information is available on other drug transporters. MDR1 is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily, and is expressed mainly in intestines, liver, kidneys and brain. A number of various types of structurally unrelated drugs are substrates for MDR1, and their intestinal absorption, hepatobiliary secretion, renal secretion and brain transport are regulated by MDR1. The first investigation on the effects of MDR1 genotypes on pharmacotherapy was reported in 2000: a silent single nucleotide polymorphism (SNP), C3435T in exon 26, was found to be associated with the duodenal expression of MDR1, and thereby the plasma concentration of digoxin after oral administration. At present, a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical investigations on the association of MDR1 genotypes with the expression and function of MDR1 in tissues, and with pharmacokinetics and pharmacodynamics have mainly focused on C3435T; however, there are still discrepancies in the results, suggesting that the haplotype of the gene should be analyzed instead of a SNP. C3435T is also reported to be a risk factor for a certain class of diseases including the inflammatory bowel diseases, Parkinson's disease and renal epithelial tumor, and this also might be explained by the effects on MDR1 expression and function. In this review, the latest reports on the effects of genetic polymorphisms of MDR1 on pharmacotherapy are summarized, and the pharmacogenetics of other transporters is briefly introduced.