INTESTINAL AND HEPATIC DRUG TRANSPORTERS

肠道和肝脏药物转运蛋白

• 批准号: 6271743
• 负责人: RICHARD B KIM
• 金额: $ 26.11万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6271743
• 关键词: African American; CHO cells; P glycoprotein; RNase protection assay; caucasian American; clearance rate; cytochrome P450; digoxin; drug interactions; drug metabolism; enzyme substrate; gastrointestinal absorption /transport; human genetic material tag; human subject; liver metabolism; multidrug resistance; pharmacogenetics; pharmacokinetics; polymerase chain reaction; protein transport; racial /ethnic difference; single strand conformation polymorphism; transfection; vaccinia virus; western blottings

Enhanced efflux of structurally-unrelated antineoplastic drugs from caner cells results in the multidrug resistance (MDR) phenotype, attributable to increased expression the MDR1 gene. The gene product, the drug efflux pump P-glycoprotein, has also been identified in normal tissues, and frequently co-localizes with members of the CYP superfamily responsible for drug metabolism, for example, CYP3A. In addition, it is now recognized that there is substantial overlap between the substrates of P-glycoprotein and CYP3A. Thus, the hypotheses to be tested in this Project have been formulated to determine the role of P-glycoprotein-mediated efflux in drug disposition by non-neoplastic tissues. Mammalian cells transfected by vaccinia with P-glycoprotein, CYP3A and their combination will be used to assess the extent to which P- glycoprotein-mediated transport of drugs of their metabolites determines apparent variability in the disposition of CYP3A substrates. In vivo studies indicate substantial variability in P- glycoprotein-mediated drug efflux, attributable to both allelic variants in the MDR1 gene and to variable expression of the transporter. Further identification, in vitro functional characterization, and population distribution of allelic variants will therefore be undertaken. Both in vitro and clinical data support an important role for P-glycoprotein-mediated transport of digoxin, which is not subject to extensive biotransformation.. Hence, to determine the extent of variability in P-glycoprotein-mediated transport in vivo, the population distribution of digoxin's renal tubular secretion and non-renal clearance will be determined in a large cohort of healthy subjects. Finally, we have isolated a partial clone which likely encodes the hepatic homolog of the another drug transporter, MRP (an MDR-related peptide). Studies are proposed to test the hypothesis that MRP HEP plays an important in hepatic drug transport. Drug transport is an increasingly recognized determinant of drug disposition; these studies will define mechanisms whereby variability in drug transport can contribute to variability in drug disposition.

增强结构无关的药物的外排 癌细胞导致多药耐药（MDR）表型， 这归因于MDR 1基因表达的增加。 基因 产品，药物外排泵P-糖蛋白，也已被 在正常组织中鉴定，并且经常与 负责药物代谢的β-内酰胺酶超家族成员， 例如CYP 3A。 此外，现在人们认识到， 是P-糖蛋白底物之间的实质性重叠， CYP3A。 因此，本项目中要检验的假设有 已制定，以确定P-糖蛋白介导的作用 药物在非肿瘤组织中的外排。 哺乳动物 用P-糖蛋白、CYP 3A和它们的结合物转染牛痘的细胞 组合将用于评估P- 糖蛋白介导的药物及其代谢产物的转运 确定CYP 3A分布的明显变异性 印刷受体. 体内研究表明，P- 糖蛋白介导的药物外排，归因于两个等位基因 MDR 1基因中的变异和MDR 1基因的可变表达 传送器。 进一步鉴定，体外功能 等位基因变体的特征和群体分布将 因此，进行。 体外和临床数据均支持 P-糖蛋白介导地高辛转运的重要作用， 其不经历广泛的生物转化。因此，为了 确定P-糖蛋白介导的 体内转运，地高辛的肾脏分布 肾小管分泌和非肾清除率将在 健康受试者的大队列。 最后，我们分离出了一部分 可能编码另一种药物肝脏同系物的克隆 转运蛋白，MRP（MDR相关肽）。 建议进行研究 为了验证MRP HEP在肝脏中起重要作用的假设， 毒品运输 药物转运是一个越来越被认识到的 药物处置的决定因素;这些研究将定义 药物转运的可变性可能有助于 药物处置的变异性。