INTESTINAL AND HEPATIC DRUG TRANSPORTERS

结构无关的抗肿瘤药物从体内的增强外流 癌细胞导致多药耐药(MDR)表型， 这是由于mdr1基因表达增加所致。基因 产品，药物外排泵P-糖蛋白，也已经被 在正常组织中发现，并经常与 负责药物新陈代谢的CYP超家族成员， 例如，CYP3A。此外，现在人们认识到，有 是P-糖蛋白底物和 细胞色素P3A。因此，本项目中要测试的假设有 被用来确定P-糖蛋白介导的作用 非肿瘤组织在药物处置中的外流。哺乳动物 用P-糖蛋白、细胞色素P3A和细胞周期蛋白3A转染痘苗病毒细胞 将使用组合来评估P- 糖蛋白介导的药物代谢物转运 确定细胞色素P3A的处置的明显变异性 底物。活体研究表明，P- 糖蛋白介导的药物外排，可归因于两个等位基因 多药耐药基因的变异与肿瘤细胞的可变型表达 传送器。进一步鉴定，体外功能 等位基因变异的特征和群体分布 因此，必须采取行动。体外和临床数据都支持 P-糖蛋白介导地高辛转运的重要作用 它不会受到广泛的生物转化的影响。因此，TO 确定P-糖蛋白介导的变异程度 地高辛肾脏的体内转运和群体分布 肾小管分泌物和非肾清除量将在 一大批健康受试者。最后，我们分离出了一个部分 可能编码另一种药物的肝脏同源物的克隆 转运蛋白，MRP(一种多药耐药相关肽)。建议进行研究 验证MRP-HEP在肝脏中起重要作用的假说 毒品运输。毒品运输是一个日益被认可的问题 药物处置的决定因素；这些研究将确定 药物运输中的可变性可能有助于 药物处置的可变性。

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.