Hepatic Drug Transporters in Drug Disposition

药物处置中的肝脏药物转运蛋白

• 批准号: 6909064
• 负责人: RICHARD B KIM
• 金额: $ 44.9万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909064
• 关键词: antihypercholesterolemic agent; biological models; cell line; clinical research; drug metabolism; human subject; liver metabolism; membrane transport proteins; model design /development; naphthalenes; patient oriented research; protein structure function; rifamycins; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Transporters are increasingly recognized as important processes in drug disposition. More recently, functional characterization of drug uptake transporters has revealed that a family of drug uptake transporters known as the Organic Anion Transporting Polypeptides (OATPs), are critical to the cellular uptake of drugs into organs such as the liver, intestine, and brain. Studies have revealed that certain human OATPs such as OATP-C and OATP-8 may be the key hepatic drug uptake transporters, while OATP-A expression at the level of the blood brain barrier may be responsible for the CNS entry of certain drugs. We are now able to show that OATP-A is expressed in the small intestines, and may be a key transporter responsible enhancing the gastrointestinal absorption of various drugs in clinical use. It is our hypothesis that intersubject variability in the expressed level and activity of OATP transporters affects drug disposition and responsiveness. However, the extent of our knowledge regarding human OATP transporters is limited. Studies carried out from this laboratory have identified a number of single nucleotide polymorphisms (SNPs) in OATP transporters importantly associated with drug disposition and response. Accordingly, in this application, studies on the role of genetic variability in certain human OATP transporters to transporter function, both in vitro and in vivo, are outlined. Specific Aim 1 is focused studies on the in vitro functional characterization of allelic variants newly identified by this laboratory in OATP-A, OATP-8 and OATP-C. In Specific Aim 2, to better understand the interplay between OATP-mediated drug uptake versus P-glycoprotein (MDR1) or MRP2 (cMOAT)-mediated drug efflux, studies are proposed on the creation of model cell lines expressing an OATP transporter along with P-glycoprotein or MRP2, in combinations reflective of organs such as the liver, intestine and brain. In Specific Aim 3, the role of commonly occurring SNPs in OATP-C, which studies from this laboratory had shown to be functionally significant in vitro, will be tested in human subjects using the well-known OATP-C-specific substrate, pravastatin, and a newly identified substrate, rifampin, as in vivo probes for this transporter. Moreover, variability in the extent of rifampin-mediated induction of the drug metabolizing enzyme, CYP3A, among subjects with variant OATP-C alleles, will also be tested.

描述（由申请人提供）：转运蛋白越来越被认为是药物处置中的重要过程。最近，药物摄取转运蛋白的功能表征已经揭示，被称为有机阴离子转运多肽（OATP）的药物摄取转运蛋白家族对于药物被细胞摄取到器官如肝、肠和脑中至关重要。研究表明，某些人OATP如OATP-C和OATP-8可能是关键的肝脏药物摄取转运蛋白，而OATP-A在血脑屏障水平的表达可能是某些药物进入CNS的原因。我们现在能够证明OATP-A在小肠中表达，并且可能是负责增强临床使用的各种药物的胃肠道吸收的关键转运蛋白。我们假设OATP转运蛋白表达水平和活性的个体间差异影响药物处置和反应性。然而，我们对人类OATP转运蛋白的了解程度是有限的。本实验室开展的研究已经确定了OATP转运蛋白中的许多单核苷酸多态性（SNP），这些单核苷酸多态性与药物处置和反应密切相关。因此，在本申请中，概述了关于某些人OATP转运蛋白的遗传变异性在体外和体内对转运蛋白功能的作用的研究。具体目标1是重点研究本实验室在OATP-A、OATP-8和OATP-C中新鉴定的等位基因变体的体外功能表征。在具体目标2中，为了更好地理解OATP介导的药物摄取与P-糖蛋白（MDR 1）或MRP 2（cMOAT）介导的药物外排之间的相互作用，提出了关于建立表达OATP转运蛋白沿着P-糖蛋白或MRP 2的模型细胞系的研究，这些模型细胞系反映了器官如肝脏、肠和脑的组合。在特定目标3中，将使用众所周知的OATP-C特异性底物普伐他汀和新鉴定的底物利福平作为该转运蛋白的体内探针，在人类受试者中检测OATP-C中常见SNP的作用（该实验室的研究已证明其在体外具有功能显著性）。此外，还将检测携带变异OATP-C等位基因的受试者中利福平介导的药物代谢酶CYP 3A诱导程度的变异性。