Hepatic Drug Transporters in Drug Disposition

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表明，一个被称为有机阴离子转运多肽（OATPs）的药物摄取转运蛋白家族对药物进入肝脏、肠道和大脑等器官的细胞摄取至关重要。研究表明，某些人类oatp如OATP-C和OATP-8可能是肝脏药物摄取的关键转运体，而OATP-A在血脑屏障水平的表达可能是某些药物进入中枢神经系统的原因。我们现在能够证明otp - a在小肠中表达，并且可能是一个关键的转运体，负责增强临床使用的各种药物的胃肠道吸收。我们的假设是，OATP转运体表达水平和活性的主体间变异性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有限。该实验室开展的研究已经确定了OATP转运体中的一些单核苷酸多态性（snp），这些多态性与药物处置和反应有重要关系。因此，在本应用中，概述了在体外和体内对某些人类OATP转运体遗传变异对转运体功能的作用的研究。Specific Aim 1重点研究本实验室新发现的OATP-A、OATP-8和OATP-C等位基因变异的体外功能表征。在Specific Aim 2中，为了更好地理解OATP介导的药物摄取与p -糖蛋白（MDR1）或MRP2 （cMOAT）介导的药物外排之间的相互作用，提出了建立表达OATP转运蛋白和p -糖蛋白或MRP2的模型细胞系的研究，结合反映肝脏、肠道和大脑等器官。在Specific Aim 3中，在otp - c中常见的snp的作用，该实验室的研究已经证明在体外具有重要的功能，将在人类受试者中使用众所周知的otp - 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体的体内探针进行测试。此外，在ooatp - c等位基因变异的受试者中，还将测试利福平介导的药物代谢酶CYP3A诱导程度的变异性。

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.