Hepatic Drug Transporters in Drug Disposition

描述(由申请人提供)：转运体越来越被认为是药物处置的重要过程。最近，药物摄取转运体的功能表征揭示了一类被称为有机阴离子转运多肽(OATPs)的药物摄取转运体家族，它们对细胞对药物进入肝脏、肠道和大脑等器官的摄取至关重要。研究表明，某些人的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OATP-A在小肠中表达，并且可能是促进临床使用的各种药物的胃肠道吸收的关键转运体。我们的假设是，OATP转运体表达水平和活性的不同受试者之间的差异影响药物的处置和反应。然而，我们对人类OATP转运蛋白的了解是有限的。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(SNPs)，这些SNPs与药物处置和反应密切相关。因此，在这一应用中，对某些人类OATP转运蛋白在体外和体内的转运蛋白功能的遗传变异性的作用的研究进行了概述。具体目标1是本实验室新发现的OATP-A、OATP-8和OATP-C等位基因变异体的体外功能特性研究。在具体目标2中，为了更好地了解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，有人建议建立表达OATP转运体和P-糖蛋白或MRP2的模型细胞系，以反映肝脏、肠道和大脑等器官的组合。在具体目标3中，本实验室的研究表明，OATP-C中常见的SNPs在体外具有显著的功能意义，将使用众所周知的OATP-C特异性底物普伐他汀和新发现的底物利福平作为该转运体的体内探针，在人体内测试SNPs的作用。此外，还将测试携带不同OATP-C等位基因的受试者中，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.