Hepatic OATP Drug Transporters and Chemotherapy Disposition

性状（由申请方提供）：被称为转运蛋白的细胞膜结合载体蛋白被认为是药物处置的重要因素。有机阴离子转运多肽（OATP）是转运蛋白的超家族，其促进多种内源性化合物和药物的细胞摄取，并且在对药物处置重要的器官（如肝、肾和肠）中表达。癌症是美国第二大常见死因，仅次于心脏病，占死亡人数的近四分之一。化疗包括大多数类型癌症的治疗支柱。虽然化学疗法是癌症治疗中的关键组成部分，但其有效性通常被狭窄的治疗指数所减弱，这增加了与施用此类药剂相关的不利的严重不良反应的风险。我们的初步数据强烈支持肝脏OATP（OATP 1B 1和-1B3）对广泛使用的化疗药物多西他赛的处置的作用。此外，常见的OATP 1B 1变体与多西他赛转运显著受损相关，这可能导致多西他赛药代动力学经常出现广泛的患者间变异性。因此，我们假设OATP 1B 1和-1B3在已知依赖于肝脏清除率的常用化疗药物（包括多西他赛、长春新碱和多柔比星）的肝脏分布和药物效应的个体间变异性中发挥重要作用。提出了旨在更好地描述动力学和抑制特征、药物应答个体间变异性的遗传基础以及OATP 1B 1和-1B3对化疗处置的体内药理学的重点研究。具体目标1的重点是使用基于体外重组牛痘的方法在异源哺乳动物细胞系统中表达野生型和变体转运蛋白，确定OATP 1B 1和-1B3对多西他赛、长春新碱和多柔比星的肝脏处置和清除的药理学作用。在特定目的2中，将使用在Oatp 1b 2敲除小鼠背景下表达OATP 1B转运蛋白的人源化转基因小鼠模型，评价OATP 1B 1和-1B3与多西他赛、长春新碱和多柔比星体内肝脏处置的药理学相关性。在具体目标3中，将通过在接受多西他赛作为其治疗方案一部分的肿瘤患者中进行一项前瞻性药物遗传学：药代动力学相关研究，探索OATP 1B 1和-1B3变体对多西他赛分布的患者间变异性的功能性后果。拟定的研究将为肝脏OATP（OATP 1B 1和-1B3）对常用化疗药物的体外和体内药理学作用提供新的重要见解。从长远来看，更全面地了解肝脏OATP的分子和临床药理学不仅对评价化疗处置、毒性和疗效具有重要意义，而且对药物发现、合理药物设计和个性化用药等广泛举措也具有重要意义。

DESCRIPTION (provided by applicant): Cell membrane-bound carrier proteins called transporters are recognized as important factors in drug disposition. The Organic Anion Transporting Polypeptides (OATPs) are a superfamily of transporter proteins that facilitate the cellular uptake of a diverse range of endogenous compounds and drugs and are expressed in organs of importance to drug disposition, such as the liver, kidney and intestine. Cancer is the second most common cause of death in the US, exceeded only by heart disease, and accounting for nearly 1 of every 4 deaths. Chemotherapy comprises the backbone of therapy for most types of cancer. While chemotherapy is a crucial component in the treatment of cancer, its effectiveness is often mitigated by narrow therapeutic indices which increases the risks for untoward serious adverse effects associated with administration of such agents. Our preliminary data strongly supports a role for the hepatic OATPs, OATP1B1 and -1B3, to the disposition of the widely used chemotherapeutic agent docetaxel. Furthermore, commonly occurring OATP1B1 variants are associated with significant impairment of docetaxel transport, which may contribute to the oft-witnessed wide interpatient variability in docetaxel pharmacokinetics. Accordingly, we hypothesize that OATP1B1 and -1B3 play important roles in the hepatic disposition and interindividual variability in drug effect of commonly used chemotherapeutic agents known to be dependent on hepatic clearance, including docetaxel, vincristine and doxorubicin. Focused studies that aim to better delineate the kinetic and inhibition profiles, genetic basis for interindividual variability in drug response, and in vivo pharmacology of OATP1B1 and -1B3 to chemotherapy disposition are proposed. Specific Aim 1 is focused on determining the pharmacologic roles of OATP1B1 and - 1B3 to the hepatic disposition and clearance of docetaxel, vincristine, and doxorubicin using an in vitro recombinant vaccinia-based method to express wild-type and variant transporters in a heterologous mammalian cell system. In Specific Aim 2, the pharmacological relevance of OATP1B1 and -1B3 to the hepatic disposition of docetaxel, vincristine and doxorubicin in vivo will be evaluated using a humanized transgenic mouse model expressing OATP1B transporters in the background of the Oatp1b2 knockout mouse. In Specific Aim 3, the functional consequences of OATP1B1 and -1B3 variants to the interpatient variability in disposition of the docetaxel will be explored by conducting a prospective pharmacogenetic:pharmacokinetic correlative study in oncology patients receiving docetaxel as part of their therapeutic regimen. The proposed studies will provide novel and important insights into the roles of the hepatic OATPs, OATP1B1 and -1B3, to the in vitro and in vivo pharmacology of commonly used chemotherapeutic agents. Long-term, a more comprehensive understanding of the molecular and clinical pharmacology of hepatic OATPs will have important implications not only for the evaluation of chemotherapy disposition, toxicity, and efficacy, but also for broad initiatives such as drug discovery, rational drug design and personalized medicine.