Hepatic OATP Drug Transporters and Chemotherapy Disposition

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。的 有机阴离子转运多肽（OATPs）是一个超家族的转运蛋白，其促进细胞内 多种内源性化合物和药物的摄取，并在对药物重要的器官中表达 如肝、肾、肠。癌症是美国第二大常见的死亡原因， 仅次于心脏病，占死亡人数的近四分之一。化疗是 大多数癌症的治疗方法。虽然化疗是治疗癌症的关键组成部分，但其 有效性通常被狭窄的治疗指数所削弱，这增加了不良严重不良反应的风险。 与这些药剂的施用相关的作用。我们的初步数据强烈支持肝脏的作用， OATP，OATP 1B 1和-1B3，对广泛使用的化疗药物多西他赛的处置。此外，委员会认为， 常见的OATP 1B 1变体与多西他赛转运的显著损害相关，这可能 导致多西他赛药代动力学中经常出现的患者间变异性。因此，我们假设 OATP 1B 1和-1B3在药物作用的肝脏分布和个体间变异性中起重要作用。 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 和阿霉素。重点研究旨在更好地描述动力学和抑制特征， 药物应答的个体间变异性以及OATP 1B 1和-1B3对化疗处置的体内药理学 被提议。具体目标1侧重于确定OATP 1B 1和-1B3对肝脏的药理学作用。 使用基于重组牛痘的体外方法测定多西他赛、长春新碱和多柔比星的分布和清除率 在异源哺乳动物细胞系统中表达野生型和变体转运蛋白。具体目标2 OATP 1B 1和-1B3与多西他赛、长春新碱和多柔比星肝处置的药理学相关性 将使用表达OATP 1B转运蛋白的人源化转基因小鼠模型，在 Oatp 1b 2基因敲除小鼠。拟议的研究将为肝脏的作用提供新的和重要的见解， OATP，OATP 1B 1和-1B3，与常用化疗药物的体外和体内药理学。长- 从长远来看，对肝OATP的分子和临床药理学的更全面的了解将有助于 这不仅对评价化疗的处置、毒性和疗效，而且对广泛的 例如药物发现、合理药物设计和个性化医疗。

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. 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.