Hepatic OATP Drug Transporters and Chemotherapy Disposition

描述（由申请人提供）：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（ooatp）是一个转运蛋白超家族，促进细胞摄取多种内源性化合物和药物，并在肝脏、肾脏和肠道等对药物处置有重要意义的器官中表达。癌症是美国第二大最常见的死亡原因，仅次于心脏病，占死亡人数的近四分之一。化疗是治疗大多数癌症的主要方法。虽然化疗是癌症治疗的重要组成部分，但其有效性往往因狭窄的治疗指标而降低，这增加了与此类药物施用相关的严重不良反应的风险。我们的初步数据有力地支持肝脏oatp， OATP1B1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OATP1B1变异与多西紫杉醇转运的显著损伤有关，这可能导致多西紫杉醇药代动力学中经常出现的广泛的患者间差异。因此，我们假设OATP1B1和-1B3在肝脏配置和已知依赖于肝脏清除的常用化疗药物（包括多西他赛、长春新碱和阿霉素）的药物效果的个体差异中发挥重要作用。我们提出了一些重点研究，旨在更好地描述OATP1B1和-1B3对化疗处置的动力学和抑制谱、药物反应个体间变异的遗传基础以及体内药理学。特异性Aim 1的重点是确定OATP1B1和- 1B3对多西紫杉醇、长春新碱和阿霉素的肝脏处置和清除的药理学作用，使用体外重组痘苗为基础的方法在异种哺乳动物细胞系统中表达野生型和变异转运体。在Specific Aim 2中，将在敲除Oatp1b2小鼠的背景下，使用表达OATP1B转运蛋白的人源化转基因小鼠模型，评估OATP1B1和-1B3与多西紫杉醇、新碱和阿霉素在体内肝脏处置的药理学相关性。在Specific Aim 3中，将对接受多西紫杉醇治疗方案的肿瘤患者进行前瞻性药物遗传：药代动力学相关研究，探讨OATP1B1和-1B3变异对多西紫杉醇处置的患者间变异性的功能影响。这些研究将为肝脏OATPs、OATP1B1和-1B3在常用化疗药物的体内和体外药理学中的作用提供新的重要见解。从长远来看，更全面地了解肝脏oops的分子和临床药理学不仅对化疗处置、毒性和疗效的评估具有重要意义，而且对药物发现、合理药物设计和个性化医疗等广泛的倡议也具有重要意义。

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.