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(OATPs)是一个超家族的转运蛋白，可促进细胞对多种内源性化合物和药物的摄取，并在肝脏、肾脏和肠道等对药物处置具有重要作用的器官中表达。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1/4。化疗是治疗大多数类型癌症的主要手段。虽然化疗是癌症治疗中的关键组成部分，但其有效性往往因治疗指数过窄而降低，这增加了与使用此类药物有关的不良严重不良反应的风险。我们的初步数据有力地支持了肝脏OATP OATP1B1和-1B3在广泛使用的化疗药物多西紫杉醇的处置中的作用。此外，常见的OATP1B1变异与多西紫杉醇转运的显著损害有关，这可能是多西紫杉醇药代动力学中患者间经常出现的广泛变异性的原因。因此，我们假设OATP1B1和-1B3在肝脏的处置和药物疗效的个体间变异性中发挥重要作用，这些药物是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。重点研究的目的是更好地描述OATP1B1和-1B3对化疗处置的动力学和抑制谱，药物反应个体间差异的遗传基础，以及体内药理学。具体目的1主要研究OATP1B1和OATP1B3对多西紫杉醇、长春新碱和阿霉素在肝脏中的转运和清除的药理作用，采用体外重组痘苗技术在异种哺乳动物细胞系统中表达野生型和变异型转运蛋白。在特定目的2中，将使用在Oatp1b2基因敲除小鼠的背景中表达OATP1B转运体的人源化转基因小鼠模型来评估OATP1B1和-1B3与多西紫杉醇、长春新碱和阿霉素在体内的肝脏处置的药理学相关性。在具体目标3中，将通过在接受多西紫杉醇治疗方案的肿瘤患者中进行前瞻性的药物遗传学：药代动力学相关性研究来探索OATP1B1和-1B3变异体对多西紫杉醇处置的患者间变异性的功能后果。这些研究将对肝脏OATP1B1和OATP1B3的作用提供新的和重要的见解，为常用化疗药物的体外和体内药理学研究提供参考。从长远来看，更全面地了解肝脏OATPs的分子和临床药理学不仅对评价化疗的处置、毒性和疗效具有重要意义，而且对于药物发现、合理的药物设计和个性化药物治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.