Hepatic OATP Drug Transporters and Chemotherapy Disposition

肝脏 OATP 药物转运蛋白和化疗处置

基本信息

批准号：
8371734
负责人：
Richard Hsinshin Ho
金额：
$ 30.62万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8371734
关键词：
ABCB1 gene Accounting Adverse effects Animal Model Antineoplastic Agents Binding Carrier Proteins Cause of Death Cell membrane Cessation of life Clinical Clinical Pharmacology Correlative Study Data Dependence Diagnosis Dose Doxorubicin Drug Compounding Drug Design Drug Kinetics Effectiveness Evaluation Family Genetic Genetic Polymorphism Genetic Variation Goals Heart Diseases Hepatic Human Impairment In Vitro Intestines Investigation Kidney Kinetics Knockout Mice Knowledge Link Liver Malignant Neoplasms Mammalian Cell Mediating Medicine Methods Molecular Molecular Weight Morbidity - disease rate Movement Mus OATP Transporters Organ P-Glycoprotein Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacology Play Property Recombinants Regimen Risk Role Solubility Substrate Specificity System Testing Therapeutic Therapeutic Index Toxic effect Transgenic Mice Transgenic Organisms United States Vaccinia Vaccinium Variant Vertebral column Vincristine base cancer pharmacology cancer therapy cancer type chemotherapeutic agent chemotherapy clinically relevant cytotoxicity docetaxel drug discovery genetic profiling improved in vivo insight ionization lipophilicity mouse model novel oncology prospective research clinical testing response success uptake

项目摘要

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.

称为转运蛋白的细胞膜结合的载体蛋白被认为是药物处置的重要因素。这有机阴离子转运多肽（OATP）是转运蛋白的超家族，可促进细胞吸收多种内源性化合物和药物，并在对药物的重要性中表达性格，例如肝脏，肾脏和肠道。癌症是美国第二常见的死亡原因，仅因心脏病而超过，每4例死亡中的近1个。化学疗法包括主链大多数类型癌症的治疗。虽然化学疗法是癌症治疗的关键成分狭窄的治疗指标通常会降低有效性与此类药物的给药相关的影响。我们的初步数据强烈支持肝的角色 OATPS（OATP1B1和-1B3），可处置广泛使用的化学治疗剂多西他赛。此外，通常发生的OATP1B1变体与多西他赛转运的重大损害有关，这可能在多西他赛药代动力学中经常有效的大室内室内变异性。因此，我们假设 OATP1B1和-1B3在药物效应的肝脏处置和个体变异性中起重要作用常用的化学治疗剂已知依赖于肝清除率，包括多西他赛，长春新碱和阿霉素。旨在更好地描述动力学和抑制概况的重点研究，遗传基础药物反应的个体变异性，OATP1B1和-1B3对化学疗法处置的体内药理学提出了。特定目标1的重点是确定OATP1B1和-1B3的药理作用使用基于体外重组的方法的多西他赛，长春新碱和阿霉素的处置和清除在异源哺乳动物细胞系统中表达野生型和变体转运蛋白。在特定的目标2中 OATP1B1和-1B3的药理相关性与多西他赛，长春新碱和阿霉素的肝脏处置将使用在背景下表达OATP1B转运蛋白的人源化转基因小鼠模型对体内进行评估 OATP1B2敲除鼠标。拟议的研究将为肝的角色提供新颖而重要的见解 OATPS，OATP1B1和-1B3，用于常用化学治疗剂的体外和体内药理学。长的- 术语，对肝燕麦的分子和临床药理学的更全面了解将具有不仅对化学疗法处置，毒性和功效的评估的重要含义，而且对广泛诸如药物发现，理性药物设计和个性化医学之类的举措。