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：
9328094
负责人：
Richard Hsinshin Ho
金额：
$ 30.61万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9328094
关键词：
ABCB1 gene Accounting Adverse effects Animal Model Antineoplastic Agents Cardiovascular Diseases Carrier Proteins Cause of Death Cell membrane Cessation of life Clinical Clinical Pharmacology Communicable Diseases Correlative Study Data Dependence Diabetes Mellitus Diagnosis Disease Dose Doxorubicin Drug Design Drug Kinetics Drug usage Effectiveness Evaluation Family Genetic Genetic Variation Goals Heart Diseases Hepatic Human Impairment In Vitro Intestines Investigation Kidney Kinetics Knockout Mice Knowledge Link Liver Malignant Neoplasms Mammalian Cell Mediating Methods Molecular Molecular Weight Morbidity - disease rate Movement Multi-Drug Resistance Mus OATP Transporters Organ P-Glycoprotein Patients Pharmaceutical Preparations Pharmacodynamics Pharmacogenetics Pharmacology Play Property Recombinants Regimen Risk Role Shapes Solubility Substrate Specificity System Testing Therapeutic Therapeutic Index Toxic effect Transgenic Mice Transgenic Organisms United States Vaccinia Variant Vertebral column Vincristine base cancer pharmacology cancer therapy cancer type chemotherapeutic agent chemotherapy clinically relevant cytotoxicity docetaxel drug discovery improved in vivo insight interpatient variability ionization lipophilicity mortality mouse model novel oncology personalized medicine prospective protein transport research clinical testing response success uptake

项目摘要

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.

描述（由申请人提供）：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。有机阴离子转运多肽（OATP）是转运蛋白的超家族，可促进各种内源性化合物和药物的细胞摄取，并在对药物处置重要性的器官中表达，例如肝脏，肾脏，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，并且每4人死亡中有近1人。化学疗法包括大多数类型癌症治疗的骨干。虽然化学疗法是癌症治疗的关键成分，但狭窄的治疗指数通常会降低其有效性，从而增加与这种药物给药相关的不良严重不良影响的风险。我们的初步数据强烈支持肝燕麦OATP1B1和-1B3的作用，以使使用广泛使用的化学治疗剂多西他赛的处置。此外，通常发生的OATP1B1变体与多西他赛转运的重大损害相关，这可能有助于多西他赛药物代动力学中经常发生的广泛的室内可变性。因此，我们假设OATP1B1和-1B3在肝脏处置和个体间变异性中起着重要作用，在普通使用的化学治疗剂的药物效应中，已知依赖于肝清除率，包括多西他赛，vincristine和dooxorubibicin。提出了旨在更好地描述动力学和抑制概况的重点研究，药物反应间个体变异性的遗传基础以及OATP1B1和-1B3对化学疗法处置的体内药理学。具体目标1的重点是使用基于体外重组疫苗的方法来确定多西他赛，vincristine和adorubicin的肝脏处置和清除的药理学作用，并使用基于体外重组疫苗的方法来表达异型哺乳动物细胞系统中的野生型和变体的转运蛋白。在特定的目标2中，将使用人源化的转基因小鼠模型在OATP1B2敲除小鼠的背景下表达OATP1B转运蛋白。在特定的目标3中，通过进行前瞻性药物遗传学：在接受多西他的治疗疗法的一部分，将通过进行前瞻性药物遗传学研究来探索OATP1B1和-1B3变体对多西他赛的处置室内差异的功能后果。拟议的研究将提供有关肝燕麦燕麦，OATP1B1和-1B3的作用的新颖和重要的见解，以对常用化学治疗剂的体外和体内药理学。长期，对肝燕麦的分子和临床药理学的更全面理解不仅对评估化学疗法处置，毒性和效力的评估都具有重要意义，而且对诸如药物发现，理性药物设计和个性化医学等广泛举措。