Hepatic OATP Drug Transporters and Chemotherapy Disposition

肝脏 OATP 药物转运蛋白和化疗处置

• 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
• 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

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.

细胞膜结合的载体蛋白称为转运蛋白，被认为是药物处置的重要因素。这个 有机阴离子转运多肽(OATPs)是一个超家族的转运蛋白，促进细胞 摄取多种内源性化合物和药物，并在对药物重要的器官中表达 性情，如肝、肾、肠。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。化疗是中坚力量 对大多数类型的癌症的治疗。虽然化疗是癌症治疗中的关键组成部分，但其 疗效往往因治疗指标狭窄而降低，这增加了严重不良反应的风险。 与给药这类药物相关的影响。我们的初步数据有力地支持了肝脏 OATP，OATP1B1和-1B3，用于处置广泛使用的化疗药物多西紫杉醇。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 在多西紫杉醇的药代动力学中，患者之间经常出现广泛的变异性。因此，我们假设 OATP1B1和-1B3在肝组织的分布和药效的个体差异中起重要作用 已知的依赖肝脏清除的常用化疗药物包括多西紫杉醇、长春新碱 和阿霉素。旨在更好地描绘动力学和抑制谱的重点研究，遗传学基础 OATP1B1和-1B3对化疗药物反应和体内药理作用的个体差异 都被提出了。具体目标1集中于确定OATP1B1和-1B3对肝脏的药理作用 体外重组痘苗法处理和清除多西紫杉醇、长春新碱和阿霉素 在异源哺乳动物细胞系统中表达野生型和变异型转运蛋白。在具体目标2中， OATP1B1和-1B3与多西紫杉醇、长春新碱和阿霉素在肝组织中的药理作用 将使用表达OATP1B转运蛋白的人源化转基因小鼠模型对vivo进行评估 Oatp1b2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，OATP1B1和-1B3，对常用化疗药物的体外和体内药理作用。长- 术语，对肝脏OATPs的分子和临床药理学将有更全面的了解 不仅对化疗处置、毒性和疗效的评估有重要意义，而且对更广泛的 药物发现、合理药物设计、个性化用药等举措。