Functions of MRP2 and MRP3 in Drug Disposition

MRP2 和 MRP3 在药物处置中的功能

• 批准号: 7287767
• 负责人: Gary D Kruh
• 金额: $ 31.05万
• 依托单位: FOX CHASE CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-19 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7287767
• 关键词: ABCC1 gene; ATP-Binding Cassette Transporters; Adverse effects; Affect; Antineoplastic Agents; Apical; Back; Biological Availability; Blood; Brain; Cell membrane; Cholestasis; Clinic; Condition; Development; Drug Efflux; Drug Kinetics; Drug Metabolic Detoxication; Enterocytes; Etoposide/Methotrexate; Family; Fetus; Genes; Genetic Polymorphism; Goals; Hepatobiliary; Hepatocyte; Human; Investigation; Kidney; Knockout Mice; Liver; Liver Dysfunction; Localized; Malignant Neoplasms; Molecular; Mus; Oral; Oral cavity; P-Glycoprotein; P-Glycoproteins; Penetration; Pharmaceutical Preparations; Pharmacogenetics; Placenta; Process; Public Health; Pump; Range; Route; Site; Surface; Testing; Therapeutic; Tissues; Translating; absorption; base; defined contribution; design; efflux pump; improved; insight; member; mouse model; uptake

DESCRIPTION (provided by applicant): Elucidating the molecular determinants of drug absorption, elimination and disposition is an important goal in cancer therapeutics because it can provide the mechanistic basis for the rational development of agents that can be administered orally, and that are better able to penetrate target tissues. In addition, it can help to predict how simultaneously administered drugs affect the pharmacokinetics (PK) of anticancer agents, inform the field of pharmacogenetics by identifying the genes for which polymorphisms are likely to impact treatment and help to explain side effects that are related to drug disposition. P-glycoprotein (PGP), an ABC transporter that functions as a plasma membrane efflux pump, is an established factor that limits oral bioavailability, facilitates hepatobiliary elimination, and restricts penetration of cancer chemotherapeutics into brain and fetus. Investigations of Pgp knock-out mouse were crucial to these insights, and the findings on the Pgp knock-out mouse were directly translated into the situation in humans. Moreover, this mouse has become a mainstay in the assessment of the impact of PGP on the PK of hundreds of drugs. Recently MRP2 and MRP3, two ABC transporters that are members of the MRP family of drug efflux pumps, have been implicated in these processes. MRP2 is localized to the same apical sites of drug uptake and elimination as is PGP (gut, hepatocytes, kidney and placenta), has the ability to transport a broad range of anticancer agents, and is known to be a factor in the hepatobiliary extrusion of several noncancer agents. In combination, these features suggest that MRP2 may be an important determinant of the PK and disposition of anticancer agents. However, its impact on cancer chemotherapeutics has not been determined in any detail. MRP3, which is able to transport etoposide and methotrexate, is localized on the basolateral surfaces of gut enterocytes, and is induced at basolateral surfaces of hepatocytes during conditions of liver dysfunction (cholestasis) in which the canalicular route of drug detoxification is blocked. These features suggest that MRP3 may promote oral bioavailability of anticancer agents, and possibly detoxify cholestatic hepatocytes by pumping cancer agents back into sinusoidal blood. Here again, the contribution of MRP3 to these processes has not been determined. To define the contribution of MRP2 and MRP3 to PK and drug disposition, we have developed mrp2 and mrp3 gene-disrupted mice, as well as a complete set of relevant double knock-out mice. The goal of this proposal is to test the hypothesis that these two pumps affect PK and drug disposition of anticancer agents by using these mouse models. Public Health Statement: Understanding the processes investigated in this proposal will promote public health by providing information that could help to improve the design of anticancer agents. These improvements could potentially allow the drugs to be given by mouth instead of intravenously, and also reduce the side effects that are associated with the way the body disposes of anticancer agents.

描述(申请人提供)：阐明药物吸收、消除和处置的分子决定因素是癌症治疗中的一个重要目标，因为它可以为合理开发可口服且能够更好地渗透靶组织的药物提供机制基础。此外，它还可以帮助预测同时给药如何影响抗癌药物的药代动力学(PK)，通过识别基因多态可能影响治疗的基因向药物遗传学领域提供信息，并帮助解释与药物处置相关的副作用。P-糖蛋白(P-gp)是一种ABC转运蛋白，起着质膜外排泵的作用，是一种公认的限制口服生物利用度、促进肝胆消除、限制癌症化疗药物进入大脑和胎儿的因素。对Pgp基因敲除小鼠的研究对这些见解至关重要，对Pgp基因敲除小鼠的研究结果直接转化为人类的情况。而且，这只鼠标已经成为评估PGP对数百种药物PK影响的中流砥柱。最近，MRP家族药物外排泵中的两个ABC转运蛋白MRP2和MRP3参与了这些过程。MRP2定位于与PGP(肠道、肝细胞、肾脏和胎盘)相同的药物摄取和消除的顶端位置，具有运输多种抗癌药物的能力，并被认为是几种非癌症药物肝胆排泄的一个因素。综上所述，这些特征提示MRP2可能是抗癌药PK和处置的重要决定因素。然而，它对癌症化疗药物的影响还没有得到任何详细的确定。MRP3能够转运依托泊苷和甲氨蝶呤，定位于肠道细胞的基底外侧表面，在肝功能障碍(胆汁淤积症)时诱导于肝细胞的基底外侧表面，从而阻断药物解毒的管道途径。这些特征表明，MRP3可能促进抗癌药物的口服生物利用度，并可能通过将抗癌药物泵回正弦血液来解毒淤胆的肝细胞。在这方面，MRP3对这些进程的贡献仍未确定。为了确定MRP2和MRP3在PK和药物处置中的作用，我们建立了mrp2和mrp3基因突变的小鼠，以及一套完整的相关双基因敲除小鼠。这项建议的目的是通过使用这些小鼠模型来检验这两个泵影响抗癌药物的PK和药物处置的假设。公共卫生声明：了解本提案中调查的过程将通过提供有助于改进抗癌药物设计的信息来促进公共健康。这些改进可能会使药物可以通过口服而不是静脉给药，还可以减少与身体处置抗癌药物的方式相关的副作用。