Functions of MRP2 and MRP3 in Drug Disposition

描述（由申请人提供）：阐明药物吸收、消除和处置的分子决定因素是癌症治疗的一个重要目标，因为它可以为合理开发可口服给药且能够更好地渗透靶组织的药物提供机制基础。此外，它可以帮助预测同时给药的药物如何影响抗癌药物的药代动力学（PK），通过识别多态性可能影响治疗的基因来告知药物遗传学领域，并帮助解释与药物处置相关的副作用。P-糖蛋白（PGP）是一种作为质膜外排泵发挥作用的ABC转运蛋白，是限制口服生物利用度、促进肝胆消除并限制癌症化疗药物渗透到大脑和胎儿中的既定因素。Pgp基因敲除小鼠的研究对这些见解至关重要，并且Pgp基因敲除小鼠的发现直接转化为人类的情况。此外，该小鼠已成为评估PGP对数百种药物PK影响的主要研究对象。最近MRP 2和MRP 3，两个ABC转运蛋白，是MRP家族的药物外排泵的成员，已经涉及这些过程。MRP 2定位于与PGP相同的药物摄取和消除的顶端位点（肠道、肝细胞、肾脏和胎盘），具有转运广泛抗癌药物的能力，并且已知是几种非癌药物肝胆排出的因素。综合而言，这些特征表明MRP 2可能是抗癌药物PK和分布的重要决定因素。然而，其对癌症化疗药物的影响尚未详细确定。能够转运依托泊苷和甲氨蝶呤的MRP 3定位于肠上皮细胞的基底外侧表面上，并且在药物解毒的小管途径被阻断的肝功能障碍（胆汁淤积）状况期间在肝细胞的基底外侧表面处被诱导。这些特征表明，MRP 3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窦状血来解毒胆汁淤积性肝细胞。同样，MRP 3对这些过程的贡献尚未确定。为了确定MRP 2和MRP 3对PK和药物处置的贡献，我们开发了mrp 2和mrp 3基因破坏的小鼠，以及一整套相关的双敲除小鼠。本提案的目的是通过使用这些小鼠模型来检验这两种泵影响抗癌药物的PK和药物分布的假设。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剂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注射给药，并且还可以减少与身体处理抗癌药物的方式相关的副作用。

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.