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. ? ? ? ?
