A MATHEMATICAL-MODEL FOR THE INHIBITION OF THE MULTIDRUG RESISTANCE-ASSOCIATED P-GLYCOPROTEIN PUMP

An extension of an earlier model of the p170 glycoprotein pump is pres ented. In an earlier work (Michelson and Slate, Bull. math. Biol. 54, 1023-1038, 1992), the pump was modeled using an energy-dependent model of facilitated diffusion. In this paper we add an inhibitor to the mo del. New equations are derived which represent either competitive or n on-competitive inhibition in the pumping action of the glycoprotein. N umerical simulations were run which provide a response surface (initia l loading concentration of inhibitor and its ability to compete with a n ideal anti-cancer drug vs a summary measure of cytoplasmic exposure) for each scenario. The importance of the exposure profile. how it is related to ultimate tumor cell survival, and the binding requirements for developing multidrug resistance inhibitors are discussed.