Drug Accumulation and Binding in P-Glycoprotein-Associated Multidrug Resistance

Abstract

Multidrug resistance (MDR) is a complex phenomenon that has been well described in experimental systems (Beck, 1987; Pastan and Gottesman, 1987, 1988; Moscow and Cowan, 1988; Bradley et al., 1988; van der Bliek and Borst, 1989; Endicott and Ling, 1989). The characteristic feature, as detailed elsewhere in this volume, is a broad cross-resistance to a variety of apparently dissimilar natural-product compounds. The pharmacologic basis for MDR appears to be a decrease in the steady-state accumulation of drug, attributed to either its decreased uptake (Ling and Thompson, 1974) or decreased retention (Danø, 1973; Skovsgaard, 1978a). In turn, decreased drug retention has been ascribed either to increased activity of an “active efflux pump,” mediated through the action of a high-molecular-weight membrane glycoprotein, known as P-glycoprotein or to a diminished binding of drug (Beck, 1987, Pastan and Gottesman, 1988; Bradley et al., 1988; van der Bliek and Borst, 1989; Endicott and Ling, 1989). For clarity, I designate this form of MDR associated with overexpression of P-glycoprotein as Pgp-MDR, to distinguish it from another type of MDR associated with alterations in the essential nuclear enzyme, topoisomerase II, that we have termed at-MDR (Danks et al., 1987, 1988; Beck et al., 1987). Although decreased steady-state accumulation of drug distinguishes Pgp-MDR from other forms of MDR, the basis for this phenomenon has only recently begun to be understood.