Many P-glycoprotein substrates do not inhibit the transport process across cell membranes

1. The critical role of P-glycoprotein (P-gp) in the clinical exposure of many pharmaceuticals and toxins has become widely appreciated. The P-gp-mediated influence can often be more significant than that of other well-known xenobiotic defence enzymes in both breadth and impact. The inhibition of P-gp, therefore, has often been examined by testing a compound for its influence on the P-gp-mediated transport of some marker substrate, often the compound is also evaluated for its active efflux mediated by P-gp. 2. Although a substrate for a xenobiotic defence enzyme is logically presumed to be an inhibitor of that enzyme toward an alternate substrate, that is not necessarily the case with a transmembrane active efflux transporter. A substrate that is ejected from the cytosolic side of the membrane bilayer that does not rapidly cross the membrane by passive diffusion back into the cell interior will not occlude the substrate binding site. Hence, some substrates may not significantly affect the overall P-gp fun...