Structure-activity relationship of P-glycoprotein substrates and modifiers

The air-water partition coefficients, K-aw, highly correlated with the corresponding lipid-water partition coefficients, K-iw, and the critical micelle concentrations. CMC, were measured for 11 compounds for which the kinetic parameters of P-glycoprotein ATPase activation (Michaelis-Menten constant, K-m, and maximal velocity, V-max) had been determined previously in inside-out vesicles of CR1R12 Chinese hamster ovary cells. In addition, the hydrogen bond donor patterns (type I and type II) relevant for substrate recognition by P-glycoprotein were determined from the energy-minimized three-dimensional structure of these compounds. A linear relation between the air-water partition coefficient, K-aw, and the inverse of the Michaelis-Menten constant, K-m, was observed such that K-m-K(aw)similar to1. The maximal velocity, V-max, was shown to decrease with the number and strength of electron donor (hydrogen bond acceptor) groups in recognition patterns. If two substrates are applied simultaneously to P-glycoprotein the compound with the higher potential to form hydrogen bonds generally acts as an inhibitor. We conclude that partitioning into the lipid membrane is the rate-limiting step for the interaction of a substrate with P-glycoprotein and that dissociation of the P-glycoprotein-substrate complex is determined by the number and strength of the hydrogen bonds formed between the substrate and the transporter. (C) 2000 Elsevier Science BN. All rights reserved.