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Structure-activity relationship of P-glycoprotein substrates and modifiers
Journal
European journal of pharmaceutical sciences
Volume
12
Number
1
Pages / Article-Number
31-40
Keywords
P-glycoprotein, multidrug resistance, Michaelis-Menten constant, K-m, maximal velocity, V-max, drug transport, P-gp ATPase activation, competitive binding, hydrogen bond formation
Abstract
The air-water partition coefficients, K(aw), highly correlated with the corresponding lipid-water partition coefficients, K(lw), 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) x K(aw) approximately = 1. 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.
