ABSTRACT
Modulators and inhibitors of multidrug efflux transporters, like P-glycoprotein, are used to reduce or inhibit multidrug resistance, MDR, which leads to a failure of the chemotherapy of e.g. cancers, epilepsy, bacterial, parasitic, and fungal diseases. Binding and transport of first-, second-, and third-generation modulators and inhibitors of P-glycoprotein are discussed, taking into account the properties of the drug (H-bonding potential, dimensions, and pK(a) values) as well as the properties of the membrane.
Subject(s)
Membrane Transport Modulators , Membrane Transport Proteins/antagonists & inhibitors , Pharmaceutical Preparations/metabolism , Animals , Biological Transport , Chemical Phenomena , Chemistry, Physical , Humans , Kinetics , Membrane Transport Proteins/metabolism , Membranes/metabolism , Proteins/antagonists & inhibitors , Proteins/metabolism , ThermodynamicsABSTRACT
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.
