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(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.
Seelig
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A
Department of Biophysical Chemistry, Biocenter, University of Basel, Klingelbergstrasse 70, Basel, Switzerland. anna.seelig@unibas.ch
Landwojtowicz
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E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000638:Amiodarone / Q000493:pharmacokinetics; D000639:Amitriptyline / Q000493:pharmacokinetics; D000818:Animals; D016466:CHO Cells; D003078:Colchicine / Q000493:pharmacokinetics; D006224:Cricetinae; D016572:Cyclosporine / Q000493:pharmacokinetics; D003630:Daunorubicin / Q000493:pharmacokinetics; D004110:Diltiazem / Q000493:pharmacokinetics; D007700:Kinetics; D008823:Micelles; D011374:Progesterone / Q000493:pharmacokinetics; D011433:Propranolol / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000493:pharmacokinetics; D014747:Vinblastine / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008823:Micelles; D000639:Amitriptyline; D011374:Progesterone; D014747:Vinblastine; D016572:Cyclosporine; D011433:Propranolol; D014700:Verapamil; D000251:Adenosine Triphosphatases; D004110:Diltiazem; D000638:Amiodarone; D003078:Colchicine; D003630:Daunorubicin