Structure-activity relationship of P-glycoprotein substrates and modifiers

Eur J Pharm Sci. 2000 Nov;12(1):31-40. doi: 10.1016/s0928-0987(00)00177-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adenosine Triphosphatases / metabolism*
  • Amiodarone / pharmacokinetics
  • Amitriptyline / pharmacokinetics
  • Animals
  • CHO Cells
  • Colchicine / pharmacokinetics
  • Cricetinae
  • Cyclosporine / pharmacokinetics
  • Daunorubicin / pharmacokinetics
  • Diltiazem / pharmacokinetics
  • Kinetics
  • Micelles
  • Progesterone / pharmacokinetics
  • Propranolol / pharmacokinetics
  • Structure-Activity Relationship
  • Verapamil / pharmacokinetics
  • Vinblastine / pharmacokinetics


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Micelles
  • Amitriptyline
  • Progesterone
  • Vinblastine
  • Cyclosporine
  • Propranolol
  • Verapamil
  • Adenosine Triphosphatases
  • Diltiazem
  • Amiodarone
  • Colchicine
  • Daunorubicin