Competitive, non-competitive and cooperative interactions between substrates of P-glycoprotein as measured by its ATPase activity

Biochim Biophys Acta. 1997 Aug 22;1361(2):169-76. doi: 10.1016/s0925-4439(97)00027-6.


We have studied the interaction between verapamil and other modulators of the P-glycoprotein ATPase from membranes of CR1R12 Chinese hamster ovary cells. Four major categories of interaction were identified. (i) Non-competitive inhibition of verapamil's stimulation of enzyme activity was found with vanadate. (ii) Competitive inhibition of the ATPase was found for the pair verapamil and cyclosporin A. (iii) Allosteric inhibition with an increase in the Hill number for verapamil was found in the cases of daunorubicin, epirubicin, gramicidin S and D, vinblastine, amiodarone, and colchicine. (iv) Cooperative stimulation of verapamil-induced ATPase activity was found with progesterone, diltiazem, amitriptyline, and propranolol. At high levels, progesterone and verapamil mutually enhanced each other's inhibitory action on the ATPase. Our data show that the substrate binding behavior of P-glycoprotein is complex with more than one binding site being present. This information could form the basis for the development of improved modulators of P-glycoprotein.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • Adenosine Triphosphatases / antagonists & inhibitors
  • Adenosine Triphosphatases / metabolism*
  • Animals
  • Binding Sites
  • CHO Cells / drug effects
  • CHO Cells / metabolism
  • Colchicine / pharmacology
  • Cricetinae
  • Daunorubicin / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Resistance, Multiple*
  • Enzyme Activation / drug effects
  • Gramicidin / pharmacology
  • Kinetics
  • Microsomes / drug effects
  • Progesterone / pharmacology
  • Vanadates / pharmacology
  • Verapamil / pharmacology
  • Vinblastine / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Gramicidin
  • Vanadates
  • Progesterone
  • Vinblastine
  • Verapamil
  • Adenosine Triphosphatases
  • Colchicine
  • Daunorubicin