Effects of cardiovascular drugs on ATPase activity of P-glycoprotein in plasma membranes and in purified reconstituted form.
Drug interactions with P-glycoprotein (Pgp) were quantitatively assessed using ATPase assay. Two experimental systems were used, (i) plasma membranes isolated from a multidrug-resistant cell line, which contained 30% Pgp as fraction of total membrane protein, and (ii) purified reconstituted Pgp. The cardioactive drugs verapamil, quinidine, diltiazem, nifedipine, and a series of digitalis analogs, interacted directly with Pgp as shown on ATPase in both systems. Apparent affinities of drug binding were calculated. Direct competition was shown between digitoxin and verapamil. Drug-drug interaction in vivo at the level of Pgp is expected from the results. This approach seems well-suited for empirical determination of drug interactions with Pgp, and prediction of drug-drug interactions.
Rebbeor
J F
JF
Department of Biochemistry and Biophysics, University of Rochester Medical Center, NY 14642, USA. rebbeor@envmed.rochester.edu
Senior
A E
AE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006224:Cricetinae; D004071:Digitalis Glycosides / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D011374:Progesterone / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D004071:Digitalis Glycosides; D009270:Naloxone; D011374:Progesterone; D000251:Adenosine Triphosphatases; D011802:Quinidine