RT Journal Article SR Electronic T1 Inhibition of P-Glycoprotein by Newer Antidepressants JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 197 OP 204 DO 10.1124/jpet.102.046532 VO 305 IS 1 A1 Weiss, Johanna A1 Dormann, Sven-Maria Gregor A1 Martin-Facklam, Meret A1 Kerpen, Christian Johannes A1 Ketabi-Kiyanvash, Nahal A1 Haefeli, Walter Emil YR 2003 UL http://jpet.aspetjournals.org/content/305/1/197.abstract AB Pharmacokinetic drug-drug interactions often occur at the level of P-glycoprotein (Pgp). To study possible interactions caused by the newer antidepressants we investigated citalopram, fluoxetine, fluvoxamine, paroxetine, reboxetine, sertraline, and venlafaxine and their major metabolites desmethylcitalopram, norfluoxetine, paroxetine-metabolite (paroxetine-M), desmethylsertraline,N-desmethylvenlafaxine, andO-desmethylvenlafaxine for their ability to inhibit Pgp. Pgp inhibition was studied by a fluorometric assay using calcein-acetoxymethylester as Pgp substrate and two different cell systems: L-MDR1 cells (model for human Pgp) and primary porcine brain capillary endothelial cells (pBCECs, model for the blood-brain barrier). Both cell systems proved to be suitable for the evaluation of Pgp inhibitory potency of drugs. All antidepressants tested exceptO-desmethylvenlafaxine showed Pgp inhibitory activity with sertraline, desmethylsertraline, and paroxetine being the most potent, comparable with the well known Pgp inhibitor quinidine. In L-MDR1 cells fluoxetine, norfluoxetine, fluvoxamine, reboxetine, and paroxetine-M revealed intermediate Pgp inhibition and citalopram, desmethylcitalopram, venlafaxine, andN-desmethylvenlafaxine were only weak inhibitors. The ranking order was similar in pBCECs. The fact that some of the compounds tested exert Pgp inhibitor effects at similar concentrations as quinidine suggests that pharmacokinetic drug-drug interactions between the newer antidepressants and Pgp substrates should now be thoroughly studied in vivo. The American Society for Pharmacology and Experimental Therapeutics