PT  - JOURNAL ARTICLE
AU  - Weiss, Johanna
AU  - Dormann, Sven-Maria Gregor
AU  - Martin-Facklam, Meret
AU  - Kerpen, Christian Johannes
AU  - Ketabi-Kiyanvash, Nahal
AU  - Haefeli, Walter Emil
TI  - Inhibition of P-Glycoprotein by Newer Antidepressants
AID  - 10.1124/jpet.102.046532
DP  - 2003 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 197--204
VI  - 305
IP  - 1
4099  - http://jpet.aspetjournals.org/content/305/1/197.short
4100  - http://jpet.aspetjournals.org/content/305/1/197.full
SO  - J Pharmacol Exp Ther2003 Apr 01; 305
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