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Vol. 305, Issue 1, 197-204, April 2003
Department of Internal Medicine VI, Clinical Pharmacology, and
Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany
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, and
O-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 except
O-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, and
N-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.
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