Abstract
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.
Footnotes
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This work was supported by Grant 01EC9902 from the German Ministry for Education and Research (Das Bundesministerium für Bildung und Forschung).
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DOI: 10.1124/jpet.102.046532
- Abbreviations:
- Pgp
- P-glycoprotein
- MDR
- multidrug resistance
- SSRI
- selective serotonin reuptake inhibitor
- pBCEC
- porcine brain capillary endothelial cell
- calcein-AM
- calcein-acetoxymethylester
- DMSO
- dimethyl sulfoxide
- f2
- concentration needed to double baseline fluorescence
- RT-PCR
- reverse transcription-polymerase chain reaction
- HHBSS
- Hanks' balanced salt solution supplemented with 10 mM HEPES
- ppgp
- porcine P-glycoprotein
- PCR
- polymerase chain reaction
- IP50
- inhibitory potency at 50 μM
- MRP
- multidrug resistance-associated protein
- paroxetine-M
- paroxetine metabolite
- MK571
- 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid
- LY335979
- 1-piperazinethanol,4-(1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl)-α-[(5-quinolinoxy)methyl]- trihydrochloride, SDZ-PSC833, valspodar
- Received November 6, 2002.
- Accepted December 30, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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