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Research ArticleNEUROPHARMACOLOGY

Inhibition of P-Glycoprotein by Newer Antidepressants

Johanna Weiss, Sven-Maria Gregor Dormann, Meret Martin-Facklam, Christian Johannes Kerpen, Nahal Ketabi-Kiyanvash and Walter Emil Haefeli
Journal of Pharmacology and Experimental Therapeutics April 2003, 305 (1) 197-204; DOI: https://doi.org/10.1124/jpet.102.046532
Johanna Weiss
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Sven-Maria Gregor Dormann
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Meret Martin-Facklam
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Christian Johannes Kerpen
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Nahal Ketabi-Kiyanvash
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Walter Emil Haefeli
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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

  • This work was supported by Grant 01EC9902 from the German Ministry for Education and Research (Das Bundesministerium für Bildung und Forschung).

  • 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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Journal of Pharmacology and Experimental Therapeutics: 305 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 1
1 Apr 2003
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Research ArticleNEUROPHARMACOLOGY

Inhibition of P-Glycoprotein by Newer Antidepressants

Johanna Weiss, Sven-Maria Gregor Dormann, Meret Martin-Facklam, Christian Johannes Kerpen, Nahal Ketabi-Kiyanvash and Walter Emil Haefeli
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 197-204; DOI: https://doi.org/10.1124/jpet.102.046532

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Research ArticleNEUROPHARMACOLOGY

Inhibition of P-Glycoprotein by Newer Antidepressants

Johanna Weiss, Sven-Maria Gregor Dormann, Meret Martin-Facklam, Christian Johannes Kerpen, Nahal Ketabi-Kiyanvash and Walter Emil Haefeli
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 197-204; DOI: https://doi.org/10.1124/jpet.102.046532
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