Induction of Multiple Drug Transporters by Efavirenz

Weiß, Johanna; Herzog, Melanie; König, Sonja K.; Storch, Caroline Henrike; Ketabi-Kiyanvash, Nahal; Haefeli, Walter E.

doi:10.1254/jphs.08209fp

Cited by 62 publications

(55 citation statements)

References 38 publications

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“…This conclusion is also consistent with an in vitro study in which sertraline was reported to be a strong inhibitor of P-gp. 25) The involvement of P-gp in the disposition of sertraline and desmethylsertraline is consistent with a recent clinical observation of placental passage of antidepressants. 26) In this study, sertraline and desmethylsertraline exhibited the lowest umbilical cord to maternal serum ratio (0.29) followed by paroxetine (0.54), fluoxetine, (0.64), and citalopram (0.71).…”

Section: Discussionsupporting

confidence: 87%

Sertraline and Its Metabolite Desmethylsertraline, but not Bupropion or Its Three Major Metabolites, Have High Affinity for P-Glycoprotein

Wang

Zhu

Gibson

et al. 2008

Biological & Pharmaceutical Bulletin

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The drug transporter protein, P-glycoprotein (P-gp), is a member of the ATP-binding cassette (ABC) superfamily that is widely localized at various human tissues including the apical membranes of the gastrointestinal tract, the biliary canalicular membranes of hepatocytes, the luminal membranes of proximal tubular epithelial cells in the kidney, the testes, the placenta and the luminal membranes of endothelial cells of the blood-brain barrier (BBB). 1,2) As a drug efflux transporter, P-gp plays important role in drug absorption, distribution, and excretion. [3][4][5] Inhibition and induction of P-gp function can result in significant drug-drug interactions.The function of P-gp in BBB can significantly limit the brain uptake of its substrate drugs and affect therapeutic outcomes of central nervous system (CNS) acting drugs. By using the ABCB1a/b Ϫ/Ϫ knockout mice, P-gp has been shown to significantly limit the brain entry of a wide variety of structurally unrelated drugs. [6][7][8][9][10][11][12][13][14] Inhibition of P-gp activity can greatly increase P-gp substrate concentrations in brain and may increase their neurotoxicity. [15][16][17] Because of the importance of P-gp in CNS drug disposition, characterization of the binding affinities of CNS drugs for P-gp has clinical implications.Newer antidepressants, i.e. the selective serotonin reuptake inhibitors (SSRIs) and multi-receptor antidepressants, venlafaxine, mirtazapine, bupropion, and nefazodone have advantages over the classical tricyclic antidepressants in lower frequency to cause unwanted side effects and are extensively used worldwide due to established antidepressants efficacy. 18) However, a substantial number of patients with antidepressant therapy still exhibit treatment resistance despite increasing doses. The reason for this resistance is unknown.Recently, the transport efficacy of most of the antidepressants by P-gp has been studied by using the ABCb1a/b Ϫ/Ϫ mouse or in vitro cell culture models [10][11][12]19) except for two drugs, sertraline and bupropion. In these reports, most of the studied antidepressants (e.g. amitriptyline, nortryptyline, citalopram, and trimipramine) were shown to be substrates of P-glycoprotein. [10][11][12]19) These results suggest that the variable expression of P-gp among patients may be an important source of variability in treatment response for the antidepressants.With availability of human P-gp membranes, we have previously used an ATPase assay method to determine the drug stimulated P-gp-ATPase activity and binding affinity of several antipsychotic drugs. 20) Our results indicated that atypical antipsychotic drugs (AAPs), risperidone, and olanzapine, were effectively transported by P-gp. The findings have been verified by our subsequent in vivo Abcb1a/b gene knockout mouse experiments, 13,14) supporting the ATPase assay to provide reliable information of P-gp substrates' binding affinity. In the present report, we studied the binding affinity of sertraline, desmethylsertraline, bupropion and its three major meta...

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Section: Discussionsupporting

confidence: 87%

Sertraline and Its Metabolite Desmethylsertraline, but not Bupropion or Its Three Major Metabolites, Have High Affinity for P-Glycoprotein

Wang

Zhu

Gibson

et al. 2008

Biological & Pharmaceutical Bulletin

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“…The cell line LS180 (available at ATCC, Manassas, VA, USA), a cell line derived from human colon adenocarcinoma, was used to investigate changes of drug transporter mRNA expression by induction [18] and to estimate the reciprocal effects on cytostatic properties of the drugs used.…”

Section: Cell Linesmentioning

confidence: 99%

“…Cells were cultured under standard cell-culture conditions as described previously [18] and were seeded 3 days before the assay.…”

Section: Cell Linesmentioning

confidence: 99%

Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy

Theile

Grebhardt

Haefeli

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In conclusion, we propose as one mechanism for FOLFOX synergism the 5-FU mediated suppression of ATP7B, the over-expression of glutathione exporters such as MRP2/ABCC2 and the decrease of glutathione levels by oxalate.

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“…Efavirenz acts as both an inducer and an inhibitor of CYP3A4. In vivo, it induces hepatic but not intestinal CYP3A4 (Mouly et al, 2002), and in vitro studies demonstrated an induction of CYP3A4 transcription by efavirenz (Hariparsad et al, 2004;Weiss et al, 2009). In vitro, efavirenz also acts as a weak CYP3A inhibitor (von Moltke et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Drug Interaction of Efavirenz and Midazolam: Efavirenz Activates the CYP3A-Mediated Midazolam 1′-Hydroxylation In Vitro

Keubler

Weiß²,

Haefeli³

et al. 2012

Drug Metab Dispos

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Induction of Multiple Drug Transporters by Efavirenz

Cited by 62 publications

References 38 publications

Sertraline and Its Metabolite Desmethylsertraline, but not Bupropion or Its Three Major Metabolites, Have High Affinity for P-Glycoprotein

Sertraline and Its Metabolite Desmethylsertraline, but not Bupropion or Its Three Major Metabolites, Have High Affinity for P-Glycoprotein

Involvement of drug transporters in the synergistic action of FOLFOX combination chemotherapy

Drug Interaction of Efavirenz and Midazolam: Efavirenz Activates the CYP3A-Mediated Midazolam 1′-Hydroxylation In Vitro

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