Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein

Wang, Jun Sheng; Zhu, Hao; Markowitz, John S.; Donovan, Jennifer L.; DeVane, C. Lindsay

doi:10.1007/s00213-006-0437-9

Cited by 113 publications

(76 citation statements)

References 55 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3,11,12) This is the first report for a minimal role of P-gp in disposition of bupropion and its three major metabolites. Our results are in good agreement with our previous pharmacokinetic study in CF1 mice, in which risperidone, a substrate and inhibitor of P-gp 22,24,27) showed negligible effects on plasma and brain concentrations of bupropion and its metabolite HB. 22) The minimal involvement of P-gp in disposition of bupropion suggests that alteration of P-gp activity is not an important source for drug-drug interactions and variable therapeutic response of bupropion.…”

Section: Discussionsupporting

confidence: 92%

“…Our results are in good agreement with our previous pharmacokinetic study in CF1 mice, in which risperidone, a substrate and inhibitor of P-gp 22,24,27) showed negligible effects on plasma and brain concentrations of bupropion and its metabolite HB. 22) The minimal involvement of P-gp in disposition of bupropion suggests that alteration of P-gp activity is not an important source for drug-drug interactions and variable therapeutic response of bupropion. The major mechanism for previous reported alteration of bupropion plasma concentrations by other perpetration drugs is by changing of the metabolic enzyme activities of bupropion.…”

Section: Discussionsupporting

confidence: 92%

“…A combination of this and cellular transport experiment in cell lines overexpressing P-gp and/or P-gp knockout mouse experiment will help to answer unequivocally if these compounds are substrates of P-gp. Our results are in good agreement with our recent in vivo drug-drug interaction study in CF1 mice, 22) in which the brain concentrations of sertraline in CF1 mice 1 h after sertraline administration were significantly increased (about 2.2-fold) by coadministration of risperidone, a potent inhibitor of P-gp. 23) In addition, sertraline also significantly increased brain concentrations and AUC values of risperidone, a substrate of P-gp.…”

Section: Discussionsupporting

confidence: 92%

“…23) In addition, sertraline also significantly increased brain concentrations and AUC values of risperidone, a substrate of P-gp. 24) These results suggest that sertraline may not only be a substrate of P-gp, but also be an effective in vivo inhibitor of P-gp 22) and can increase brain entry of other substrates of P-gp. This conclusion is also consistent with an in vitro study in which sertraline was reported to be a strong inhibitor of P-gp.…”

Section: Discussionmentioning

confidence: 90%

See 3 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 90%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Why the IC50 for the inhibition of AB by CPZ in intact cells decreased with incubation time and ultimately surpasses its IC50 for its direct effect on Complex I in isolated mitochondria is unclear. This is unlikely to relate to its behaviour as a blocker of P-GP mediated efflux since both HAL and RIS also block P-GP with potencies nearly identical to that of CPZ [19].…”

Section: Effect Of Antipsychotics On Mitochondrial Electron Transportmentioning

confidence: 98%

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Elmorsy

Smith

2015

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Antipsychotics (APs) are widely used medications, however these are not without side effects such as disruption of blood brain barrier function (BBB). To investigate this further we have studied the chronic effects of the typical APs, chlorpromazine (CPZ) and haloperidol (HAL) and the atypical APs, risperidone (RIS) and clozapine (CLZ), on the bioenergetics of human micro-vascular endothelial cells (HBVECs) of the BBB. Alamar blue (AB) and ATP assays showed that these APs impair bioenergenesis in HBVECs in a concentration and time dependent manner. However since these effects were incomplete they suggest a population of cell bioenergetically heterogeneous, an idea supported by the bistable nature by which APs affected the mitochondrial transmembrane potential. CPZ, HAL and CLZ inhibited the activity of mitochondrial complexes I and III.Our data demonstrates that at therapeutic concentrations, APs can impair the bioenergetic status of HBVECs, an action that help explains the adverse side effects of these drugs when used clinically.

show abstract

Antipsychotic Drugs

et al. 2015

View full text Add to dashboard Cite

Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein

Abstract: Pharmacokinetic interactions due to inhibition of P-gp activity by the antipsychotics appear possible and warrant further investigation.

Cited by 113 publications

References 55 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

Bioenergetic disruption of human micro-vascular endothelial cells by antipsychotics

Antipsychotic Drugs

Contact Info

Product

Resources

About