In vitro P-glycoprotein affinity for atypical and conventional antipsychotics

Boulton, David W.; DeVane, C. Lindsay; Liston, Heidi L.; Markowitz, John S.

doi:10.1016/s0024-3205(02)01680-6

Cited by 249 publications

(172 citation statements)

References 12 publications

Supporting

Mentioning

158

Contrasting

Unclassified

Order By: Relevance

“…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.…”

mentioning

confidence: 80%

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

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

mentioning

confidence: 80%

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

View full text Add to dashboard Cite

show abstract

“…Alternatively, these APs may possess passive membrane permeability so high such that their rate of influx is larger than, and overwhelms that, of the Pglycoprotein efflux pathway; a scenario already demonstrated for CPZ in 20 BBB models (Seelig, 2007). Although these APs at ~30µM can stimulate the ATPase activity of P-glycoprotein and are perhaps substrates for transportation (Boulton et al, 2002), the observation that at similar concentrations they actually inhibit the ability of this protein to extrude the amphiphilic molecule, RH123 from cells (Wang et al, 2006) at excessively high concentrations of APs subsequent damage to the BBB would make it leaky, not just to blood solutes and components with ensuing extravasation (Pardridge et al, 1973;Ben-Schachar et al, 1994), were purchased from Sigma-Aldrich (Poole, UK) unless stated otherwise.…”

Section: Mechanisms Of Cytotoxicitymentioning

confidence: 97%

Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier

et al. 2014

View full text Add to dashboard Cite

show abstract

“…[45][46][47] The difference in drugs is likely not the reason for the discrepant results, because risperidone has a higher affinity for P-glycoprotein than olanzapine and thus a stronger effect would be expected. 10 It is not clear which of the ABCB1 polymorphisms is functional, and variable patterns of LD in the region can lead to different association results. Haplotype analysis would be useful to identify the genetic variants that have a role in drug response, but given our small sample size could not be carried out.…”

Section: Pharmacogenetics Of Risperidone In Autismmentioning

confidence: 99%

“…The rapid and complete absorption of risperidone after oral administration in the small intestine is mainly mediated by the P-glycoprotein, encoded by the ABCB1 gene, which acts as a barrier to drug absorption. 10 In the liver, risperidone is extensively metabolized by CYP2D6 to the active metabolite 9-OH-risperidone. 11 The CYP2D6 gene is extremely polymorphic and its variants are classified, based on encoded protein activity level, into four different phenotypes, which have a profound influence in the outcome of drug therapy: (1) extensive metabolizers, carry one or two alleles with normal function; (2) intermediate metabolizers, carry two decreased-function alleles or are heterozygous for one deficient allele and one decreased-function allele; (3) poor metabolizers, carry two non-functional alleles; (4) ultrarapid metabolizers, carry multiple copies of functional alleles.…”

Section: Introductionmentioning

confidence: 99%

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Almeida²,

et al. 2009

View full text Add to dashboard Cite

Little has been reported on the factors, genetic or other, that underlie the variability in individual response, particularly for autism. In this study we simultaneously explored the effects of multiple candidate genes on clinical improvement and occurrence of adverse drug reactions, in 45 autistic patients who received monotherapy with risperidone up to 1 year. Candidate genes involved in the pharmacokinetics (CYP2D6 and ABCB1) and pharmacodynamics (HTR2A, HTR2C, DRD2, DRD3, HTR6) of the drug, and the brain-derived neurotrophic factor (BDNF) gene, were analysed. Using the generalized estimating equation method these genes were tested for association with drug efficacy, assessed with the Autism Treatment Evaluation Checklist, and with safety and tolerability measures, such as prolactin levels, body mass index (BMI), waist circumference and neurological adverse effects, including extrapyramidal movements. Our results confirm that risperidone therapy was very effective in reducing some autism symptoms and caused few serious adverse effects. After adjusting for confounding factors, the HTR2A c.-1438G4A, DRD3 Ser9Gly, HTR2C c.995G4A and ABCB1 1236C4T polymorphisms were predictors for clinical improvement with risperidone therapy. The HTR2A c.-1438G4A, HTR2C c.68G4C (p.C33S), HTR6 c.7154-2542C4T and BDNF c.196G4A (p.V66M) polymorphisms influenced prolactin elevation. HTR2C c.68G4C and CYP2D6 polymorphisms were associated with risperidone-induced increase in BMI or waist circumference. We thus identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Although association results require replication, given the small sample size, the study makes a preliminary contribution to the personalized therapy of risperidone in autism.

show abstract

In vitro P-glycoprotein affinity for atypical and conventional antipsychotics

Cited by 249 publications

References 12 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

Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood–brain barrier

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

Contact Info

Product

Resources

About