The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein

Wang, Junsheng; Ruan, Yi; Taylor, Robin M.; Donovan, Jennifer L.; Markowitz, John S.; DeVane, C. Lindsay

doi:10.1017/s1461145704004390

Cited by 134 publications

(99 citation statements)

References 14 publications

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“…Subsequent in vivo studies in P-gp knockout mouse models by our group and others revealed that brain concentration, and ratio of brain-to-plasma concentrations of RSP and its major metabolite, PALI, were significantly higher in knockout mice vs wild-type animals (Wang et al, 2004a;Doran et al, 2005). These results indicated that both RSP and PALI are substrates of P-gp and that their disposition might be influenced by the functional Results are reported as mean7SD, n ¼ 3.…”

Section: Discussionmentioning

confidence: 93%

“…Our previous work showed that the increase of brain-to-plasma ratio of PALI compared to RSP was greater in P-gp knockout mice than control mice (Wang et al, 2004a). Although both these compounds are P-gp substrates, the added capability of RSP to inhibit P-gp at the level of the BBB suggests a potential for enhancing the entry of PALI into the central nervous system when PALI is formed following the oral administration of RSP.…”

Section: Discussionmentioning

confidence: 99%

“…However, the off-rate for dissociation from human cloned D 2 receptor is faster for PALI (60 s) compared to RSP (27 min) (Seeman, 2005). By using the P-gp knockout mouse model, we and others have demonstrated that both RSP and PALI are P-gp substrates and their entry into the brain is dramatically limited by P-gp in the BBB (Wang et al, 2004a;Doran et al, 2005). Following intraperitoneal (i.p.)…”

Section: Introductionmentioning

confidence: 87%

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Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

Zhu

Wang

Markowitz

et al. 2006

Neuropsychopharmacol

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Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentrationdependent manner. The IC 50 values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 mM, respectively, whereas the IC 50 values of PALI were 4100 mM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood-brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1-50 mM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC 50 value of 5.87 mM. Following exposure to 10 mM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

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Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

Zhu

Wang

Markowitz

et al. 2006

Neuropsychopharmacol

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“…Specifically, risperidone was selected as a drug in which net efflux across the BBB was expected. There are several reports based on Mdr1a KO models demonstrating that Pgp reduces risperidone uptake into the brains of both mice (Wang et al, 2004;Doran et al, 2005;Summerfield et al, 2006) and rats (Bundgaard et al, 2012). Using plasma and brain homogenate free fraction analysis, efflux asymmetry was observed in mice (Mau- (Watson et al, 2009).…”

Section: Compartmental Pk Parameter Estimates Based On Simultaneous Fmentioning

confidence: 99%

Microdialysis Evaluation of Clozapine and N-Desmethylclozapine Pharmacokinetics in Rat Brain

et al. 2012

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ABSTRACT:A significant barrier to realization of the full potential of clozapine as a therapeutic agent in the treatment of schizophrenia is the substantial interpatient variability that exists along the therapeutic continuum of no response-efficacious response-adverse response. Genetic polymorphisms that manifest as highly variable pharmacodynamic and pharmacokinetic measures are its expected causes. To support investigations that seek to understand these causes, the plasma and central nervous system pharmacokinetics of clozapine were determined in rats, the latter using microdialysis sampling. Results obtained with clozapine and Ndesmethylclozapine, a pharmacologically active human metabolite that was administered to a separate group of animals, support a conclusion of net carrier-mediated efflux of both compounds across the blood-brain barrier. These results are supported by the replication of published findings regarding the passive transport and net efflux transport of two model compounds, escitalopram and risperidone, respectively. The results obtained with clozapine and N-desmethylclozapine are considered a first step in the development of preclinical pharmacokinetic-pharmacodynamic models that will support deeper mechanistic studies of clozapine in in vivo pharmacology, as well as the development of translational models that augment pharmacogenetic investigations that seek to improve the safety and efficacy of clozapine therapeutic intervention in the treatment of schizophrenia.

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“…The two mouse genes are supposed to exhibit similar characteristics as the human isoform. Accordingly, the abcb1ab knockout mouse model has been a valuable tool to identify drugs that are P-gp substrates (Doran et al, 2005;Karlsson et al, 2011;Karlsson et al, 2010;Kirschbaum et al, 2008;Uhr et al, 2000;Wang et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

Karlsson¹,

Carlsson²,

Hiemke³

et al. 2013

European Neuropsychopharmacology

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According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the S-enantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp. P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10 mg/kg) or escitalopram (5 mg/kg). Serum and brain samples were collected 1-6 h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. In brain, 3-fold higher concentrations of S-and R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls. The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.

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The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein

Cited by 134 publications

References 14 publications

Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro

Microdialysis Evaluation of Clozapine and N-Desmethylclozapine Pharmacokinetics in Rat Brain

Altered brain concentrations of citalopram and escitalopram in P-glycoprotein deficient mice after acute and chronic treatment

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