P-glycoprotein interaction with risperidone and 9-OH-risperidone studiedin vitro, in knock-out mice and in drug-drug interaction experiments

Ejsing, Thomas Broeng; Pedersen, Anne D.; Línnet, Kristían

doi:10.1002/hup.720

Cited by 53 publications

(41 citation statements)

References 32 publications

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“…Risperidone and its metabolite 9-OH-risperidone are well studied P-gp substrates in mice with profound P-gp effects on extent of brain penetration shown by at least 10 times higher K p values in knockout mice in a range of different studies (Wang et al, 2004;Doran et al, 2005;Ejsing et al, 2005). These reports aligned well with the present results showing that these compounds were the most pronounced substrates in the test set with increases in K p values in similar ranges in both mice and rats.…”

Section: Discussionsupporting

confidence: 90%

Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice

Bundgaard¹,

Jensen²,

Garmer³

2011

Drug Metab Dispos

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ABSTRACT:The experiments described herein compared the extent of in vivo P-glycoprotein (P-gp)-mediated brain efflux between rats and mice for a set of known central nervous system compounds. With use of newly introduced genetically modified mdr1a-deficient rats and their gene-competent counterparts, the brain to plasma distribution was assessed and compared with the distribution pattern in mdr1a-deficient and wild-type mice. Four compounds (aripiprazole, citalopram, risperidone, and venlafaxine) were administered using a continuous subcutaneous osmotic minipump infusion paradigm. Steady-state brain and plasma concentrations of the compounds, including selected metabolites (9-hydroxyrisperidone, O-desmethyl-venlafaxine and N-desmethyl-venlafaxine) were measured in mdr1a-deficient rats and mice and their wild-type counterparts along with their free fractions to determine total and unbound brain to plasma distribution between genotypes within and between species. The results revealed qualitative as well as quantitative similarities between P-gp functionality in vivo at the blood-brain barrier level in rats and mice. All compounds tested were shown to have a significantly higher brain to plasma distribution in both mdr1a-deficient rats and mice compared with that in their wild-type counterparts. Moreover, the relative enhancement in extent of brain penetration between mdr1a-deficient and wild-type rats could be directly correlated to the enhancement ratios obtained in mice. From the unbound brain to unbound plasma distributions, the impact of P-gp on the overall brain penetration capabilities showed minor differences between rats and mice for the compounds tested. In conclusion, a comparable functional role of P-gp between rats and mice with respect to brain efflux mediated by this transporter is suggested.

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Section: Discussionsupporting

confidence: 90%

Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice

Bundgaard¹,

Jensen²,

Garmer³

2011

Drug Metab Dispos

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“…The metabolite possesses intrinsic potency similar to the parent. Deconvolution of the relative contributions of each to efficacy is challenging because of potential differences in brain penetrability caused by P-glycoprotein, for which both parent and metabolite are substrates Ejsing et al, 2005). In mouse, risperidone and 9-hydroxyrisperidone brain penetration appear to be hampered 10-and 20-fold, respectively, as shown by comparison of brain/plasma ratios in multidrug resistance knockout mice.…”

Section: Procainamidementioning

confidence: 99%

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Obach

2013

Pharmacol Rev

138

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“…Studies 7,8, and 9 investigated the effects of lurasidone on the PK of digoxin, midazolam, and the oral contraceptive steroids ethinyl estradiol and norelgestromin, respectively. Digoxin is a substrate for P-gp [25][26][27] and is potentially susceptible to interactions involving drugs that inhibit or induce this transporter. CYP3A4 inhibitors or inducers often have corresponding effects on P-gp [25].…”

Section: Discussionmentioning

confidence: 99%

Lurasidone drug-drug interaction studies: a comprehensive review

Chiu

Ereshefsky

Preskorn

et al. 2014

Drug Metabolism and Drug Interactions

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Background: To evaluate potential drug-drug interactions with the atypical antipsychotic lurasidone. Methods: Seven phase I studies were conducted to investigate the effects of repeated dosing of ketoconazole, diltiazem, rifampin, or lithium on the pharmacokinetics (PK) of single oral doses of lurasidone, or the effects of repeated dosing of lurasidone on the PK of digoxin, midazolam, or the oral contraceptive norgestimate/ethinyl estradiol. Two 6-week, phase III studies included evaluation of the potential for interaction between lurasidone and lithium or valproate. Maximum serum or plasma concentration (C max ) and area under the concentration-time curve (AUC) were calculated. Results: Concomitant ketoconazole administration resulted in a 6.8-fold increase in lurasidone C max and a 9.3-fold increase in lurasidone AUC; concomitant diltiazem administration resulted in 2.1-and 2.2-fold increases, respectively. Rifampin decreased lurasidone C max and AUC (one-seventh and onefifth of lurasidone alone, respectively). Steady-state dosing with lurasidone increased C max and AUC 0-24 (AUC from time 0 to 24 h postdose) of digoxin by 9% and 13%, respectively, and of midazolam by 21% and 44%, respectively. There were no significant interactions between lurasidone and lithium, valproate, ethinyl estradiol, or norelgestromin (the major active metabolite of norgestimate). Conclusions: Lurasidone PK is altered by strong cytochrome P450 (CYP) 3A4 inhibitors or inducers, and coadministration is contraindicated; whereas moderate CYP3A4 inhibitors have less effect, and lurasidone dosage restrictions are recommended. No dose adjustment

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P-glycoprotein interaction with risperidone and 9-OH-risperidone studiedin vitro, in knock-out mice and in drug-drug interaction experiments

Cited by 53 publications

References 32 publications

Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice

Species Comparison of In Vivo P-Glycoprotein-Mediated Brain Efflux Using mdr1a-Deficient Rats and Mice

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

Lurasidone drug-drug interaction studies: a comprehensive review

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