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Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine
INTRODUCTION: : Cariprazine, a dopamine D(3)-preferring D(3)/D(2) receptor partial agonist and serotonin 5-HT(1A) receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the co...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Dove
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754336/ https://www.ncbi.nlm.nih.gov/pubmed/31571826 http://dx.doi.org/10.2147/DDDT.S188760 |
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author | Kiss, Béla Némethy, Zsolt Fazekas, Károly Kurkó, Dalma Gyertyán, István Sághy, Katalin Laszlovszky, István Farkas, Bence Kirschner, Norbert Bolf-Terjéki, Etelka Balázs, Ottilia Lendvai, Balázs |
author_facet | Kiss, Béla Némethy, Zsolt Fazekas, Károly Kurkó, Dalma Gyertyán, István Sághy, Katalin Laszlovszky, István Farkas, Bence Kirschner, Norbert Bolf-Terjéki, Etelka Balázs, Ottilia Lendvai, Balázs |
author_sort | Kiss, Béla |
collection | PubMed |
description | INTRODUCTION: : Cariprazine, a dopamine D(3)-preferring D(3)/D(2) receptor partial agonist and serotonin 5-HT(1A) receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy. METHODS: In vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. RESULTS: Similar to cariprazine, both metabolites showed high affinity for human D(3), D(2L), 5-HT(1A), 5-HT(2A), and 5-HT(2B) receptors, albeit with higher selectivity than cariprazine for D(3) versus D(2) receptors. In [(35)S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D(2) and D(3) receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D(2) and D(3) receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT(1A) receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT(2B) receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D(3) receptor occupancy in rat brain; however, cariprazine was more potent for D(2) receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D(2) receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine. CONCLUSION: Overall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy. |
format | Online Article Text |
id | pubmed-6754336 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Dove |
record_format | MEDLINE/PubMed |
spelling | pubmed-67543362019-09-30 Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine Kiss, Béla Némethy, Zsolt Fazekas, Károly Kurkó, Dalma Gyertyán, István Sághy, Katalin Laszlovszky, István Farkas, Bence Kirschner, Norbert Bolf-Terjéki, Etelka Balázs, Ottilia Lendvai, Balázs Drug Des Devel Ther Original Research INTRODUCTION: : Cariprazine, a dopamine D(3)-preferring D(3)/D(2) receptor partial agonist and serotonin 5-HT(1A) receptor partial agonist, has two major human metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). The metabolite pharmacology was profiled to understand the contribution to cariprazine efficacy. METHODS: In vitro receptor binding and functional assays, electrophysiology, animal models, microdialysis, and kinetic-metabolism approaches were used to characterize the pharmacology of DCAR and DDCAR. RESULTS: Similar to cariprazine, both metabolites showed high affinity for human D(3), D(2L), 5-HT(1A), 5-HT(2A), and 5-HT(2B) receptors, albeit with higher selectivity than cariprazine for D(3) versus D(2) receptors. In [(35)S]GTPγS binding assays, cariprazine and DDCAR were antagonists in membranes from rat striatum and from cells expressing human D(2) and D(3) receptors, and were partial agonists in membranes from rat hippocampus. In cAMP signaling assays, cariprazine, DCAR, and DDCAR acted as partial agonists at D(2) and D(3) receptors; cariprazine and DDCAR were full agonists, whereas DCAR was a partial agonist at 5-HT(1A) receptors. Cariprazine, DCAR, and DDCAR were pure antagonists at human 5-HT(2B) receptors. Cariprazine and DDCAR increased rat striatal dopamine and reduced cortical serotonin turnover. Cariprazine and DDCAR showed similar in vivo D(3) receptor occupancy in rat brain; however, cariprazine was more potent for D(2) receptor occupancy. Both cariprazine and DDCAR dose-dependently but partially suppressed the spontaneous activity of midbrain dopaminergic neurons in rats, with the parent compound being more potent but shorter acting than its metabolite. Consistent with the D(2) receptor occupancy profile, DDCAR was 3- to 10-fold less potent than cariprazine in rodent models of antipsychotic-like activity. Following acute cariprazine administration, DDCAR was detected in the rodent brain but at much lower levels than cariprazine. CONCLUSION: Overall, in vitro and in vivo pharmacological profiles of DCAR and DDCAR demonstrated high similarity with cariprazine, suggesting that the major metabolites of cariprazine contribute significantly to its clinical efficacy. Dove 2019-09-16 /pmc/articles/PMC6754336/ /pubmed/31571826 http://dx.doi.org/10.2147/DDDT.S188760 Text en © 2019 Kiss et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). |
spellingShingle | Original Research Kiss, Béla Némethy, Zsolt Fazekas, Károly Kurkó, Dalma Gyertyán, István Sághy, Katalin Laszlovszky, István Farkas, Bence Kirschner, Norbert Bolf-Terjéki, Etelka Balázs, Ottilia Lendvai, Balázs Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine |
title | Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine |
title_full | Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine |
title_fullStr | Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine |
title_full_unstemmed | Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine |
title_short | Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine |
title_sort | preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754336/ https://www.ncbi.nlm.nih.gov/pubmed/31571826 http://dx.doi.org/10.2147/DDDT.S188760 |
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