Work

Preclinical pharmacodynamic and pharmacokinetic characterization of the major metabolites of cariprazine

Year: 2019

Type: article

Abstract: 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. Keywords: dopamine, serotonin, schizophrenia, bipolar disorder, desmethyl-cariprazine, didesmethyl-cariprazine

Source: Drug Design Development and Therapy

DOI: 10.2147/dddt.s188760