Metabolism of Vabicaserin in Mice, Rats, Dogs, Monkeys, and Humans

Abstract

ABSTRACT:Vabicaserin is a potent 5-hydroxytryptamine 2C agonist that is currently being developed for the treatment of the psychotic symptoms of schizophrenia. In this study, in vitro and in vivo metabolism of vabicaserin was evaluated in mice, rats, dogs, monkeys, and humans, and the structures of the metabolites were characterized by liquid chromatography/mass spectrometry and NMR spectroscopy. Vabicaserin underwent three major metabolic pathways in vitro: NADPH-dependent hydroxylation, NADPH-independent imine formation, and carbamoyl glucuronidation. After a single oral dose, vabicaserin was extensively metabolized in animals and humans, and its metabolites were mainly excreted via the urine in mice and rats. Along with the metabolites observed in vitro, secondary metabolism via oxidation and conjugation of the primary metabolites generated from the abovementioned three pathways yielded a number of additional metabolites in vivo. Carbamoyl glucuronidation was the major metabolic pathway in humans but a minor pathway in rats. Although carbamoyl glucuronidation was a major metabolic pathway in mice, dogs, and monkeys, oxidative metabolism was also extensive in these species. Hydroxylation occurred in all species, although different regional selectivity was apparent. The imine pathway also appeared to be common to several species, because vabicaserin imine was observed in humans and hydroxyl imine metabolites were observed in mice, rats, and dogs. A nitrone metabolite of vabicaserin was observed in dogs and humans but not in other species. In conclusion, the major metabolic pathways for vabicaserin in humans and nonclinical safety species include carbamoyl glucuronidation, hydroxylation, formation of an imine, and a nitrone.

A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the “Metabolites in Safety Testing” Regulatory Guidance

“…M12 accounted for greater than 50% of total drug-related material in circulation based on mass spectrometry and UV response data. Based on the mixed matrix method (Tong et al, 2010a;Ma and Chowdhury, 2011;Takahashi et al, 2017), M12 was disproportionate in human circulation and not covered in rat and dog toxicology species (less than 0.1% preclinical/clinical exposure) and this was subsequently confirmed by a bioanalytical assay with an authentic standard. M12 was determined to be formed and circulating in rabbit plasma and provided coverage for the embryo fetal development study (seg II).…”

“…It is extensively metabolized in animal species (mouse, rat, dog, monkey) and in human both in vitro and in vivo (Tong et al, 2010b). The predominant metabolic pathway in humans was due to carbamoyl glucuronidation; however, other metabolic pathways including oxidation (with formation of multiple hydroxyl metabolites) and formation of imine and nitrone metabolites were also observed (Tong et al, 2010a was also the major entity in human urine, and this metabolic pathway may account for >50% of the total clearance based on urinary concentrations (Tong et al, 2010b). Even though formation of M6 was observed in animal species, the systemic exposures to M6 relative to parent appeared to be less than humans (higher amounts in mice, dogs and monkeys; very low amounts in rats and rabbits), as determined using validated LC/MS/MS methods.…”

“…One of the minor metabolites (M5, a nitrone metabolite) was synthesized (Tong et al, 2010a), bioanalytical assays were validated and sufficient exposure coverage in animals was demonstrated. However, at least two secondary metabolites formed by both hydroxylation and nitrone pathways and three other minor metabolites might also reach or exceed the 10% threshold relative to parent.…”

“…For this comparison, typically discrete time-collected pools across all subjects or "AUC pools" (Hamilton et al, 1981;Hop et al, 1998) are prepared. First, relative quantities in human and animal samples are compared using the mixed matrix methodology (Gao et al, 2010;Ma et al, 2010;Tong et al, 2010a;Takahashi et al, 2017) in order to identify potential issues as soon as possible. This method is practical and robust.…”

Selective serotonin 5-HT2C receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues

“…In a compound series recently developed at Wyeth Research, vabicaserin (SCA-136) was identified as a selective 5-HT 2C R full agonist (K i = 3 nM; efficacy 100% relative to 5-HT), a 5-HT 2B R antagonist (IC 50 = 29 nM) and a very weak 5-HT 2A R antagonist (IC 50 = 1,650 nM) (Rosenzweig-Lipson, et al, 2007a; Tong, et al, 2010a; Tong, et al, 2010b). Vabicaserin has been in clinical trials to evaluate antipsychotic potential (www.clinicaltrials.gov).…”