Species Differences in the Formation of Vabicaserin Carbamoyl Glucuronide

Abstract

ABSTRACT:Vabicaserin is a potent 5-hydroxtryptamine 2C full agonist with therapeutic potential for a wide array of psychiatric disorders. Metabolite profiles indicated that vabicaserin was extensively metabolized via carbamoyl glucuronidation after oral administration in humans. In the present study, the differences in the extent of vabicaserin carbamoyl glucuronide (CG) formation in humans and in animals used for safety assessment were investigated. After oral dosing, the systemic exposure ratios of CG to vabicaserin were approximately 12 and up to 29 in monkeys and humans, respectively, and the ratios of CG to vabicaserin were approximately 1.5 and 1.7 in mice and dogs, respectively. These differences in systemic levels of CG are likely related to species differences in the rate and extent of CG formation and elimination. Whereas CG was the predominant circulating metabolite in humans and a major metabolite in mice, dogs, and monkeys, it was a relatively minor metabolite in rats, in which oxidative metabolism was the major metabolic pathway. Although the CG was not detected in plasma or urine of rats, approximately 5% of the dose was excreted in bile as CG in the 24-h collection postdose, indicating the rat had the metabolic capability of producing the CG. In vitro, in a CO 2 -enriched environment, the CG was the predominant metabolite in dog and human liver microsomes, a major metabolite in monkey and mice, and only a very minor metabolite in rats. Carbamoyl glucuronidation and hydroxylation had similar contributions to vabicaserin metabolism in mouse and monkey liver microsomes. However, only trace amounts of CG were formed in rat liver microsomes, and other metabolites were more prominent than the CG. In conclusion, significant differences in the extent of formation of the CG were observed among the various species examined. The exposure ratios of CG to vabicaserin were highest in humans, followed by monkeys, then mice and dogs, and lowest in rats, and the in vitro metabolite profiles generally correlated well with the in vivo metabolites.Vabicaserin is a potent 5-hydroxtryptamine 2C (5-HT 2C ) full agonist and shows in vitro functional selectivity for 5-HT 2C over 5-hydroxtryptamine 2A (5-HT 2A ) and 5-hydroxtryptamine 2B (5-HT 2B ) receptors . Vabicaserin is effective in several animal models that are predictive of antipsychotic activity, with an atypical antipsychotic profile (Marquis et al., 2006). Administration of vabicaserin decreases nucleus accumbens dopamine without affecting striatal dopamine, which indicates mesolimbic selectivity (Marquis et al., 2006;Wacker and Miller, 2008). This profile is consistent with potential efficacy in the treatment of the psychotic symptoms of schizophrenia with decreased liability for extrapyramidal side effects. In addition, long-term administration of vabicaserin significantly decreases the number of spontaneously active mesocorticolimbic dopamine neurons without affecting nigrostriatal dopamine neurons (Marquis et al., 2006), consistent with the effects of atypi...

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

“…In vitro incubations were conducted to isolate metabolites by HPLC for structure elucidation as well as to evaluate in vitro metabolite profiles in various species. In vitro incubations with liver microsomes of mouse, rat, dog, monkey, and human in the presence of NADPH and UDPGA were the same as described previously (Tong et al, 2010). In brief, […”

“…After a single oral dose to healthy human volunteers, the CG was the predominant metabolite in human plasma and urine, with average CG-to-vabicaserin concentration ratios ranging from 8 to 74 in plasma and 96 to 537 in urine (Tong et al, 2010). However, oxidative metabolism also appeared to be occurring in vitro in liver microsomes (Tong et al, 2010).…”

“…Formation of a carbamoyl glucuronide (CG) was the major metabolic pathway in human liver microsomes with bicarbonate buffer and a CO 2 -enriched environment in the presence of both NADPH and uridine 5Ј-diphosphoglucuronic acid trisodium salt (UDPGA) (Tong et al, 2010). After a single oral dose to healthy human volunteers, the CG was the predominant metabolite in human plasma and urine, with average CG-to-vabicaserin concentration ratios ranging from 8 to 74 in plasma and 96 to 537 in urine (Tong et al, 2010).…”

“…After a single oral dose to healthy human volunteers, the CG was the predominant metabolite in human plasma and urine, with average CG-to-vabicaserin concentration ratios ranging from 8 to 74 in plasma and 96 to 537 in urine (Tong et al, 2010). However, oxidative metabolism also appeared to be occurring in vitro in liver microsomes (Tong et al, 2010). Although, the in vivo formation of oxidative metabolites was evident from their presence in plasma and urine, the structures of those metabolites were previously not established due to limited availability of human biological samples (Tong et al, 2010).…”

“…However, oxidative metabolism also appeared to be occurring in vitro in liver microsomes (Tong et al, 2010). Although, the in vivo formation of oxidative metabolites was evident from their presence in plasma and urine, the structures of those metabolites were previously not established due to limited availability of human biological samples (Tong et al, 2010). Therefore, the purpose of the current study was to generate and isolate sufficient amounts of these oxidative metabolites, elucidate the structures of the major vabicaserin metabolites by liquid chromatography/mass spectrometry (LC/MS) and NMR spectroscopy, determine mass balance in the safety species, and compare in vitro and in vivo metabolite profiles of vabicaserin in humans and nonclinical safety species.…”