PT  - JOURNAL ARTICLE
AU  - Zeen Tong
AU  - Appavu Chandrasekaran
AU  - William DeMaio
AU  - Ronald Jordan
AU  - Hongshan Li
AU  - Robin Moore
AU  - Nagaraju Poola
AU  - Peter Burghart
AU  - Theresa Hultin
AU  - JoAnn Scatina
TI  - Species Differences in the Formation of Vabicaserin Carbamoyl Glucuronide
AID  - 10.1124/dmd.109.028639
DP  - 2010 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 581--590
VI  - 38
IP  - 4
4099  - http://dmd.aspetjournals.org/content/38/4/581.short
4100  - http://dmd.aspetjournals.org/content/38/4/581.full
SO  - Drug Metab Dispos2010 Apr 01; 38
AB  - 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 CO2-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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics