@article {Yangdmd.110.037044, author = {Jing Yang and Li Ding and Linlin Hu and Wenjuan Qian and Shaohong Jin and Xiaoping Sun and Zhenzhong Wang and Wei Xiao}, title = {Metabolism of Gambogic Acid in Rats: a Rare Intestinal Metabolic Pathway Responsible for its Final Disposition}, elocation-id = {dmd.110.037044}, year = {2010}, doi = {10.1124/dmd.110.037044}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Gambogic acid (GA) is a promising natural anticancer candidate. Although the anticancer activity of GA has been well demonstrated, information regarding the metabolic fate of GA is limited. Previous studies suggest that GA is mainly excreted into intestinal tract in rats through bile after i.v. administration, whereas only traces appeared in the feces, suggesting that GA is metabolized abundantly in the intestine. However, there is no report about the intestinal metabolism of GA either in animals or humans. In this study, two sulfonic acid metabolites of GA were found abundantly in the fecal samples of rats after i.v. administration and their structures were identified as 10-α sulfonic acid GA and 10-β sulfonic acid GA by comparison of the retention time and spectral data with those of synthesized reference substances using LC-DAD-MS/MS. This rare intestinal metabolic pathway mainly involves Michael addition of sulfite ion to the 9, 10 carbon-carbon double bond of α,β-unsaturated ketone. Additionally, a more detailed metabolic profile in rats is proposed according to the results of in vitro and in vivo studies. It is found that GA can be metabolized by a variety of routes, including mono-oxidation, hydration, glutathionylation, glucuronidation, glucosidation in the liver of rats. These findings provide information on the major metabolic soft spot of GA in the intestine and liver of rats, which is not only useful in the future human metabolic study of this compound, but also of value in the metabolic studies of GA analogues.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2010/12/29/dmd.110.037044}, eprint = {https://dmd.aspetjournals.org/content/early/2010/12/29/dmd.110.037044.full.pdf}, journal = {Drug Metabolism and Disposition} }