@article {Miao445, author = {Zhuang Miao and Gianluca Nucci and Neeta Amin and Raman Sharma and Vincent Mascitti and Meera Tugnait and Alfin D. Vaz and Ernesto Callegari and Amit S. Kalgutkar}, title = {Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects}, volume = {41}, number = {2}, pages = {445--456}, year = {2013}, doi = {10.1124/dmd.112.049551}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The disposition of ertugliflozin (PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter 2, was studied after a single 25-mg oral dose of [14C]-ertugliflozin to healthy human subjects. Mass balance was achieved with approximately 91\% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 40.9\% and 50.2\%, respectively. The absorption of ertugliflozin in humans was rapid with a Tmax at \~{}1.0 hour. Of the total radioactivity excreted in feces and urine, unchanged ertugliflozin collectively accounted for \~{}35.3\% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidation of the glycoside hydroxyl groups to yield three regioisomeric metabolites, M4a, M4b, and M4c (\~{}39.3\% of the dose in urine), of which M4c was the major regioisomer (\~{}31.7\% of the dose). The structure of M4a and M4c were confirmed to be ertugliflozin -4-O-β- and -3-O-β-glucuronide, respectively, via comparison of the HPLC retention time and mass spectra with authentic standards. A minor metabolic fate involved oxidation by cytochrome P450 to yield monohydroxylated metabolites M1 and M3 and des-ethyl ertugliflozin (M2), which accounted for \~{}5.2\% of the dose in excreta. In plasma, unchanged ertugliflozin and the corresponding 4-O-β- (M4a) and 3-O-β- (M4c) glucuronides were the principal components, which accounted for 49.9, 12.2, and 24.1\% of the circulating radioactivity. Overall, these data suggest that ertugliflozin is well absorbed in humans, and eliminated largely via glucuronidation.}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/41/2/445}, eprint = {https://dmd.aspetjournals.org/content/41/2/445.full.pdf}, journal = {Drug Metabolism and Disposition} }