PT  - JOURNAL ARTICLE
AU  - Zhuang Miao
AU  - Gianluca Nucci
AU  - Neeta Amin
AU  - Raman Sharma
AU  - Vincent Mascitti
AU  - Meera Tugnait
AU  - Alfin D. Vaz
AU  - Ernesto Callegari
AU  - Amit S. Kalgutkar
TI  - Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects
AID  - 10.1124/dmd.112.049551
DP  - 2013 Feb 01
TA  - Drug Metabolism and Disposition
PG  - 445--456
VI  - 41
IP  - 2
4099  - http://dmd.aspetjournals.org/content/41/2/445.short
4100  - http://dmd.aspetjournals.org/content/41/2/445.full
SO  - Drug Metab Dispos2013 Feb 01; 41
AB  - 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.