Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects.

The disposition of ertugliflozin(PF-04971729), an orally active selective inhibitor of the sodium-dependent glucose cotransporter2, was studied after a single 25-mg oral dose of [ 14 C]- ertugliflozinto 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 fecesand urine was 40.9% and 50.2%, respectively. The absorption of ertugliflozinin humans was rapid with a T max at ∼1.0 hour. Of the total radioactivity excreted in fecesand urine, unchanged ertugliflozincollectively accounted for ∼35.3% of the dose, suggestive of moderate metabolic elimination in humans. The principal biotransformation pathway involved glucuronidationof 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 ertugliflozinand the corresponding 4- O - β - (M4a) and 3- O - β - (M4c) glucuronideswere the principal components, which accounted for 49.9, 12.2, and 24.1% of the circulating radioactivity. Overall, these data suggest that ertugliflozinis well absorbed in humans, and eliminated largely via glucuronidation.