RT Journal Article
SR Electronic
T1 Pharmacokinetics, Metabolism, and Excretion of the Antidiabetic Agent Ertugliflozin (PF-04971729) in Healthy Male Subjects
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 445
OP 456
DO 10.1124/dmd.112.049551
VO 41
IS 2
A1 Zhuang Miao
A1 Gianluca Nucci
A1 Neeta Amin
A1 Raman Sharma
A1 Vincent Mascitti
A1 Meera Tugnait
A1 Alfin D. Vaz
A1 Ernesto Callegari
A1 Amit S. Kalgutkar
YR 2013
UL http://dmd.aspetjournals.org/content/41/2/445.abstract
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.