Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects.
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Miao Z, Nucci G, Amin N, Sharma R, Mascitti V, Tugnait M, Vaz AD, Callegari E, Kalgutkar AS
Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects.
Drug Metab Dispos. 2013 Feb;41(2):445-56. doi: 10.1124/dmd.112.049551. Epub 2012 Nov 20.
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- 23169609 [ View in PubMed]
- 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 [(14)C]-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 T(max) at approximately 1.0 hour. Of the total radioactivity excreted in feces and urine, unchanged ertugliflozin collectively accounted for approximately 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 ( approximately 39.3% of the dose in urine), of which M4c was the major regioisomer ( approximately 31.7% of the dose). The structure of M4a and M4c were confirmed to be ertugliflozin -4-O-beta- and -3-O-beta-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 approximately 5.2% of the dose in excreta. In plasma, unchanged ertugliflozin and the corresponding 4-O-beta- (M4a) and 3-O-beta- (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.
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- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Ertugliflozin Sodium/glucose cotransporter 2 Protein Humans YesInhibitorDetails - Drug Reactions
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