title: Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects.
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 ∼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.
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, New Chemical Entities, Groton, CT, USA.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Miao
authors.forename: Gianluca
authors.initials: G
authors.lastname: Nucci
authors.forename: Neeta
authors.initials: N
authors.lastname: Amin
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.forename: Vincent
authors.initials: V
authors.lastname: Mascitti
authors.forename: Meera
authors.initials: M
authors.lastname: Tugnait
authors.forename: Alfin D
authors.initials: AD
authors.lastname: Vaz
authors.forename: Ernesto
authors.initials: E
authors.lastname: Callegari
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001711:Biotransformation; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D020719:Glucuronides; D007004:Hypoglycemic Agents; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C570288:ertugliflozin