title: Assessment of the drug interaction risk for remogliflozin etabonate, a sodium-dependent glucose cotransporter-2 inhibitor: evidence from in vitro, human mass balance, and ketoconazole interaction studies.
abstract: Remogliflozin etabonate is the ester prodrug of remogliflozin, a selective sodium-dependent glucose cotransporter-2 inhibitor. This work investigated the absorption, metabolism, and excretion of [(14)C]remogliflozin etabonate in humans, as well as the influence of P-glycoprotein (Pgp) and cytochrome P450 (P450) enzymes on the disposition of remogliflozin etabonate and its metabolites to understand the risks for drug interactions. After a single oral 402 ± 1.0 mg (106 ± 0.3 μCi) dose, [(14)C]remogliflozin etabonate is rapidly absorbed and extensively metabolized. The area under the concentration-time curve from 0 to infinity [AUC((0-∞))] of plasma radioactivity was approximately 14-fold higher than the sum of the AUC((0-∞)) of remogliflozin etabonate, remogliflozin, and 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-β-d-glucopyranoside (GSK279782), a pharmacologically active N-dealkylated metabolite. Elimination half-lives of total radioactivity, remogliflozin etabonate, and remogliflozin were 6.57, 0.39, and 1.57 h, respectively. Products of remogliflozin etabonate metabolism are eliminated primarily via renal excretion, with 92.8% of the dose recovered in the urine. Three glucuronide metabolites made up the majority of the radioactivity in plasma and represent 67.1% of the dose in urine, with 5-methyl-1-(1-methylethyl)-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-β-d-glucopyranosiduronic acid (GSK1997711) representing 47.8% of the dose. In vitro studies demonstrated that remogliflozin etabonate and remogliflozin are Pgp substrates, and that CYP3A4 can form GSK279782 directly from remogliflozin. A ketoconazole clinical drug interaction study, along with the human mass balance findings, confirmed that CYP3A4 contributes less than 50% to remogliflozin metabolism, demonstrating that other enzyme pathways (e.g., P450s, UDP-glucuronosyltransferases, and glucosidases) make significant contributions to the drug's clearance. Overall, these studies support a low clinical drug interaction risk for remogliflozin etabonate due to the availability of multiple biotransformation pathways.
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Sigafoos
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bowers
authors.forename: Stephen
authors.initials: S
authors.lastname: Castellino
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Culp
authors.forename: David S
authors.initials: DS
authors.lastname: Wagner
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Reese
authors.forename: Joan E
authors.initials: JE
authors.lastname: Humphreys
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Hussey
authors.forename: Robin L
authors.initials: RL
authors.lastname: O'Connor Semmes
authors.forename: Anita
authors.initials: A
authors.lastname: Kapur
authors.forename: Wenli
authors.initials: W
authors.lastname: Tao
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dobbins
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Polli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D005960:Glucosides / Q000493:pharmacokinetics* / Q000494:pharmacology; D020719:Glucuronides / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D011720:Pyrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D012306:Risk; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005960:Glucosides; D020719:Glucuronides; D011720:Pyrazoles; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; C532127:remogliflozin etabonate