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 [14C]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, [14C]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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
ABBREVIATIONS:
- SGLT
- sodium-dependent glucose cotransporter
- GSK
- GlaxoSmithKline
- GSK189075
- 5-methyl-1-(1-methylethyl)-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-6-O-[(ethyloxy)carbonyl]-β-d-glucopyranoside
- GSK189074
- 5-methyl-1-(1-methylethyl)-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-β-d-glucopyranoside
- Pgp
- P-glycoprotein
- P450
- cytochrome P450
- GSK279782
- 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-β-d-glucopyranoside
- GSK333081
- 4-[(4-hydroxyphenyl)methyl]-5-methyl-1-(1-methylethyl)-1H-pyrazol-3-yl-β-d-glucopyranoside
- GSK1132678
- 1,2-dihydro-5-methyl-4-[[4-(1-methylethoxy)phenyl]methyl]-1-(1-methylethyl)-3H-pyrazol-3-one
- GSK1997711
- 5-methyl-1-(1-methylethyl)-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1Hpyrazol-3-yl β-d-glucopyranosiduronic acid
- GSK1997714
- 5-methyl-1-(1-methylethyl)-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-2-O-β-d-glucopyranuronosyl-β-d-glucopyranoside
- GSK355993
- 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-β-d-glucopyranosiduronic acid
- MDR
- multidrug resistance
- HLM
- human liver microsomes
- AE
- adverse event
- LC-MS/MS
- liquid chromatography-tandem mass spectrometry
- LC
- liquid chromatography
- MS
- mass spectrometry
- MS/MS
- tandem mass spectrometry
- AUC(0-∞)
- area under the concentration-time profile from zero time to infinity
- CI
- confidence interval
- HPLC
- high-performance liquid chromatography
- MDCKII
- Madin-Darby canine kidney II
- GF120918
- N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide.
- Received June 14, 2012.
- Accepted July 27, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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