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

被引:34
作者
Sigafoos, James F.
Bowers, Gary D.
Castellino, Stephen
Culp, Amanda G.
Wagner, David S.
Reese, Melinda J.
Humphreys, Joan E.
Hussey, Elizabeth K. [2 ]
Semmes, Robin L. O'Connor [2 ]
Kapur, Anita [2 ]
Tao, Wenli [2 ]
Dobbins, Robert L. [2 ]
Polli, Joseph W. [1 ]
机构
[1] GlaxoSmithKline Inc, Drug Metab & Pharmacokinet, Dept Drug Metab & Pharmacokinet, Res Triangle Pk, NC 27709 USA
[2] GlaxoSmithKline Inc, Dept Clin Pharmacol, Res Triangle Pk, NC 27709 USA
关键词
DIABETES-MELLITUS; SELECTIVE-INHIBITION; SGLT2; INHIBITORS; BETA-GLUCOSIDASE; CYTOCHROME-P450; TRANSPORTERS; REABSORPTION; GLYCOSIDES; MECHANISM; POTENT;
D O I
10.1124/dmd.112.047258
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 [C-14]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 mu Ci) dose, [C-14]remogliflozin etabonate is rapidly absorbed and extensively metabolized. The area under the concentration-time curve from 0 to infinity [AUC((0-infinity))] of plasma radioactivity was approximately 14-fold higher than the sum of the AUC((0-infinity)) of remogliflozin etabonate, remogliflozin, and 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl-beta-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-beta-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.
引用
收藏
页码:2090 / 2101
页数:12
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