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
| Autor: | Wenli Tao, J. Sigafoos, Robert L. Dobbins, Anita Kapur, Stephen Castellino, David S. Wagner, Joan E. Humphreys, Joseph W. Polli, Melinda J. Reese, Elizabeth K. Hussey, Gary D Bowers, Amanda G. Culp, Robin L. O'Connor Semmes |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Adult
Male Risk Remogliflozin etabonate Metabolite Administration Oral Pharmaceutical Science Pharmacology Excretion Young Adult chemistry.chemical_compound Glucuronides Cytochrome P-450 Enzyme System Glucosides Sodium-Glucose Transporter 2 medicine Cytochrome P-450 CYP3A Humans Drug Interactions ATP Binding Cassette Transporter Subfamily B Member 1 Sodium-Glucose Transporter 2 Inhibitors biology CYP3A4 Cytochrome P450 Middle Aged Drug interaction Ketoconazole chemistry Area Under Curve Microsomes Liver biology.protein Pyrazoles Female Glucuronide Half-Life medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 40:2090-2101 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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