RT Journal Article
SR Electronic
T1 In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II (SGLT2) Inhibitor, in Animals and Humans
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.109.029165
DO 10.1124/dmd.109.029165
A1 Mary T Obermeier
A1 Ming Yao
A1 Ashish Khanna
A1 Barry Koplowitz
A1 Mingshe Zhu
A1 Wenying Li
A1 Bernard Komoroski
A1 Sreeneeranj Kasichayanula
A1 Lorell Discenza
A1 William Washburn
A1 Wei Meng
A1 Bruce A. Ellsworth
A1 Jean M. Whaley
A1 William G. Humphreys
YR 2009
UL http://dmd.aspetjournals.org/content/early/2009/12/08/dmd.109.029165.abstract
AB Dapagliflozin (2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol; BMS-512148) is a potent sodium-glucose cotransporter type II inhibitor in animals and humans and is currently under development for the treatment of type 2 diabetes. The preclinical characterization of dapagliflozin, to allow compound selection and prediction of behavior in the clinic, involved Caco-2 cell permeability studies, CYP inhibition and induction studies, CYP reaction phenotyping, metabolite identification in hepatocytes and pharmacokinetics in rats, dogs, and monkeys. Dapagliflozin was found to have good permeability across Caco-2 cell membranes. It was found to be a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin was not found to be an inhibitor or an inducer of human CYP enzymes. The in vitro metabolic profiles of dapagliflozin after incubation with hepatocytes from mice, rats, dogs, monkeys, and humans were qualitatively similar. Rat hepatocyte incubations showed the highest turnover and dapagliflozin was most stable in human hepatocytes. Prominent in vitro metabolic pathways observed were glucuronidation, hydroxylation, and O-deethylation. Pharmacokinetic parameters for dapagliflozin in preclinical species revealed a compound with adequate oral exposure, clearance, and elimination half-life, consistent with the potential for single daily dosing in humans. Indeed, the pharmacokinetics in humans after a single dose of 50 mg of 14C-labeled dapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.The American Society for Pharmacology and Experimental Therapeutics