@article {Obermeierdmd.109.029165, author = {Mary T Obermeier and Ming Yao and Ashish Khanna and Barry Koplowitz and Mingshe Zhu and Wenying Li and Bernard Komoroski and Sreeneeranj Kasichayanula and Lorell Discenza and William Washburn and Wei Meng and Bruce A. Ellsworth and Jean M. Whaley and William G. Humphreys}, title = {In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II (SGLT2) Inhibitor, in Animals and Humans}, elocation-id = {dmd.109.029165}, year = {2009}, doi = {10.1124/dmd.109.029165}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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}, issn = {0090-9556}, URL = {https://dmd.aspetjournals.org/content/early/2009/12/08/dmd.109.029165}, eprint = {https://dmd.aspetjournals.org/content/early/2009/12/08/dmd.109.029165.full.pdf}, journal = {Drug Metabolism and Disposition} }