In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans

Drug Metab Dispos. 2010 Mar;38(3):405-14. doi: 10.1124/dmd.109.029165. Epub 2009 Dec 8.


(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin; 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 pharmacological and dispositional behavior in the clinic, involved Caco-2 cell permeability studies, cytochrome P450 (P450) inhibition and induction studies, P450 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 P450 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. The pharmacokinetics in humans after a single dose of 50 mg of [(14)C]dapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.

Publication types

  • Clinical Trial
  • Comparative Study

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Benzhydryl Compounds
  • Biological Availability
  • Biotransformation
  • Caco-2 Cells
  • Cells, Cultured
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Cytochrome P-450 Enzyme System / metabolism
  • Dogs
  • Drug Evaluation, Preclinical
  • Glucosides / blood
  • Glucosides / pharmacokinetics*
  • Glucosides / pharmacology*
  • Glucosides / urine
  • Half-Life
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / urine
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / biosynthesis
  • Isoenzymes / metabolism
  • Kinetics
  • Macaca fascicularis
  • Male
  • Membrane Transport Modulators / blood
  • Membrane Transport Modulators / pharmacokinetics*
  • Membrane Transport Modulators / pharmacology*
  • Membrane Transport Modulators / urine
  • Mice
  • Mice, Inbred BALB C
  • Microsomes, Liver / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sodium-Glucose Transporter 2 Inhibitors*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Benzhydryl Compounds
  • Cytochrome P-450 Enzyme Inhibitors
  • Glucosides
  • Hypoglycemic Agents
  • Isoenzymes
  • Membrane Transport Modulators
  • Sodium-Glucose Transporter 2 Inhibitors
  • dapagliflozin
  • Cytochrome P-450 Enzyme System