Abstract
(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 [14C]dapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.029165.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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- SGLT
- sodium-glucose cotransporter
- ADME
- absorption, distribution, metabolism, and excretion
- dapagliflozin/BMS-512148
- (2S,3R,4R,5S,6R)-2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol
- HPLC
- high-performance liquid chromatography
- P450
- cytochrome P450
- HLM
- human liver microsome
- ACN
- acetonitrile
- LC/MS/MS
- liquid chromatography/tandem mass spectroscopy
- TRA
- total radioactivity
- P-gp
- P-glycoprotein
- GF120918
- N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide
- fu
- fraction unbound
- DMSO
- dimethyl sulfoxide
- LC/MS
- liquid chromatography/mass spectrometry
- ODS
- octyl dodecyl sulfate, C18
- CPM
- counts per minute
- BQL
- below quantifiable limit
- AUC
- area under the concentration/time curve
- CL
- total body clearance
- MRT
- mean residence time
- Vss
- volume of distribution at steady state
- CLR
- renal clearance
- GFR
- glomerular filtration rate
- F
- oral bioavailability
- A
- apical
- B
- basolateral
- Tmax
- time that peak concentrations are reached
- BMS-511926
- 2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
- BMS-639432
- 2S,3R,4R,5S,6R)-2-(4-chloro-3-((4-ethoxyphenyl) (hydroxy)methyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.
- Received July 1, 2009.
- Accepted December 7, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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