Abstract
(1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-1-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol (PF-04971729), a potent and selective inhibitor of the sodium-dependent glucose cotransporter 2, is currently in phase 2 trials for the treatment of diabetes mellitus. This article describes the preclinical species and in vitro human disposition characteristics of PF-04971729 that were used in experiments performed to support the first-in-human study. Plasma clearance was low in rats (4.04 ml · min−1 · kg−1) and dogs (1.64 ml · min−1 · kg−1), resulting in half-lives of 4.10 and 7.63 h, respectively. Moderate to good bioavailability in rats (69%) and dogs (94%) was observed after oral dosing. The in vitro biotransformation profile of PF-04971729 in liver microsomes and cryopreserved hepatocytes from rat, dog, and human was qualitatively similar; prominent metabolic pathways included monohydroxylation, O-deethylation, and glucuronidation. No human-specific metabolites of PF-04971729 were detected in in vitro studies. Reaction phenotyping studies using recombinant enzymes indicated a role of CYP3A4/3A5, CYP2D6, and UGT1A9/2B7 in the metabolism of PF-04971729. No competitive or time-dependent inhibition of the major human cytochrome P450 enzymes was discerned with PF-04971729. Inhibitory effects against the organic cation transporter 2-mediated uptake of [14C]metformin by PF-04971729 also were very weak (IC50 = ∼900 μM). Single-species allometric scaling of rat pharmacokinetics of PF-04971729 was used to predict human clearance, distribution volume, and oral bioavailability. Human pharmacokinetic predictions were consistent with the potential for a low daily dose. First-in-human studies after oral administration indicated that the human pharmacokinetics/dose predictions for PF-04971729 were in the range that is likely to yield a favorable pharmacodynamic response.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040675.
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ABBREVIATIONS:
- T2DM
- type 2 diabetes mellitus
- PF-04971729
- (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol
- HPLC
- high-performance liquid chromatography
- CP-100,356
- N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine
- P450
- cytochrome P450
- UGT
- UDP-glucuronosyltransferase
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- h
- human
- OCT
- organic cation transporter 2
- HEK
- human embryonic kidney
- DMSO
- dimethyl sulfoxide
- P-gp
- P-glycoprotein
- BCRP
- breast cancer resistance protein
- AUC
- area under the plasma concentration/time curve
- CID
- collision-induced dissociation
- A
- apical
- B
- basolateral
- MS
- mass spectrometry.
- Received May 15, 2011.
- Accepted June 20, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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