Document Detail

Preclinical Species and Human Disposition of (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 Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 (SGLT2) and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus.
MedLine Citation:
PMID:  21690265     Owner:  NLM     Status:  Publisher    
(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 (SGLT2), is currently in phase 2 trials for the treatment of diabetes mellitus. The paper describes the preclinical species and in vitro human disposition characteristics of PF-04971729, which were performed to support the first-in-human study. Plasma clearance was low in rats (4.04 ml/min/kg) and dogs (1.64 ml/min/kg) resulting in half-lives of 4.10 hours and 7.63 hours, 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 mono-hydroxylation, 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 [(14)C]-metformin by PF-04971729 also were very weak (IC(50) ~ 900μM). 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 following 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.
Amit S Kalgutkar; Meera Tugnait; Tong Zhu; Emi Kimito; Zhuang Miao; Vincent Mascitti; Xin Yang; Beijing Tan; Robert L Walsky; Jonathan Chupka; Bo Feng; Ralph Robinson
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-6-20
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  -     ISSN:  1521-009X     ISO Abbreviation:  -     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-6-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1 Pfizer Global Research and Development;
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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