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Research ArticleArticle

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Amit S. Kalgutkar, Meera Tugnait, Tong Zhu, Emi Kimoto, Zhuang Miao, Vincent Mascitti, Xin Yang, Beijing Tan, Robert L. Walsky, Jonathan Chupka, Bo Feng and Ralph P. Robinson
Drug Metabolism and Disposition September 2011, 39 (9) 1609-1619; DOI: https://doi.org/10.1124/dmd.111.040675
Amit S. Kalgutkar
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Meera Tugnait
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Tong Zhu
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Emi Kimoto
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Zhuang Miao
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Vincent Mascitti
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Xin Yang
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Beijing Tan
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Robert L. Walsky
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Jonathan Chupka
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Bo Feng
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Ralph P. Robinson
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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.

  • 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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Drug Metabolism and Disposition: 39 (9)
Drug Metabolism and Disposition
Vol. 39, Issue 9
1 Sep 2011
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Research ArticleArticle

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Amit S. Kalgutkar, Meera Tugnait, Tong Zhu, Emi Kimoto, Zhuang Miao, Vincent Mascitti, Xin Yang, Beijing Tan, Robert L. Walsky, Jonathan Chupka, Bo Feng and Ralph P. Robinson
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1609-1619; DOI: https://doi.org/10.1124/dmd.111.040675

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Research ArticleArticle

Preclinical Species and Human Disposition of PF-04971729, a Selective Inhibitor of the Sodium-Dependent Glucose Cotransporter 2 and Clinical Candidate for the Treatment of Type 2 Diabetes Mellitus

Amit S. Kalgutkar, Meera Tugnait, Tong Zhu, Emi Kimoto, Zhuang Miao, Vincent Mascitti, Xin Yang, Beijing Tan, Robert L. Walsky, Jonathan Chupka, Bo Feng and Ralph P. Robinson
Drug Metabolism and Disposition September 1, 2011, 39 (9) 1609-1619; DOI: https://doi.org/10.1124/dmd.111.040675
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