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Research ArticleArticle

Metabolism Distribution and Excretion of a Matrix Metalloproteinase-13 Inhibitor, 4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic Acid Hydroxyamide (CP-544439), in Rats and Dogs: Assessment of the Metabolic Profile of CP-544439 in Plasma and Urine of Humans

Deepak Dalvie, Theresa Cosker, Tracey Boyden, Sue Zhou, Clinton Schroeder and Michael J. Potchoiba
Drug Metabolism and Disposition September 2008, 36 (9) 1869-1883; DOI: https://doi.org/10.1124/dmd.108.022566
Deepak Dalvie
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Theresa Cosker
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Tracey Boyden
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Sue Zhou
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Clinton Schroeder
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Michael J. Potchoiba
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Abstract

The metabolism and disposition of 4-[4-(4-fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide (CP-544439), a selective inhibitor of matrix metalloproteinase-13, was investigated in rats and dogs following oral administration of [14C]CP-544439. Both species showed quantitative recovery of the radiolabel, and feces was the major route of excretion. Whole-body autoradioluminography study in rats suggested distribution of CP-544439 in all tissues except central nervous system. The radiolabel was rapidly eliminated from most tissues except the periodontal ligament. Metabolism of CP-544439 was extensive in both species. Only 8.4 and 1.5% of the total dose constituted unchanged CP-544439 in the rat and dog, respectively. Similarly, pharmacokinetic analysis of [14C]CP-544439 and unchanged CP-544439 indicated that the exposure of the parent drug was 16 and 6.5% of the total radioequivalents in rat and dog, respectively. Metabolic profiling revealed that CP-544439 was primarily metabolized via glucuronidation, reduction, and hydrolysis. Glucuronidation was the primary route of metabolism in dogs, whereas reduction of the hydroxamate moiety was the major pathway in rats. Human plasma and urine obtained from a dose escalation study in healthy human volunteers were also analyzed in this study to assess the metabolism of CP-544439 in humans and ensure that selected animal species were exposed to all major metabolites formed in humans. Analysis suggested that CP-544439 was metabolized via all three pathways in humans consistent with rat and dog; however, the glucuronide conjugate M1 was the major circulating and excretory metabolite in humans. Preliminary in vitro phenotyping studies indicated that glucuronide formation is primarily catalyzed by UGT1A1, 1A3, and 1A9.

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  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.022566.

  • ABBREVIATIONS: MMP, matrix metalloproteinase; OA, osteo arthritis; HSA, human serum albumin; AAG, α1-acid glycoprotein; HPLC, high-performance liquid chromatography; UGT, uridine diphosphoglucuronosyl transferase; PEG, polyethylene glycol; SD rats, Sprague-Dawley rats; AUC0-tlast, area under the plasma concentration-versus-time curve; WBAL, whole body autoradioluminography; GIT, gastrointestinal tract; CP-544439, 4-[4-(4-fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic acid hydroxyamide.

    • Received May 27, 2008.
    • Accepted June 16, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (9)
Drug Metabolism and Disposition
Vol. 36, Issue 9
1 Sep 2008
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Metabolism Distribution and Excretion of a Matrix Metalloproteinase-13 Inhibitor, 4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic Acid Hydroxyamide (CP-544439), in Rats and Dogs: Assessment of the Metabolic Profile of CP-544439 i…
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Research ArticleArticle

Metabolism Distribution and Excretion of a Matrix Metalloproteinase-13 Inhibitor, 4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic Acid Hydroxyamide (CP-544439), in Rats and Dogs: Assessment of the Metabolic Profile of CP-544439 in Plasma and Urine of Humans

Deepak Dalvie, Theresa Cosker, Tracey Boyden, Sue Zhou, Clinton Schroeder and Michael J. Potchoiba
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1869-1883; DOI: https://doi.org/10.1124/dmd.108.022566

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Research ArticleArticle

Metabolism Distribution and Excretion of a Matrix Metalloproteinase-13 Inhibitor, 4-[4-(4-Fluorophenoxy)-benzenesulfonylamino]tetrahydropyran-4-carboxylic Acid Hydroxyamide (CP-544439), in Rats and Dogs: Assessment of the Metabolic Profile of CP-544439 in Plasma and Urine of Humans

Deepak Dalvie, Theresa Cosker, Tracey Boyden, Sue Zhou, Clinton Schroeder and Michael J. Potchoiba
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1869-1883; DOI: https://doi.org/10.1124/dmd.108.022566
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