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Research ArticleArticle

FORMATION AND PROTEIN BINDING OF THE ACYL GLUCURONIDE OF A LEUKOTRIENE B4 ANTAGONIST (SB-209247): RELATION TO SPECIES DIFFERENCES IN HEPATOTOXICITY

Jane R. Kenny, James L. Maggs, Justice N. A. Tettey, Andrew W. Harrell, Steven G. Parker, Stephen E. Clarke and B. Kevin Park
Drug Metabolism and Disposition February 2005, 33 (2) 271-281; DOI: https://doi.org/10.1124/dmd.104.001677
Jane R. Kenny
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James L. Maggs
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Justice N. A. Tettey
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Andrew W. Harrell
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Steven G. Parker
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Stephen E. Clarke
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B. Kevin Park
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Abstract

SB-209247 [(E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid], an anti-inflammatory leukotriene B4 receptor antagonist, was associated in beagle dogs but not male rats with an inflammatory hepatopathy. It also produced a concentration-dependent (10-1000 μM) but equal leakage of enzymes from dog and rat precision-cut liver slices. The hepatic metabolism of SB-209247 was investigated with reference to the formation of reactive acyl glucuronides. [14C]SB-209247 (100 μmol/kg) administered i.v. to anesthetized male rats was eliminated by biliary excretion of the acyl glucuronides of the drug and its sulfoxide. After 5 h, 1.03 ± 0.14% (mean ± S.E.M., n = 4) of the dose was bound irreversibly to liver tissue. The sulfoxide glucuronide underwent pH-dependent rearrangement in bile more rapidly than did the SB-209247 conjugate. [14C]SB-209247 was metabolized by sulfoxidation and glucuronidation in rat and dog hepatocytes, and approximately 1 to 2% of [14C]SB-209247 (100 μM) became irreversibly bound to cellular material. [14C]SB-209247 sulfoxide and glucuronide were the only metabolites produced by dog, rat, and human liver microsomes in the presence of NADPH and UDP-glucuronic acid (UDPGA), respectively. Vmax values for [14C]SB-209247 glucuronidation by dog, rat, and human microsomes were 2.6 ± 0.1, 1.2 ± 0.1, and 0.4 ± 0.0 nmol/min/mg protein, respectively. Hepatic microsomes from all three species catalyzed UDPGA-dependent but not NADPH-dependent irreversible binding of [14C]SB-209247 (100-250 μM) to microsomal protein. Although a reactive acyl glucuronide was formed by microsomes from every species, the binding did not differ between species. Therefore, neither the acute cellular injury nor glucuronidation-driven irreversible protein binding in vitro is predictive of the drug-induced hepatopathy.

Footnotes

  • This study was supported by SmithKline Beecham and GlaxoSmithKline through a studentship awarded to J.R.K. The LC-MS system was purchased and maintained with grants from the Wellcome Trust. B.K.P. was a Wellcome Principal Research Fellow.

  • This work was in part presented at the Winter 2001 meeting of the British Pharmacological Society, London, United Kingdom, 18-20 December [Kenny et al. (2002) Br J Clin Pharmacol53:446P] and the 2002 Annual Congress of the British Toxicology Society, Canterbury, Kent, United Kingdom, 8-10 April [Kenny et al. (2002) Toxicology178:57-58] and published as abstracts.

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

  • doi:10.1124/dmd.104.001677.

  • ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; SB-209247, (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid; LTB4, leukotriene B4; UGT, uridine diphosphate glucuronosyltransferase; UDPGA, UDP-glucuronic acid; SB-215244, (E)-3-[6-[[(2,6-dichlorophenyl)-sulfinyl]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2-propenoic acid; HPLC, high-performance liquid chromatography; LC-MS, liquid chromatography-mass spectrometry; LDH, lactate dehydrogenase; BIIL 284, carbamic acid, [[4-[[3-[[4-[1-(4-hydroxyphenyl)-1-methyl-ethyl]phenoxy]methyl]phenyl]methoxy]phenyl]iminomethyl]-, ethyl ester.

  • ↵1 Present address: AstraZeneca R&D Charnwood, Loughborough, Leicestershire, UK.

  • ↵2 Present address: Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow, UK.

    • Received July 28, 2004.
    • Accepted October 28, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (2)
Drug Metabolism and Disposition
Vol. 33, Issue 2
1 Feb 2005
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Research ArticleArticle

FORMATION AND PROTEIN BINDING OF THE ACYL GLUCURONIDE OF A LEUKOTRIENE B4 ANTAGONIST (SB-209247): RELATION TO SPECIES DIFFERENCES IN HEPATOTOXICITY

Jane R. Kenny, James L. Maggs, Justice N. A. Tettey, Andrew W. Harrell, Steven G. Parker, Stephen E. Clarke and B. Kevin Park
Drug Metabolism and Disposition February 1, 2005, 33 (2) 271-281; DOI: https://doi.org/10.1124/dmd.104.001677

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Research ArticleArticle

FORMATION AND PROTEIN BINDING OF THE ACYL GLUCURONIDE OF A LEUKOTRIENE B4 ANTAGONIST (SB-209247): RELATION TO SPECIES DIFFERENCES IN HEPATOTOXICITY

Jane R. Kenny, James L. Maggs, Justice N. A. Tettey, Andrew W. Harrell, Steven G. Parker, Stephen E. Clarke and B. Kevin Park
Drug Metabolism and Disposition February 1, 2005, 33 (2) 271-281; DOI: https://doi.org/10.1124/dmd.104.001677
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