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
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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.
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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.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.104.001677.
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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.
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↵1 Present address: AstraZeneca R&D Charnwood, Loughborough, Leicestershire, UK.
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↵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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