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Formation and protein binding of the acyl glucuronide of a leukotriene b4 antagonist (sb-209247) relation to species differences in hepatotoxicity

Kenny, J.R. and Maggs, J.L. and Tettey, J.N.A. and Harrell, A.W. and Parker, S.G. and Clarke, S.E. and Park, B.K. (2005) Formation and protein binding of the acyl glucuronide of a leukotriene b4 antagonist (sb-209247) relation to species differences in hepatotoxicity. Drug Metabolism and Disposition, 33 (2). pp. 271-281. ISSN 1521-009X

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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.