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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

Department of Pharmacology and Therapeutics, The University of Liverpool, Liverpool, United Kingdom (J.R.K., J.L.M., J.N.A.T., B.K.P.); and Pre-Clinical Development, GlaxoSmithKline, the Frythe, Welwyn, Hertfordshire, United Kingdom (A.W.H., S.G.P., S.E.C.)

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. V_max 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.