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

nylethoxy)-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 pro-duced a concentration-dependent (10–1000 M) 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 mol/ kg) administered i.v. to anesthetized male rats was eliminated by biliary excretion of the acyl glucuronides of the drug and its sul-foxide. 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 M) became irre