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P Dogterom and J Rothuizen
Institute of Toxicology, Swiss Federal Institute of Technology.
Precision-cut liver slices from rats and dogs were used to investigate in vitro the metabolism of tolbutamide. Tolbutamide (100 microM) was incubated with liver slices in 12-well plates (rat: 1 slice/well; dog: 4 slices/well) for up to 9 hr. In rats, qualitative sex differences were found in tolbutamide metabolism, whereas in dogs quantitative sex differences were found. In male and female rats, the major metabolite was hydroxytolbutamide, with minor amounts of carboxytolbutamide. In both sexes, the formation rates of these metabolites were the same. In male rats, also the "dog-specific" metabolites, p-tolylsulfonylurea and p-tolylsulfonamide, were found. No direct toxicity of tolbutamide and its metabolites was observed. In male and female dogs, the major metabolite was p-tolylsulfonylurea, with smaller amounts of hydroxy- and carboxytolbutamide. Formation rates of the various tolbutamide metabolites in male dogs were approximately 3 times higher than in female dogs. The "dog-specific" metabolite p-tolylsulfonamide could not be detected. These results show that precision-cut liver slices are capable of detecting hitherto unknown species and sex differences in the metabolism of tolbutamide. Liver slices are a promising in vitro method for the study of comparative drug metabolism.
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