COMPARATIVE METABOLISM OF THIABENDAZOLE IN CULTURED-HEPATOCYTES FROM RATS, RABBITS, CALVES, PIGS, AND SHEEP, INCLUDING THE FORMATION OF PROTEIN-BOUND RESIDUES

Cultured hepatocytes from fat, rabbit, calf, pig, and sheep were used to study metabolism and formation of protein-bound residues of thiaben dazole ([C-14]TBZ), a benzimidazole anthelmintic and fungicide. In all investigated species, major pathways corresponded to 5-hydroxylation of TBZ and its further conjugation. However, marked interspecies diffe rences in rates of TBZ disappearance and Ei-hydroxy metabolite formati on were demonstrated. Rabbit hepatocytes presented the fastest TBZ bio transformation and were the mast extensive hydroxylators. By contrast, the lowest capacity of oxidation was observed for the rat. Two uniden tified minor metabolites, designated M1 and M2, were particularly prod uced by sheep hepatocytes. Moreover, the protein-bound residues in the se cells, which could be related to cytochrome P450-dependent oxidatio n, were formed in 4 times greater amounts than in the other animal cel ls. These findings substantiate hepatocytes as an in vitro model for p rediction of hepatic metabolism in vivo.