Biotransformation of dimetridazole by primary cultures of pig hepatocytes.

摘要

Monolayer cultures of pig hepatocytes were used to investigate the role of the liver in the biotransformation of dimetridazole (1,2-dimethyl-5-nitroimidazole). 14C-labelled dimetridazole (DMZ) was primarily hydroxylated to 1-methyl-2-hydroxymethyl-5-nitroimidazole (up to 90%) and to a minor extent N-demethylated to 2-methyl-(4,5)-nitroimidazole (6-10%). Prolonged incubation with the parent drug but also the 2-hydroxymethyl metabolite resulted in the formation of 2 other minor metabolites. No evidence was obtained for the formation of a cysteine or glutathione conjugate involved in the detoxification of reactive intermediates. In addition to free metabolites, there was a time-related formation of protein-bound metabolites up to a maximum of 30 pmol/mg of protein after exposure to 50μM DMZ for 48 h. In general, these metabolites accounted for 0.06-0.15% of the metabolized DMZ. Unextractable metabolites were also observed after incubation of cells with the 2-hydroxymethyl and 1-desmethyl metabolites. It is concluded that the 1-desmethyl and 2-hydroxymethyl metabolite are the major metabolites formed by pig hepatocytes.