The in vitro metabolism of
SDZ HDL 376, a thiocarbamide developed for the treatment of
atherosclerosis, was investigated in rat, dog, monkey, and human liver microsomes, as well as in rat and human liver slices. [14C]
SDZ HDL 376 was extensively metabolized in all the species except human. In rat liver microsomes an S-
oxide was the major metabolite. In human and monkey microsomes,
carbon hydroxylation was favored. The
NADPH-dependent oxidation of
SDZ HDL 376 resulted in covalent binding to microsomal
protein. Addition of GSH to the incubations decreased protein binding in a concentration-dependent manner and resulted in a novel SDZ HDL 376-GSH adduct. Adduct formation required
NADPH and was mediated predominantly by
cytochrome P450. Inhibition of
cytochrome P450 by
1-aminobenzotriazole resulted in a 95% decrease in adduct formation, while heat inactivation of
flavin-containing
monooxygenases resulted in
a 10% decrease. Unlike other thiocarbamides which form
disulfide adducts with GSH, the
SDZ HDL 376 adduct contained a
thioether linkage as characterized by LC/MS/MS and reference to a synthetic standard. Reactions performed with [35S]GSH resulted in a [35S]SDZ HDL 376-GSH adduct, demonstrating the
sulfur was derived from GSH. Adduct formation was faster in rat microsomal reactions compared to human microsomes. Other structurally unrelated thiocarbamides (phenylthiourea, methimazole, 2-mercaptobenzimidazole, 2-mercaptoquinazoline, and 2-propyl-6-thiouracil) did not form similar adducts in rat liver microsomes supplemented with GSH. Therefore, the GSH adduct of
SDZ HDL 376 is unique for this type of thiocarbamide. These results suggest that the bioactivation and detoxification of
SDZ HDL 376 differ significantly from other thiocarbamides. Furthermore, the in vitro formation of S-
oxides and GSH adducts in rat hepatic tissue, and ring hydroxylation and glucuronidation in human hepatic tissue, suggests rats may be more susceptible to the toxicity of
SDZ HDL 376 compared to humans.