Metabolism of Thiabendazole and Teratogenic Potential of Its Metabolites in Pregnant Mice

Abstract

In connection with the teratogenic activity of thiabendazole (TBZ), the metabolic fate of 14C-TBZ in pregnant mice was studied by administration of the drug in olive oil and gum arabic as vehicles. Absorption of TBZ in the olive oil group occurred more rapidly than in the gum arabic group, and the maximum blood level in the former group was 7-fold higher than that in the latter group. 5-Hydroxylated TBZ (5-HY TBZ), its glucuronide and its sulfate were identified as urinary and fecal metabolites. A very small quantity of N-methyl TBZ was also identified for the first time in the urine and feces. The percentages of TBZ, 5-HY TBZ, and the glucuronide and sulfate of 5-HY TBZ in the urine were 12—15, 22—24, 28—29 and 30—31%, respectively. About 97% of the dose was excreted into the urine (60—62%) and the feces (34—37%) within 7d in each group. In a limb bud cell culture system for the assay of teratogenic potential, the concentrations of TBZ, 5-HY TBZ and N-methyl TBZ necessary to reduce the amounts of cartilage proteoglycan by 50% were estimated to. be about 0.09, 0.09 and 0.24 mM, respectively. However, the concentrations of 5-HY TBZ glucuronide and sulfate were over 2 mM. Consequently, teratogenesis caused by TBZ appeared to be induced by the high levels of direct-acting teratogens such as TBZ and 5-HY TBZ when olive oil was used as a vehicle. © 1987, The Pharmaceutical Society of Japan. All rights reserved.