Metabolic fate of S,S,S-tributyl phosphorotrithioate (DEF) in the lactating goat

1. Metabolism of [1-14C] DEF (S,S,S-1-14C-tributyl phosphorotrithioate, 1) in the lactating goat has been investigated. A goat was dosed orally by capsule on 3 consecutive days at a rate of 0.82 mg/kg body weight/day based on 25 times the maximum DEF residue anticipated in animal feed. 2. Urine and milk were collected throughout the study. The goat was killed 21 h following the last treatment, and kidney, liver and composite samples of muscle and fat were collected. The radioactive residue levels (following the three doses) were 3.45 ppm in liver, 0.35 ppm in kidney, 0.19 ppm in fat, 0.06 ppm in muscle and 0.12 ppm in milk collected at the final 16 h and prior to killing. 3. Urinary metabolic profile indicated that DEF was efficiently metabolized to many metabolites. Tissue and milk extracts also indicated that DEF was extensively metabolized. 4. DEF comprised 31 and 5% of the total radioactive residue in fat and milk, respectively. The amount of DEF in liver, kidney and muscle represented < 1% of the total radioactive residue. 5. A major metabolite, 3-hydroxybutylmethyl sulphone (HBM sulphone, UP3), was found in tissue, milk and urine. The identification of this metabolite was accomplished by a combination of MS, nmr and comparison with an authentic standard. The glucuronide (UP1) and sulphate (UP2) conjugates of HBM sulphone were found in urine, and the sulphate conjugate was a major metabolite in kidney. 6. The hydrolytic products of DEF, S,S-dibutyl phosphorodithioate (Dibufos, U16) and S-butyl phosphorothiate (Bufos, U8), were identified as minor components in urine, comprising 5 and 4% of the total radioactive residue, respectively. Butyl mercaptan was not found, but mixed disulphides of butyl mercaptan with either glutathione (U10, 3%) or N-acetyl cysteine (U13, 2%) were found. 7. Direct evidence for the incorporation of DEF residue into natural constituents was also established. Fatty acids from milk and fat were isolated and shown to be radioactive.