Zinc pyridinethione: Serum metabolites of zinc pyridinethione in rabbits, rats, monkeys, and dogs after oral dosing

Abstract

The metabolites of zinc pyridinethione (ZPT) in the systemic circulation of female rabbits and monkeys and male rats and dogs were studied after 1 mg [ 14C]ZPT/kg body wt was administered by oral gavage. In all four species, the blood radioactivity concentration showed a complex kinetic pattern. An initial maximum at 1 to 8 hr after dosing coincided with the rapid formation and elimination of several polar metabolites, while a secondary broad peak or plateau paralleled the slow accumulation of a single metabolite. In rats, this latter metabolite was identified as 2-(methylsulfonyl)pyridine (MSP) by spectral and chromatographic comparisons with the synthetic compound. Its concentration in rat serum was proportional to the quantity of ZPT dosed over the range of 0.2 to 10 mg ZPT/kg. its presence as a long-lived circulating metabolite is significant for estimating the systemic load of ZPT. The biotransformations which produce MSP involve a multistep sequence of methylation, oxidation, and reduction. Three minor serum metabolites, 2-(methylthio)pyridine-1-oxide, 2-(methylthio)pyridine, and 2-(methylsulfinyl)pyridine-1-oxide, are apparently the intermediate compounds in the biotransformation of ZPT to MSP. Subchronic feeding of [ 14C]ZPT produced early signs of hindlimb paralysis in a rat in 6 days; the serum concentration of ZPT-derived metabolites increased linearly over this interval. Since MSP was the only major serum metabolite likely to accumulate, infusion studies were conducted to see if MSP would produce paralysis. Although the duration of infusion and the serum concentrations of MSP attained were greater than those predicted to produce paralysis from the ZPT feeding study, no paralysis was observed.