Disposition of zinc pyrithione in the rat

Abstract

The pharmacokinetic profile of orally administered [2,6- 14C]-labelled zinc pyrithione (ZPT) was defined in male and female rats and was used to predict the blood concentrations of 14C at steady state correlating with the skeletal-muscle weakness observed in long-term feeding tests and mechanism studies. The 14C concentration was determined in blood, urine and faeces as a function of time following oral administration of doses of 0·5, 1·25 and 12·5 mg [ 14C]ZPT/kg. The major route of elimination from the body was the urine, in which all the ZPT appeared as metabolites. Mass-spectroscopic analysis of the urine indicated that a minor metabolite was 2-mercaptopyridine- N-oxide and the major metabolites were S-glucuronides of 2-mercaptopyridine- N-oxide. Radioassay of tissues indicated that ZPT was rapidly excreted and was not retained in the body to any significant degree. A two-compartment open model was used to describe the dynamics of ZPT in males and females given 0·5, 1·25 or 12·5 mg/kg. Kinetic constants for the same dose indicated sex differences in plasma elimination, renal clearance, time required for attainment of maximum blood concentration and rate of absorption. The ratio for 14C binding in red blood cells and plasma, respectively, was 5:1 at 96 hr and increased to ⩾ 45:1 at 240 hr, a probable reason for the low renal clearance rates. No sex difference in the concentration of 14C in blood at steady-state levels (maximum and minimum) was seen with the 0·5 mg/kg dose, but a significant difference was apparent at 1·25 mg/kg, the concentration being higher in the females. The significantly lower blood concentration of 14C in the males, in conjunction with the apparent higher rate of metabolism in the male, provide a reasonable explanation for the demonstrated sex difference in the dietary level of ZPT capable of producing an effect.