Species differences in the disposition and metabolism of sulfinpyrazone

Abstract

1. The disposition and metabolism of sulfinpyrazone have been studied in rats, guineapigs, rabbits, dogs, rhesus monkeys and miniature swine after intravenous administration of 100mg/kg of ¹⁴C-labelled drug.

2. In all species, the integrated plasma concentration (AUC, 0-24h) of total radioactivity was almost completely covered by the sum of the AUC-values of unchanged sulfinpyrazone and six metabolites, i.e. the sulphide, the sulphone, p-hydroxy-sulfinpyrazone, the p-hydroxy-sulphide, the p-hydroxy-sulphone and 4-hydroxy-sulfinpyrazone.

3. Comparison of the plasma level profiles of unchanged sulfinpyrazone and the metabolites revealed pronounced differences between the species. Unchanged sulfinpyrazone was the most prominent compound in plasma of rats, dogs, monkeys and swine, whereas the sulphide metabolite predominated in guinea-pigs. In plasma of rabbits, these two compounds were found in similar amounts.

4. Species with predominant renal excretion of the ¹⁴C dose, i.e. rabbits, dogs and monkeys, eliminated sulfinpyrazone to a high extent unchanged. The renal excretion of the sulphide metabolite was low in all species.

5. Species differences in the biotransformation of sulfinpyrazone explain previously observed differences in inhibitory effect on platelet aggregation. This effect is intensive and long-lasting in species showing high plasma concentrations of the sulphide metabolite.