No abstract

The pharmacokinetics of sulfinpyrazone, and the plasma levels of its sulfide and sulfone metabolites, have been determined after a single oral dose (400 mg) and during steady-state conditions (4 x 200 mg daily for 6 days) in healthy female volunteers. The plasma half-lives of sulfinpyrazone, the sulfone and the sulfide were 3.7, 3.2 and 14.7 h, respectively, during steady-state. After a single dose and during steady state conditions the half-lives of sulfinpyrazone and the sulfone did not differ significantly. The trough plasma levels of the sulfide metabolite exceeded those of the parent compound in four of the six volunteers on the last day of the study. The data suggest that in man the most likely candidate for the prolonged inhibition of platelet aggregation observed after treatment with sulfinpyrazone is its sulfide metabolite, because of its prolonged elimination.

Sulphinpyrazone is an antiplatelet agent in vivo and in vitro. Two active metabolites, a sulphide (S) and a hydroxylated sulphide (S‐OH) have been identified in rabbit and human plasma and a selective and sensitive g.c.‐m.s.‐method for quantitative determination of the sulphide and hydroxylated sulphide in plasma and urine has been evolved which allows concentrations down to 5 ng ml−1 for the sulphide and 30 ng ml−1 for the hydroxylated sulphide to be detected. The time course of the metabolite concentrations in plasma corresponds to the biological findings, suggesting that the metabolites contribute significantly to the in vivo effects of the drug.

A HPLC‐method for rapid, simultaneous and specific determination of proxyphylline, theophylline, glyphylline, theobromine, caffeine and 3‐methylxanthine using 8‐chlorotheophylline as internal standard is presented. Using 20 μl deproteinised serum samples for injection, the detection limits for theophylline and proxyphylline are about 0.040 and 0.055 μg per ml serum or plasma, respectively, and the corresponding sensitivities are about 0.033 and 0.048 μg compound for 0.0044 absorbance units at 280 nm. In duplicate analyses the coefficient of variation is less than 3%. A number of frequently used drugs did not interfere in the analyses of serum samples from patients under treatment or in experiments with drug additions to serum samples.

1 The plasma concentrations of sulphinpyrazone and four of its metabolites are reported together with the amounts excreted in urine. Eight insulin-requiring diabetics were investigated, all treated with sulphinpyrazone 600-800 mg day-for 2.5 years or more. 2 Blood samples were drawn before the first morning dose and 2 h later. The mean plasma concentrations were (t = 0 h -t = 2 h): sulphinpyrazone 7.1-16.0>gml-'; sulphide 2.8-4.3 gigml-1; sulphone 1.7-4.8 pgmlm'; p-OH-sulphide 0.67-0.89 Fg ml-; p-OH-sulphinpyrazone 0. 10-0.16 pg ml-'. Statistically significant correlations were found between the plasma concentrations at t = 0 of the sulphide and the p-OH-sulphide and that of sulphinpyrazone. 3 In urine, a very wide range in excretion of unconjugated compounds was observed. Sulphinpyrazone were excreted in amounts corresponding to 1-30% of the daily dose. The metabolites were generally excreted in amounts corresponding to less than 1 % of the daily dose; however, up to 3% was found as the sulphone. 4 Increases of the concentrations of all compounds in urine were found after treatment with f-glucuronidase indicating 0-conjugation with glucuronic acid. 5 Since both the sulphide and the sulphone were found more active as inhibitors of platelet function in vitro than their parent compound, they may together constitute the major part of the platelet inhibitory drug activity in plasma during long-term therapy with sulphinpyrazone.