A. Kirstein Pedersen

Plasma levels of sulfinpyrazone and of two of its metabolites after a single dose and during the steady state

SummaryThe 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 (4×200 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.

Clinical Pharmacokinetics and Potentially Important Drug Interactions of Sulphinpyrazone

SummarySulphinpyrazone is a derivative of Phenylbutazone. It was originally introduced as a uricosuric agent but in recent years it has been investigated for effects on platelet function.Sulphinpyrazone and its metabolites can be measured in blood and urine using high performance liquid chromatography and gas chromatography-mass spectrometry. It is almost completely absorbed and maximum plasma concentrations are found about 2 hours after oral administration. The decay of the plasma concentration of sulphinpyrazone when administered intravenously is best described by an open 3-compartment model with half-lives of the α-, β-and γ-phases at about 0.3, 3 and 6 hours, respectively. The volume of distribution has been calculated to be 60ml/kg. Sulphinpyrazone and its unconjugated metabolites are strongly (98 to 99%) bound to plasma proteins. The total clearance of sulphinpyrazone has been estimated at 20 to 25ml/min.25 to 50% of a sulphinpyrazone dose is excreted in the urine in unchanged form. The remainder is metabolised via several pathways; a sulphide metabolite is the predominant circulating metabolite reaching levels about 25 % of that of sulphinpyrazone. The sulphide is probably important for the antiplatelet effect of sulphinpyrazone, but not for the uricosuric action. The sulphone metabolite and parahydroxylated metabolites are of minor quantitative significance. All metabolites are excreted as C-glucuronides;onlya small proportion of metabolites is excreted in O-glucuronidated or in unconjugated form in urine.Decreased renal function apparently does not influence plasma concentrations of sulphinpyrazone, and dosage changes in patients with renal dysfunction do not seem warranted.Several drug interactions have been reported involving displacement from plasma proteins, inhibition and induction of hepatic microsomal metabolism, and influence on renal tubular secretion. Clinically the most important interactions seem to be potentiation of the effects of oral anticoagulants, Phenytoin and tolbutamide, and inhibition of the uricosuric effect of probenecid and salicylate.No data comparing plasma concentrations and clinical effects are available.

Two metabolites of sulphinpyrazone and their identification and determination by mass spectrometry

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.

Determination of sulfinpyrazone and two of its metabolites in human plasma and urine by gas chromatography and selective detection.

A selective and sensitive gas chromatographic method for simultaneous determination of sulfinpyrazone and two of its metabolites (the para-hydroxylated metabolite and the sulfone metabolite) in biological fluids using alkali flame ionization detection (AFID), electron capture detection (ECD) and mass fragmentographic detection is described. The compounds are extracted from the samples, methylated and separated on 2% OV-17 or 3% OV-225 columns. Phenylbutazone is used as internal standard. Standard curves are linear. The coefficient of variation at 10 microgram/ml of sulfinpyrazone in plasma was shown to be 1.8% (AFID), and the detection limits were 0.1 microgram/ml (AFID) and 10 ng/ml (ECD). Mass spectra of the methylated compounds are shown and serum concentration curves after oral administration of 100 mg sulfinpyrazone to two persons are determined together with the excreted amounts of drug and metabolites.