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

Jakobsen, Preben; Ak, Pedersen

doi:10.1111/j.2042-7158.1981.tb13717.x

Cited by 14 publications

(3 citation statements)

References 8 publications

(2 reference statements)

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“…The results obtained by McDonald (1977), McDonald et al (1980), Gordon and Pearson (1978), Pfister et al (980) and Westwick et al (1979a,b) suggest that sulphinpyrazone acts primarily as a cyclo-oxygenase inhibitor, probably with a more pronounced action on platelet cyclo-oxygenase than vessel wall cyclo-oxygenase. In some models, the sulphone appears to be less active than the parent drug (Westwick et al,I 979a,b), while in other models (Kirstein Pedersen and Jakobsen, 1981 ;McDonald et al, 1980;Pay et al, 198 I) it seems to be about 2.5 times as active. The sulphide, possessing better in vivo anti-inflammatory properties than sulphinpyrazone (Domenjoz, 1960), is 10 to 25 times as active in the inhibition of platelet function (Butler et al, 1980;Kirstein Pedersen and Jakobsen, 1981;Pay et al, 1981;Ruegg, 1976), while the activity of the parahydroxy metabolites is much lower than that of the parent compound.…”

Section: Biological Activity Of Metabolitesmentioning

confidence: 94%

“…During long term treatment with doses giving plasma concentrations of approximately 7 to 16J.lg/ ml sulphinpyrazone, steady-state concentrations of 3 to 4J.lg/ml (sulphide), 2 to 5J.lg/ml (sulphone), 0.6 to 0.9pg/ml (p-OH-sulphide) and 0.1 to 0.2J.lg/ml (p-OH-sulphinpyrazone) were found (Kirstein Pedersen and Jakobsen, 1981). Similar plasma concentration data were recently reported by Maguire et al (J 979), who measured sulphinpyrazone concentrations of 5 to 12J.1g/ml and sulphide levels of 2 to 4J.lg/ ml during the first week of treatment with sulphinpyrazone 800mg per day.…”

Section: Plasma and Urine Concentrations Of Metabolitesmentioning

confidence: 97%

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Clinical Pharmacokinetics and Potentially Important Drug Interactions of Sulphinpyrazone

Pedersen

Jakobsen

Kampmann

et al. 1982

Clinical Pharmacokinetics

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Sulphinpyrazone 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 per/ormance 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 Q{ the plasma concentration qf sulphinpyrazone when administered intravenously is best described by an open 3-compartment model with ha(f-lives Qf the n-, ~ and v-phases at about 0.3, 3 and 6 hours, respectively. The volume oj distribution has been calculated to be 60ml I kg. Sulphinpyrazone and its uncon}ugated metabolites are strongly (98 to 99 %) bound to plasma proteins. The total clearance of sulphinpyrazone has been estimated at 20 to 25mllmin. 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 ofsulphinpyrazone. The sulphide is probably important for the antiplatelet effect qf sulphinpyrazone, but not for the uricosuric action. The sulphone metabolite and parahydroxylated metabolites are of minor quantitative SignIficance. A II metabolites are excreted as C-glucuronides; only a small proportion Q{ metabolites is excreted in O-glucuronidated or in unconJugatedform in urine.Decreased renal function apparently does not il'!f/uence plasma concentrations Q{ sulphinpyrazone, and dosage changes in patients with renal dysfunction do not seem warranted.Several drug interactions have been reported involving displacement/rom plasma proteins, inhibition and induction Qf hepatic microsomal metabolism, and influence on renal tubular secretion. Clinically the most important interactions seem to be potentiation Qf the effects Q{ oral anticoagulants, phenytoin and tolbutamide, and inhibition of the uricosuric effect Q{probenecid and salicylate.No data comparing plasma concentrations and clinical effects are available.

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Section: Biological Activity Of Metabolitesmentioning

confidence: 94%

Section: Plasma and Urine Concentrations Of Metabolitesmentioning

confidence: 97%

Clinical Pharmacokinetics and Potentially Important Drug Interactions of Sulphinpyrazone

Pedersen

Jakobsen

Kampmann

et al. 1982

Clinical Pharmacokinetics

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“…This is in accordance with previous acute studies in which intravenous administration of a single dose of sulfinpyrazone [Burns el al., 1957] or of one of its active metabolites [Tm et al, 1956], the sulfide analog [Jakobsen and Kirstein Pedersen. 1981], had no effect on inulin clearance in normal volunteers.…”

Section: Discussionmentioning

confidence: 99%

Effects of Sulfinpyrazone on Renal Function and Prostaglandin Formation in Man

Rosenkranz

Fejes-Tóth

Diener

et al. 1985

Nephron

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Sulfinpyrazone (800 mg/day for 6 days) significantly reduced the excretion of the main urinary prostaglandin E metabolite by 54% in 6 healthy female volunteers. While sulfinpyrazone did not affect inulin clearance, clearances of creatinine and PAH were significantly diminished by 18.0 and 44.7%, respectively. In the anaesthetized dog sulfinpyrazone decreased PAH clearance and PAH extraction concomitantly without affecting renal blood flow. These results show that clearances of creatinine and PAH do not reliably reflect glomerular filtration and renal perfusion, respectively, during sulfinpyrazone administration. Whereas sodium balance and body weight were not significantly different between the first control period and sulfinpyrazone administration, net sodium excretion significantly increased from 121.6 ± 5.4 mEq/day during sulfinpyrazone treatment to 139.3 ± 6.6 mEq/day during the following control period, while body weight significantly decreased indicating modest sodium retention during drug administration. Plasma renin activity, vascular sensitivity to angiotensin II, and urinary excretion of the enzymes N-acetylglucosaminidase and alanineaminopeptidase were not affected by sulfinpyrazone administration. In summary, sulfinpyrazone caused a decrease of total body prostaglandin E formation in healthy female volunteers together with a moderate sodium retention. Despite inhibition of prostaglandin synthesis, glomerular filtration rate, plasma renin activity, or pressor effects of angiotensin II were not altered.

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Correlation between inhibitory effect on platelet aggregation and disposition of sulfinpyrazone and its metabolites in rabbits. Part II: Multiple dose study

Kuo

Ritschel

1987

Biopharm & Drug Disp

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In a crossover study rabbits were given perorally sulfinpyrazone (SO) and the sulfide metabolite (S) every 24 h for 5 days on separate occasions and inhibition of aggregation was measured. The results showed: the dosage regimen is effective if the minimum effective concentration of S is defined to be between 0.5-1.0 microgram ml-1, and the repeated dosing did not cause changes in disposition kinetics except that the terminal half-life of S was reduced after dosing with S. No significant accumulations in trough concentration and inhibition of aggregation were observed. The results obtained in this study could provide some useful information for design of dosage regimen and blood level monitoring for humans.

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

Cited by 14 publications

References 8 publications

Clinical Pharmacokinetics and Potentially Important Drug Interactions of Sulphinpyrazone

Clinical Pharmacokinetics and Potentially Important Drug Interactions of Sulphinpyrazone

Effects of Sulfinpyrazone on Renal Function and Prostaglandin Formation in Man

Correlation between inhibitory effect on platelet aggregation and disposition of sulfinpyrazone and its metabolites in rabbits. Part II: Multiple dose study

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