The role of the gut flora in the reduction of sulphinpyrazone in the rat

Renwick, A.G.; Evans, Susan P.; Sweatman, Trevor W.; Cumberland, Janet; George, Charles F.

doi:10.1016/0006-2952(82)90713-4

Cited by 52 publications

(22 citation statements)

References 15 publications

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“…However, these metabolites were not detected in urine after oral administration. It was demonstrated in previous studies that sulphoxide drugs are metabolised to sulphides by the intestinal flora (15)(16)(17). It has been suggested that BOF-4272 is also metabolised to BOF-4269 (the sulphide metabolite of BOF-4272) by the intestinal flora in the rat, whereas little BOF-4272 is metabolised to BOF-4269 in the rat liver (12).…”

Section: Resultsmentioning

confidence: 99%

Biotransformation of BOF-4272, a sulfoxide-containing drug, in the cynomolgus monkey

Naito

Nishimura

Jin³

1999

Eur. J. Drug Metab. Pharmacokinet.

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BOF-4272, (+/-)-8-(3-methoxy-4-phenylsulfinylphenyl) pyrazolo[1,5-a]-1,3,5-triazine-4(1H)-one), is a new drug intended for the treatment of hyperuricemia. This report describes the pharmacokinetics and detailed metabolic pathways of BOF-4272 in the cynomolgus monkey, which were investigated using the metabolites found in plasma, urine, and faeces after intravenous and oral administration. M-4 was the main metabolite in plasma after intravenous administration. M-3 and M-4 were the main metabolites in plasma after oral administration. The Cmax and AUC(0-t) of M-4 were the highest of all the metabolites after intravenous administration. The Cmax and AUC(0-t) of M-3 were the highest of all the metabolites, and those of M-4 were the second highest, after oral administration. M-4 and M-3 were the main metabolites detected in urine and faeces, respectively, after intravenous administration, with M-4 and M-3 at 47.2% in urine and 19.1% in faeces, respectively, within 120 h after administration. M-4 was the only metabolite detected in urine after oral administration, at about 5% within 120 h after administration. M-3 was detected in faeces at 17.0% within 120 h after oral administration. These results suggest that, in the cynomolgus monkey, BOF-4272 is rapidly biotransformed to a main metabolite (M-4, a sulphoxide-containing metabolite of BOF-4272) and that M-4 is mainly excreted in urine and possibly also in bile, with subsequent conversion to M-3 by the intestinal flora. It is expected that the biotransformation of BOF-4272 would be similar in healthy human volunteers.

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Section: Resultsmentioning

confidence: 99%

Biotransformation of BOF-4272, a sulfoxide-containing drug, in the cynomolgus monkey

Naito

Nishimura

Jin³

1999

Eur. J. Drug Metab. Pharmacokinet.

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“…Since this metabolite has been reported to be up to 16 times more potent as an inhibitor of platelet cyclo-oxygenase than sulphinpyrazone it- self, the metabolite may be responsible for the main action on platelets during regular dosing (Del Maschio et al 1984;Pay et al 1980). Studies in animals (Renwick et al 1982;Strong et al 1984b) and in humans (Strong et al 1984a) have shown that the gut flora are responsible for the production of the active sulphide metabolite. Thus variations in sulphide formation would be expected to occur due to differences in the delivery of sulphinpyrazone to the hind gut, and the activity and/or numbers of sulphinpyrazone reducing bacteria in the colon and rectum (Strong et al I 984a).…”

Section: Clinical Pharmacology Group University Of Southampton Soutmentioning

confidence: 93%

Effects of Ischaemic Heart Disease, Crohnʼs Disease and Antimicrobial Therapy on the Pharmacokinetics of Sulphinpyrazone

Strong

Angus

Oates

et al. 1986

Clinical Pharmacokinetics

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The renewed interest in sulphinpyrazone in recent years has arisen from its potential to inhibit platelet aggregation. In vivo much of the activity is probably due to the thioether or sulphide metabolite which has a greater potency and a longer half-life than the parent compound. The sulphide metabolite is formed exclusively by the gut microflora in man. The pharmacokinetics of sulphinpyrazone (200 mg orally) have been studied, with particular attention to the formation of the sulphide metabolite, in groups of patients who might be expected to show abnormal formation of this active metabolite due to altered delivery of the drug to the lower gut or altered gut flora. Five patients studied 1 month after a myocardial infarction did not differ markedly from young, normal volunteers with respect to either sulphinpyrazone or its metabolite. Crohn's disease in the quiescent phase did not significantly alter the pharmacokinetics or metabolism of the drug, but 1 patient who had undergone a hemicolectomy formed negligible concentrations of the active metabolite. Antimicrobial therapy produced highly variable results with almost complete suppression of sulphide formation in some subjects but no apparent effect in others.

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“…Oral doses of the drugs sulphinpyrazone and sulindac are completely absorbed and their metabolites excreted in the bile of humans (Renwick et al, 1982;Renwick et al, 1986;Strong et al, 1984b), while dimethyl sulphoxide and dimethyl sulphone are excreted in the urine as metabolites of methyl sulphide administered subcutaneously to rabbits (Williams et al, 1966). Oral doses of the drugs sulphinpyrazone and sulindac are completely absorbed and their metabolites excreted in the bile of humans (Renwick et al, 1982;Renwick et al, 1986;Strong et al, 1984b), while dimethyl sulphoxide and dimethyl sulphone are excreted in the urine as metabolites of methyl sulphide administered subcutaneously to rabbits (Williams et al, 1966).…”

Section: Iii2 Sulphides Sulphoxides/sulphones and Sulphonatesmentioning

confidence: 99%

“…In vitro under anaerobic conditions, the sulphoxide anti-inflammatory drug sulphinpyrazone is reduced approximately six times faster in cultures with cecum contents than with liver cell homogenates from either rats (Renwick et al, 1982) or rabbits (Strong et al, 1984a). Oral doses of the sulphoxide drugs sulindac and sulphinpyrazone, which are completely absorbed and excreted in the bile of humans, are bioactivated by reduction to the corresponding monosulphides (Renwick et al, 1982;Renwick et al, 1986;Strong et al, 1984b).…”

Section: Figure Iii1 Biotransformation Of Disulphides Thiols and Rmentioning

confidence: 99%

Flavouring Group Evaluation 8, Revision 1 (FGE.08Rev1): Aliphatic and alicyclic mono-, di-, tri-, and polysulphides with or without additional oxygenated functional groups from chemical groups 20 and 30

Flavourings¹

2010

EFSA Journal

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The role of the gut flora in the reduction of sulphinpyrazone in the rat

Cited by 52 publications

References 15 publications

Biotransformation of BOF-4272, a sulfoxide-containing drug, in the cynomolgus monkey

Biotransformation of BOF-4272, a sulfoxide-containing drug, in the cynomolgus monkey

Effects of Ischaemic Heart Disease, Crohnʼs Disease and Antimicrobial Therapy on the Pharmacokinetics of Sulphinpyrazone

Flavouring Group Evaluation 8, Revision 1 (FGE.08Rev1): Aliphatic and alicyclic mono-, di-, tri-, and polysulphides with or without additional oxygenated functional groups from chemical groups 20 and 30

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