Pharmacokinetics of single doses of sulphinpyrazone and its major metabolites in plasma and urine.

Bradbrook, ID; John, VA; Morrison, P. J.; Rogers, H. J.; Spector, R. G.

doi:10.1111/j.1365-2125.1982.tb01353.x

Cited by 11 publications

(2 citation statements)

References 14 publications

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“…4, A-C, and Table 1, respectively. For patients receiving standard clinical doses of RIF (600 mg), SUL (200 mg), and PIO (45 mg), the reported pharmacokinetic parameters were 8500 ng/ml (C max ) and 28,100 ng ⅐ h Ϫ1 ⅐ ml Ϫ1 (AUC 0-ϱ ) for RIF (Polk et al, 2001); 19,500 ng/ml (C max ) and 79,600 ng ⅐ h Ϫ1 ⅐ ml Ϫ1 (AUC 0-ϱ ) for SUL (Bradbrook et al, 1982); and 1300 to 1600 ng/ml (C max ) and 14,600 to 17,400 ng ⅐ h Ϫ1 ⅐ ml Ϫ1 (AUC 0-ϱ ) for PIO (Budde et al, 2003). On the basis of these data, we estimated that doses of 3 to 10 mg/kg RIF, 2 to 10 mg/kg SUL, and 2 mg/kg PIO resulted in exposure in mice similar to that in humans receiving a standard dose of these drugs.…”

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confidence: 99%

Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line

Hasegawa

Kapelyukh²,

Tahara³

et al. 2011

Mol Pharmacol

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Cytochrome P450 (P450) 3A4 is the predominant P450 enzyme expressed in human liver and intestine, and it is involved in the metabolism of approximately 50% of clinically used drugs. Because of the differences in the multiplicity of CYP3A genes and the poor correlation of substrate specificity of CYP3A proteins between species, the extrapolation of CYP3A-mediated metabolism of a drug from animals to man is difficult. This situation is further complicated by the fact that the predictability of the clinically common drug-drug interaction of pregnane X receptor (PXR)-mediated CYP3A4 induction by animal studies is limited as a result of marked species differences in the interaction of many drugs with this receptor. Here we describe a novel multiple humanized mouse line that combines a humanization for PXR, the closely related constitutive androstane receptor, and a replacement of the mouse Cyp3a cluster with a large human genomic region carrying CYP3A4 and CYP3A7. We provide evidence that this model shows a human-like CYP3A4 induction response to different PXR activators, that it allows the ranking of these activators according to their potency to induce CYP3A4 expression in the human liver, and that it provides an experimental approach to quantitatively predict PXR/CYP3A4-mediated drug-drug interactions in humans.

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mentioning

confidence: 99%

Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line

Hasegawa

Kapelyukh²,

Tahara³

et al. 2011

Mol Pharmacol

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“…Up to 20-fold interindividual variations in sulphide formation have been reported after single oral doses of sulphinpyrazone to normal volunteers (Bradbrook et al 1982;Mahony et al 1983;Strong et al I 984a). In addition, the production of sulphide is altered in patients whose intestinal motility is affected by disease or by the administration of drugs such as metoclopramide (Strong et al 1984a).…”

Section: Clinical Pharmacology Group University Of Southampton Soutmentioning

confidence: 95%

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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Renal clearance of sulphinpyrazone in man

Lentjes

Rüssel

Ginneken

1986

Eur J Clin Pharmacol

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Six healthy young volunteers received a single dose of sulphinpyrazone 200 mg p.o. Plasma concentration and urinary excretion rate curves showed large intersubject variation for sulphinpyrazone and its metabolites. The sulphide metabolite could only be detected in plasma and not before 3-7 h after ingestion. The total recovery in urine of all compounds varied from 30-56% of the dose. In two subjects the mean residence time of sulphinpyrazone was twice as long as in the other subjects (10.4 h compared with 4.6 h), but the area under the plasma concentration-time curve was comparable to that in the others (mean: 3.0 mg X ml-1 X min), indicating that drug absorption was quantitatively similar but delayed. The renal clearance of sulphinpyrazone varied from 14-40 ml X min-1 (mean: 28 ml X min-1). In view of the very high plasma protein binding of sulphinpyrazone, active tubular secretion is the predominant mechanism in its renal clearance. The same holds for the sulphone metabolite, which has a mean renal clearance of 24 ml X min-1, and even more for the p-hydroxysulphinpyrazone metabolite, which has a renal clearance of 118 ml X min-1. No unambiguous evidence was found in favour of concentration-dependent renal clearance of sulphinpyrazone or its metabolites over the concentration range studied. The renal clearance, especially of sulphinpyrazone, appeared to be dependent on urine pH and not on urine flow rate.

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Pharmacokinetics of single doses of sulphinpyrazone and its major metabolites in plasma and urine.

Cited by 11 publications

References 14 publications

Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line

Quantitative Prediction of Human Pregnane X Receptor and Cytochrome P450 3A4 Mediated Drug-Drug Interaction in a Novel Multiple Humanized Mouse Line

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

Renal clearance of sulphinpyrazone in man

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