Biotransformation and pharmacokinetics of sulfinpyrazone (Anturan�) in man

Dieterle, W.; Faigle, J. W.; Mory, H.; Richter, Wilhelm J.; Theobald, W

doi:10.1007/bf00614010

Cited by 69 publications

(22 citation statements)

References 9 publications

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“…It has been reported previously that phenylbutazone and sulfinpyrazone, which are both C-glucuronidated in humans (Dieterle et al, 1975;Aarbakke, 1978), inhibit the glucuronidation of AZT in vitro (Resetar et al, 1991;Rajaonarison et al, 1992). The present study confirmed that phenylbutazone and sulfinpyrazone inhibited UGT2B7, the enzyme responsible for AZT glucuronidation.…”

Section: Discussionmentioning

confidence: 91%

Selectivity of Substrate (Trifluoperazine) and Inhibitor (Amitriptyline, Androsterone, Canrenoic Acid, Hecogenin, Phenylbutazone, Quinidine, Quinine, and Sulfinpyrazone) “Probes” for Human Udp-Glucuronosyltransferases

Uchaipichat¹,

Mackenzie²,

Elliot³

et al. 2006

Drug Metabolism and Disposition

224

201

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ABSTRACT:Relatively few selective substrate and inhibitor probes have been identified for human UDP-glucuronosyltransferases (UGTs). This work investigated the selectivity of trifluoperazine (TFP), as a substrate, and amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone, as inhibitors, for human UGTs. Selectivity was assessed using UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15 expressed in HEK293 cells. TFP was confirmed as a highly selective substrate for UGT1A4. However, TFP bound extensively to both HEK293 lysate and human liver microsomes in a concentration-dependent manner (fu inc 0.20-0.59). When corrected for nonspecific binding, K m values for TFP glucuronidation were similar for both UGT1A4 (4.1 M) and human liver microsomes (6.1 ؎ 1.2 M) as the enzyme sources. Of the compounds screened as inhibitors, hecogenin, alone, was selective; significant inhibition was observed only for UGT1A4 (IC 50 1.5 M). Using phenylbutazone and quinine as "models," inhibition kinetics were variously described by competitive and noncompetitive mechanisms. Inhibition of UGT2B7 by quinidine was also investigated further, because the effects of this compound on morphine pharmacokinetics (a known UGT2B7 substrate) have been ascribed to inhibition of P-glycoprotein. Quinidine inhibited human liver microsomal and recombinant UGT2B7, with respective K i values of 335 ؎ 128 M and 186 M. In conclusion, TFP and hecogenin represent selective substrate and inhibitor probes for UGT1A4, although the extensive nonselective binding of the former should be taken into account in kinetic studies. Amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone are nonselective UGT inhibitors.

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Section: Discussionmentioning

confidence: 91%

Selectivity of Substrate (Trifluoperazine) and Inhibitor (Amitriptyline, Androsterone, Canrenoic Acid, Hecogenin, Phenylbutazone, Quinidine, Quinine, and Sulfinpyrazone) “Probes” for Human Udp-Glucuronosyltransferases

Uchaipichat¹,

Mackenzie²,

Elliot³

et al. 2006

Drug Metabolism and Disposition

224

201

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“…This metabolite was reported to be a major metabolite in humans (Dieterle et al, 1980). A secondary C-glucuronide metabolite of sulfinpyrazone, i.e., a metabolite of its sulfone metabolite, has also been reported (Dieterle et al, 1975). Studies have shown that recombinant human UGT1A9 catalyzed the formation of sulfinpyrazone-Cglucuronide in vitro (Kerdpin et al, 2006).…”

Section: Carbon-linked Glucuronidesmentioning

confidence: 99%

Unusual Glucuronides

Argikar¹

2012

Drug Metabolism and Disposition

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ABSTRACT:Glucuronidation reaction is catalyzed by mammalian uridine diphosphoglucuronosyl transferases by using uridine diphosphoglucuronic acid as a cosubstrate. Conjugation of glucuronic acid to nucleophilic functional groups in chemical entities results in formation of glucuronides. As anticipated, a number of nucleophilic functional groups such as hydroxyl, phenolic, acyl, primary secondary and tertiary amino, etc. in a diverse set of chemical compounds are known to form the corresponding glucuronides. Glucuronides have been reported to be formed at carbon atoms, selenium atoms, and upon N-carbamoylation of primary and secondary amino groups. Glucuronides are also believed to be the end products of metabolism. However, there are examples where glucuronidation results in further oxidative or conjugative biotransformation reactions. The objective of this review is to highlight unusual glucuronide conjugates. Diglucuronide conjugates reported in the literature fall under two distinct categories. Use of prefixes such as "bis" versus "di" has been previously proposed for separating the two types of diglucuronides. In spite of this, literature reports for diconjugative glucuronide metabolites reflect interchangeable use of "bisglucuronides" and "diglucuronides." Furthermore, the application of such prefixes does not adhere to recommendations of International Union of Pure and Applied Chemistry nomenclature for substituent groups. Therefore, an effort is made in this review to document the historic reports for diglucuronides into two distinct types for sake of clarity and to allow differentiation between the two types of diconjugative metabolites. Overall, this commentary centers on unusual glucuronide metabolites that result from conjugation at uncommon functional groups, glucuronides undergoing ensuing oxidative or conjugative metabolic transformations. Structural and mechanistic aspects are also discussed.

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“…Methods Fifty-eight apparently healthy male mongrel dogs that weighed [22][23][24][25][26][27][28][29][30][31][32] kg were used for the study. After an 18-hour period of fasting, all dogs on the day of the experiment were anesthetized with morphine sulfate (3 mg/kg i.m.)…”

mentioning

confidence: 99%

Effect of sulfinpyrazone on ventricular fibrillation during acute myocardial ischemia.

Moschos¹,

Jorgensen²,

Regan³

1981

Circulation

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SUMMARY In patients treated with sulfinpyrazone, an apparent reduction in the incidence of sudden death and presumed ventricular fibrillation has been reported. Using an intact animal model without microcirculatory thrombosis, we studied the effects of sulfinpyrazone on ischemic myocardium in 58 anesthetized dogs divided into three groups: control untreated (n = 24), group 1 (n = 16), treated daily with 300 mg of sulfinpyrazone for 7 days, and group 2 (n = 18), treated daily with 300 mg of sulfinpyrazone for 7 days but omitting treatment on day 8. Although consistent hemodynamic differences were not apparent, the degree of injury determined by ECG mapping was significantly lower in group 1. The incidence of fibrillation was 54% for control and 0% in group 1. Group 2 had a 44% incidence, suggesting a limited duration of action. The apparent absence of microcirculatory thrombosis in this model suggests other mechanisms of action. A significantly smaller increase in tissue water and Na+ and smaller loss of K+ in group 1 may have contributed to the lower incidence of fibrillation, perhaps through selective prostaglandin inhibition.THE USE of drugs in coronary artery disease that interfere with platelet function' has been prompted by the presumed role of the latter in the pathogenesis of ischemic heart disease.2-' Recent developments on the effects of platelet-active agents on prostaglandin metabolism have suggested several mechanisms that might affect the course of coronary artery disease.5'6 Our studies with aspirin in a canine model have indicated that aspirin did not significantly inhibit formation of experimentally induced platelet thrombus in the epicardial coronary vessels but survival rate was significantly increased.7 In patients treated with sulfinpyrazone in the postinfarction period, there was an apparent reduction in the incidence of sudden death,8 and presumably ventricular fibrillation, an effect that may be independent of antiplatelet activity.9' 10 These considerations prompted us to study the effects of sulfinpyrazone on ischemic myocardium using an animal model with nonthrombotic coronary occlusion, which permitted the study of sulfinpyrazone in the absence of evident platelet microaggregates.Methods Fifty-eight apparently healthy male mongrel dogs that weighed 22-32 kg were used for the study. After an 18-hour period of fasting, all dogs on the day of the experiment were anesthetized with morphine sulfate (3 mg/kg i.m.) and sodium pentobarbital (20 mg/kg i.v.) and were placed on a respiratory pump to maintain adequate ventilation. Through vessels exposed by small skin incisions, catheters were placed under From

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Biotransformation and pharmacokinetics of sulfinpyrazone (Anturan�) in man

Cited by 69 publications

References 9 publications

Selectivity of Substrate (Trifluoperazine) and Inhibitor (Amitriptyline, Androsterone, Canrenoic Acid, Hecogenin, Phenylbutazone, Quinidine, Quinine, and Sulfinpyrazone) “Probes” for Human Udp-Glucuronosyltransferases

Selectivity of Substrate (Trifluoperazine) and Inhibitor (Amitriptyline, Androsterone, Canrenoic Acid, Hecogenin, Phenylbutazone, Quinidine, Quinine, and Sulfinpyrazone) “Probes” for Human Udp-Glucuronosyltransferases

Unusual Glucuronides

Effect of sulfinpyrazone on ventricular fibrillation during acute myocardial ischemia.

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