The effect of sulphinpyrazone on oxidative drug metabolism in man: Inhibition of tolbutamide elimination

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Abstract
Summary The effect of sulphinpyrazone on tolbutamide elimination was investigated in 6 healthy male volunteers. Co-administration of sulphinpyrazone (200 mg, 6 hourly) reduced mean plasma tolbutamide clearance by 40% and prolonged mean tolbutamide half-life by 80%. Twenty four hours after the cessation of a one week period of chronic sulphinpyrazone therapy tolbutamide plasma clearance (30% reduction) and half-life (19% prolongation) were still significantly different to control values, even though sulphinpyrazone could not be detected in the plasma of any of the subjects at this time. In vitro studies of the plasma protein binding of tolbutamide demonstrated concentration dependent binding but displacement of tolbutamide by sulphinpyrazone in vitro only became apparent at high concentrations of added sulphinpyrazone. Although the concentration dependence of tolbutamide protein binding demonstrated in vitro was also observed in the subject plasma samples, the magnitude of this effect was small. It is concluded that sulphinpyrazone and its metabolite(s) decrease the plasma clearance of tolbutamide by inhibition of oxidative metabolism.