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

Abstract

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.

Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition.

“…Tolbutamide plasma protein binding was measured by equilibrium dialysis in the 2, 6 and 24 h samples on each occasion (Miners et al, 1982). To monitor for subject safety blood glucose was measured using Dextrostix (Ames) and a reflectance meter (Ames glucometer) before and at 0.5, 1, 2, 4 and 6 h after each tolbutamide infusion.…”

Verapamil disposition‐effects of sulphinpyrazone and cimetidine.

“…As the major metabolic pathways for verapamil involve oxidative N-dealkylation (Eichelbaum et al, 1979), drugs known to alter hepatic drug oxidation represent potential influences on verapamil metabolism and thus presystemic clearance. Two such agents are the histamine H2-receptor antagonist, cimetidine, an inhibitor of the metabolic clearance of a number of drugs undergoing oxidation (Somogyi & Gugler, 1982), and the uricosuric and antiplatelet agent, sulphinpyrazone which has both inhibitory (Miners et al, 1982) and inducing (Birkett et al, 1983) effects on drug oxidation. The present study has investigated in the same healthy individuals the effect of pretreatment with sulphinpyrazone and with cimetidine on the disposition of verapamil following separate oral and intravenous doses.…”

Failure of ‘therapeutic’ doses of beta‐adrenoceptor antagonists to alter the disposition of tolbutamide and lignocaine.

“…administered lignocaine to assess the relative importance of changes in haemodynamic factors and drug metabolising enzyme activity due to these ,Badrenoceptor blockers. (Nation et al, 1978) and tolbutamide plasma protein binding was determined by equilibrium dialysis (Miners et al, 1982).…”