The effects of pretreatment with cimetidine (1 gm daily for 3 days) on the disposition of lidocaine were examined in 18 healthy subjects, seven of whom were chronic cigarette smokers. Each subject received separate oral (200 mg) and intravenous (75 or 100 mg) doses of lidocaine before and after cimetidine. After cimetidine, lidocaine apparent oral clearance (Clo) reduced 42% +/- 7%; oral bioavailability increased 35% +/- 10%; and systemic clearance (Cls) and volume of distribution at steady-state (Vdss) decreased 21% +/- 6% and 20% +/- 7%. Elimination t 1/2 was unchanged. Calculated values for Cls after cimetidine based on reduction in Clo and consequent decrease in hepatic extraction ratio correlated significantly with observed values for Cls (r = 0.67). Women had larger Vdss (64% +/- 19%), longer t 1/2 (50% +/- 18%), and greater oral lidocaine bioavailability (63% +/- 29%) than did men. There was no sex difference in and no influence of cigarette smoking on the effects of cimetidine. The results indicate that cimetidine reduces metabolic clearance of lidocaine. The consequent reduced hepatic extraction explains the observed reduction in Cls.
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.
The effect of sulphinpyrazone administration on the anticoagulant response was investigated in five patients receiving long-term treatment with warfarin. Sulphinpyrazone caused a rapid increase in prothrombin (PT) ratio in all five patients and warfarin dose had to be reduced by a mean of 46% to maintain the PT ratio in the therapeutic range. PT ratio and daily warfarin requirement returned to previous levels when sulphinpyrazone was ceased. Warfarin protein binding was not altered during sulphinpyrazone administration and sulphinpyrazone added to plasma in vitro did not increase warfarin free fraction. The average racemic plasma warfarin concentration over a dosage interval when adjusted for warfarin dose was not altered by sulphinpyrazone administration. The most likely mechanism for this drug interaction is a stereoselective effect of sulphinpyrazone on the metabolism of the warfarin enantiomers.
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