METABOLIC BASIS FOR THE SUPRA‐ADDITIVE EFFECT OF THE ETHANOL‐DIAZEPAM COMBINATION IN MICE

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Abstract
1 The comination of ethanol and diazepam elicits additive or supra-additive pharmacological effects in animals and humans. Since the mouse appeared to be a reasonably good animal model for man, this species was examined to determine if a biochemical basis for these effects could be established. 2 The effect of ethanol (3 g/kg, orally), administered 0.5 h before [14C]-diazepam (5 mg/kg, orally), on the pharmacokinetics of diazepam in male Swiss Webster mice was examined. 3 At 4, 6, 8 and 12 h after dosing, blood levels of 14C were higher in ethanol pretreated mice than in vehicle pretreated controls. A tissue distribution study indicated that ethanol had similar effects on levels of 14C in most tissues at 2, 6 and 12 hours. 4 Both pretreated and control mice eliminated approximately 25% of the dose of isotope in the urine and 50% in the faeces by 48 hours. 5 Biliary excretion was the major route of clearance in mice in which the bile ducts had been cannulated and ethanol reduced excretion at all time periods examined up to 12 hours. 6 Oxazepam (the glucuronide in bile) and desmethyl diazepam were the major metabolites identified in bile, plasma and brain. Ethanol reduced oxazepam levels but increased desmethyl diazepam levels, suggesting that 3-hydroxylation of desmethyl diazepam was inhibited by ethanol. 7 The accumulation of the pharmacologically active desmethyl diazepam in the brains of ethanol pretreated mice offers an explanation for the supra-additive effect of the ethanol-diazepam combination on motor coordination.