INCREASED SYSTEMIC AVAILABILITY OF DRUGS DURING ACUTE ETHANOL INTOXICATION - STUDIES WITH MEPHENYTOIN IN THE DOG

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Abstract
The influence of ethanol on the fate of orally administered drugs which normally undergo a high presystemic elimination is as yet ill-defined. Experiments were designed in 4 nonanesthetized dogs with mephenytoin [MT] as model compound. The drug was administered p.o. or i.v., and throughout an 8-h period ethanol (100 mg/kg h) or saline was infused according to a cross-over design. Concentrations of MT and its main metabolites, nirvanol [NN] and P-OH-MT, were determined by GLC. In experiments with oral MT administration and ethanol infusion, MT peak plasma concentrations were elevated by 87.0 .+-. 15.2% (S.E.M.) The average area under the plasma concentration time curve was increased to 229% of control. Ethanol also reduced metabolite formation; the area under the plasma concentration time curve for NN was reduced by 40%. Urinary output of NN was diminished to 51% and of P-OH-MT to 73%. Drug ethanol interactions may be particularly prominent for orally administered drugs which normally are subject to a high presystemic elimination. This mechanism might be a clinically relevant cause for ethanol related drug toxicity.

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