Increased systemic availability of drugs during acute ethanol intoxication: studies with mephenytoin in the dog

The influence of ethanol on the fate of orally administered drugs which normally undergo a high presystemic elimination is as yet ill-defined. Experiments, therefore, were designed in four nonanesthetized dogs with mephenytoin as model compound. The drug was administered p.o. or i.v., and throughout an 8-hr period ethanol (100 mg kg-1 hr-1) or saline was infused according to a cross-over design. Concentrations of mephenytoin and its main metabolites, nirvanol and p-hydroxymephenytoin, were determined by gas-liquid chromatography. In experiments with oral mephenytoin administration and ethanol infusion, mephenytoin peak plasma concentrations were elevated by 87.0 +/- 15.2% (S.E.M.) (P less than .005, n = 4). Correspondingly, the average area under the plasma concentration time curve was increased to 229% of control (P less than .005). Ethanol also reduced metabolite formation; the area under the plasma concentration time curve for nirvanol was reduced by 40% (P less than .005). Urinary output of nirvanol was diminished to 51% and of p-hydroxymephenytoin to 73% (P less than .05, n = 12). It is concluded that 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.