Kinetics of drug action in disease states. VII. Effect of experimental renal dysfunction on the pharmacodynamics of ethanol in rats.

This investigation was designed to determine if renal dysfunction is associated with an increased sensitivity to the CNS depressant effect of ethanol. Adult female Lewis rats were given injections of either 2 or 5 mg/kg of uranyl nitrate (saline for controls) or had both ureters ligated (sham operation for controls) to provide different experimental models of renal dysfunction. Normal and renal dysfunction (ureter-ligated) rats were infused i.v. with ethanol at rates of 8.1, 16.3 or 32.6 mg/min; concentrations of ethanol in cerebrospinal fluid, serum and brain at onset of loss of righting reflex were independent of infusion rate in both groups, indicating rapid equilibration of ethanol between the sampling sites and the biophase. Ethanol concentrations in cerebrospinal fluid at onset and offset (after approximately 110 min of sleep) of loss of righting reflex were not significantly different, reflecting negligible acute tolerance development under the experimental conditions. Ethanol concentrations at onset of loss of righting reflex in cerebrospinal fluid, serum and brain of rats with severe renal dysfunction (5 mg/kg of uranyl nitrate-treated and ureterligated groups) were slightly but statistically significantly lower than in normal controls. This difference was relatively much smaller than the difference in phenobarbital concentrations observed in a similar preceding study, which is consistent with the different mechanisms of action of alcohols and barbiturates.