Kinetics of Drug Action in Disease States XII: Effect of Experimental Liver Diseases on the Pharmacodynamics of Phenobarbital and Ethanol in Rats

Abstract

This investigation was designed to determine if liver diseases can modify the pharmacodynamics of the central nervous system depressants phenobarbital and ethanol. Two experimental models of liver diseases in rats were used: extrahepatic cholestasis produced by bile duct ligation and hepatic necrosis induced by carbon tetrachloride administration. Phenobarbital (both models) or ethanol (cholestasis model only) was infused slowly intravenously until the rats lost their righting reflex. Drug concentrations in serum, brain, and cerebrospinal fluid at that time were determined in the diseased animals as well as in shamoperated or solvent‐treated controls. Phenobarbital concentrations at the onset of action were not significantly different between controls and either 5‐d or 12‐d cholestatic rats, except for total serum concentrations which were lower in the cholestatic groups due to reduced protein binding. Ethanol concentrations were slightly but statistically significantly lower in 12‐d cholestatic rats as compared with controls. Neither 5‐d nor 12‐d carbon tetrachloride‐induced hepatic dysfunction had any significant effect on phenobarbital concentrations at the onset of loss of righting reflex, except for a marginal decrease in the cerebrospinal fluid concentration of rats that had been treated for 5 d with the hepatotoxin. It was concluded that, under the experimental conditions, the hepatic diseases investigated did not have appreciable effects on the central nervous system response to the hypnotic action of phenobarbital and ethanol.