Effects of halothane anesthesia on the biodisposition of ketamine in rats

Ketamine, a highly lipophilic drug, was rapidly distributed into highly vascular organs and subsequently redistributed to less well perfused tissues, with concurrent hepatic metabolism and urinary and biliary excretion, after both i. m. and i. v. administration in the rat. Halothane, a potent cardiovascular depressant, was found to prolong the plasma and brain half-life of ketamine (50 mg/kg i.m.) and also increased the duration of ketamine-induced ataxia when the two drugs were administered concomitantly. Halothane anesthesia (0.8% halothane in oxygen) produced a decrease in the rate of uptake and delayed distribution and redistribution of ketamine (50 mg/kg i. m.), while the rate of urinary excretion of ketamine was not significantly altered. Similarly, redistribution of intravenously administered ketamine (30 mg/kg i. v.) was slowed in the presence of halothane. In vitro hepatic microsomal metabolism of ketamine and its principle N-demethylated metabolite, metabolite I, was inhibited noncompetitively by halothane with inhibitor constants (Ki) for halothane estimated to be 1.56 and 1. 64 mM,respectively. The gas anesthetic also decreased the overall rate of in vivo metabolism of ketamine (30 mg/kg i. v.) in a concentration-dependent manner. Thus halothane anesthesia by decreasing uptake, distribution, redistribution and metabolism of intramuscularly administered ketamine produced significant prolongation of its pharmacologic action on the central nervous system. Our results imply that concomitant use of inhalational anesthetics may prolong pharmacologic actions of other agents via effects on distribution/redistribution processes as well as on metabolism.