EFFECTS OF HALOTHANE ANESTHESIA ON BIODISPOSITION OF KETAMINE IN RATS

Abstract

After both i.m. and i.v. administration 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. Halothane, a potent cardiovascular depressant, prolonged the plasma and brain half-life of ketamine (50 mg/kg i.m.) and also increased the duration of ketamine-induced ataxia when the 2 drugs were administered concomitantly. Halothane anesthesia (0.8% halothane in O2) 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 i.v. ketamine (30 mg/kg) was slowed in the presence of halothane. In vitro hepatic microsomal metabolism of ketamine and its principal 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. Halothane anesthesia by decreasing uptake, distribution, redistribution and metabolism of i.m. ketamine produced significant prolongation of its pharmacologic action on the CNS. Concomitant use of inhalational anesthetics may prolong pharmacologic actions of other agents via effects on distribution/redistribution processes as well as on metabolism.