ON THE CEREBRAL ACCUMULATION OF KETAMINE AND THE RELATIONSHIP BETWEEN METABOLISM OF THE DRUG AND ITS PHARMACOLOGICAL EFFECTS

¹ Department of Pharmacology, University of California, San Francisco, San Francisco, California

Rat brain slices accumulated ketamine rapidly to levels 2.3 times higher than those in the incubation medium. The process was saturable but was not influenced by 2,4-dinitrophenol or sodium iodoacetate. Equilibrium dialysis studies demonstrated no selective binding of ketamine to subcellular components of rat brain homogenates. Determination of the partition coefficients of ketamine and its N-demethylated product (metabolite I) indicated that both compounds were highly lipid soluble which may account for their rapid accumulation by cerebral tissues. The i.v. administration of metabolite I to rats caused central nervous system effects including hypnosis, ataxia and agitation, but of shorter duration than equivalent doses of ketamine. Brain levels of metabolite I required to maintain hypnotic effects were determined to be 33 µg/g of tissue. Maximum brain levels of metabolite I achieved after i.v. ketamine (20 mg/kg) were 6 µg/g of tissue which suggested that cerebral accumulation of the metabolite does not contribute greatly to the hypnotic effects observed after administration of the parent drug. The pretreatment of rats with phenobarbital caused a 5-fold increase in the rate of ketamine metabolism by hepatic tissue in vitro, whereas SKF 525-A pretreatment inhibited ketamine metabolism by 35% and prolonged the half-life of the drug in vivo. Neither pretreatment had significant effects on the duration of hypnosis caused by ketamine, but phenobarbital pretreatment decreased and SKF 525-A pretreatment increased, the duration of posthypnotic ataxia and agitation.