The plasma concentrations of ketamine, N-demethylketamine (I), and the cyclohexene metabolite (II) formed by oxidation of I were determined at various times after rapid i.v. administration of 15 mg of ketamine HCl/kg of body weight to dogs. A pharmacokinetic model that included two compartments for ketamine and one compartment for each metabolite was developed. Ketamine distributed rapidly with (t 1/2)alpha averaging 1.95 min. The apparent volumes of the central and peripheral compartments for ketamine averaged 542 and 1940 ml/kg of body weight, respectively, and the (t 1/2)beta averaged 61 min. The model indicated that 62% of ketamine was transformed to I and that 11% of I was converted to II. The apparent volumes of distribution of I and II averaged 61% and 59% of body weight, respectively. The total body clearances (plasma) of ketamine, I, and II averaged 32.2, 89.4, and 8.54 ml/min/kg, respectively. Plasma protein binding was determined by equilibrium dialysis; it averaged 53.5% for ketamine (concentration range 0.34-19.5 micrograms/ml), 60.3% for I (0.05-19.6 micrograms/ml), and 70.1% for II (0.09-0.58 micrograms/ml). A minimum anesthetic concentration of 3 micrograms ketamine HCl/ml plasma was used with the model to predict that the duration of ketamine anesthesia after an i.m. dose would not be significantly affected if the absorption t 1/2 varied from 0.48 to 31 min. The model also predicted that accumulation of I and II would not interfere with ketamine anesthesia that was prolonged by repeated doses, each dose administered i.v. on termination of anesthesia from the previous dose.