Abstract
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 α 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 )β 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 μg/ml), 60.3% for I (0.05– 19.6 μg/ml), and 70.1% for II (0.09– 0.58 μg/ml). A minimum anesthetic concentration of 3 μg 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 t1/2 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.
Similar content being viewed by others
References
R. W. Virtue, J. M. Alanis, M. Mori, R. T. Lafargue, J. H. K. Vogel, and D. R. Metcalf. An anesthetic agent: 2-Orthochlorophenyl, 2-methylamino cyclohexanone HC1. (CI-581).Anesthesiology. 28:823–833 (1967).
M. L. Cohen, S.-L. Chan, W. L. Way, and A. J. Trevor. Distribution in the brain and metabolism of ketamine in the rat after intravenous administration.Anesthesiology 39:370–376 (1973).
J. Wieber, R. Gugler, J. H. Hengstmann, and H. J. Dengler. Pharmacokinetics of ketamine in man.Anaesthetist 24:260–263 (1975).
M. P. Marietta, W. L. Way, N. Castagnoli, Jr., and A. J. Trevor. On the pharmacology of the ketamine enantiomorphs in the rat.J. Pharmacol. Exp. Ther. 202:157–165 (1977).
S. Ryder, W. L. Way, and A. J. Trevor. Comparative pharmacology of the optical isomers of ketamine in mice.eur. J. Pharmacol. 49:15–23 (1978).
T. Chang and A. J. Glazko. A gas chromatographic assay for ketamine in human plasma.Anesthesiology 36:401–404 (1972).
J. D. Baggot and J. W. Blake. Disposition kinetics of ketamine in the domestic cat.Arch. Int. Pharmacodyn. Ther. 220:115–124 (1976).
J. S. Kaka, P. A. Klavano, and W. L. Hayton. Pharmacokinetics of ketamine in the horse.Am. J. Vet. Res. 40:978–981 (1979).
M. P. Marietta, P. F. White, C. R. Pudwill, W. L. Way, and A. J. Trevor. Biodisposition of ketamine in the rat: Self-induction of metabolism.J. Pharmacol. Exp. Ther. 196:536–544 (1976).
P. F. White, M. P. Marietta, C. R. Pudwill, W. L. Way, and A. J. Trevor. Effects of halothane anesthesia on the biodisposition of ketamine in rats.J. Pharmacol. Exp. Ther. 196:545–555 (1976).
L. Z. Benet. General treatment of linear mammillary models with elimination from any compartment as used in pharmacokinetics.J. Pharm. Sci. 61:536–541 (1972).
C. M. Metzler, G. L. Elfring, and A. J. McEwen. A package of computer programs for pharmacokinetic modeling.Biometrics 30:562–563 (1974).
S. Feldman. Drug distribution.Med. Clin. North Am. 58:917–926 (1974).
H. D. Green. Circulatory system: physical principles. In O. Glasser (ed.),Medical Physics, Vol. 2, Year Book Publishers, Chicago, 1950, p. 244.
H. R. Adams, J. L. Parker, and B. P. Mathew. The influence of ketamine on inotropic and chronotropic responsiveness of heart muscle.J. Pharmacol. Exp. Ther. 201:171–183 (1977).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kaka, J.S., Hayton, W.L. Pharmacokinetics of ketamine and two metabolites in the dog. Journal of Pharmacokinetics and Biopharmaceutics 8, 193–202 (1980). https://doi.org/10.1007/BF01065193
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/BF01065193