Summary
The regional distribution of diazepam (DZP) was established in eleven discrete brain areas in the rat afteri.m. chronic treatment (15 days; 5 mg/kg/day). In addition, the kinetic profiles of this drug were investigated in plasma, eryhtrocytes, and three CNS regions (nucleus caudatus, hippocampus, and cerebellum) upon which the pharmacokinetic study was focused. The modifications occuring in plasma-protein binding and erythrocytes binding were reported. In the CNS, the DZP was rapidly distributed; its concentrations and its kinetic profiles were not uniform in the different brain areas studied. The highest amount of DZP was noted in the hypothalamus, while nucleus caudatus and colliculi also presented important DZP levels. Concerning the kinetic parameters after chronic administration, an increase in the elimination half-life time value in central and peripheral compartments, as compared to values reported after acute administration, was observed. The study of cerebral DZP levels as compared with those in the erythrocytes or in plasma suggests a linear correlation in the three CNS areas investigated. These experimental results demonstrate the interest of such studies for psychotropic drug monitoring.
Similar content being viewed by others
References
Balantuono C., Reggi G., Tognoni G. and Garattini S. (1980): Drugs: Benzodiazepines clinical pharmacology and therapeutic use,19, 195–219.
Browne T.R. and Penry J.K. (1973): Epilepsia: Benzodiazepines in the treatment of epilepsy. A review,14, 277–310.
Mandelli M., Tognoni G. and Garattini S. (1978): Clin. Pharmacokinet.: Clinical pharmacokinetics of diazepam.3, 72–91.
Valli M., Jadot G., Bruguerolle B., Hariton C. et Bouyard P. (1982): Thérapie: A propos du passage intraérythrocytaire de six médicaments.37, 601–602.
Hariton C., Valli M., Jadot G., Bruguerolle B. et Bouyard P. (1982): in Pharmacologie et Toxicologie Vétérinaires, Les Colloques de l’INRA,8, p. 143–146, INRA Publ., Paris.
Jadot G., Bruguerolle B., Valli M. et Bouyard P. (1980): Ann. Biol. Clin.: Détermination de la fraction plasmatique libre des substances médicamenteuses.38, 379–380.
Glowinski J. and Iversen L.L. (1966): J. Neurochem.: Regional studies of catecholamines in the rat brain. Part. I.13, 655–669.
Zingales I.A. (1973): J. Chromatogr.: Diazepam metabolism during chronic medication. Unbound fraction in plasma, erythrocytes and urine.75, 55–78.
Garattini S., Marcucci F. and Mussini E. (1969): In Ciba Foundation Symposium on Gas Chromatography in Biology and Medicine, p. 161–172, R. Porter, London.
Gomeni C. and Gomeni R. (1978): Comput. Biomed. Res.: IGPHARM, Interactive graphic package for pharmacokinetic analysis.11, 345–361.
Marcucci F., Guaitani A., Kvétina J., Mussini E. and Garattini S. (1968): Eur. J. Pharmacol.: Species differences In diazepam metabolism and anticonvulsant effect.4, 467–470.
Garattini S., Mussini E., Marcucci F. and Guaitini A. (1973): in The Benzodiazepines. Ed.: Garattini S., Mussini E. and Randall L.O. p. 75–97, Raven Press, New York.
Caccia S., Carli M., Garattini S., Poggesi E., Rech R. and Samanin R. (1980): Arch. Int. Pharmacodyn.: Pharmacological activities of clobazam and diazepam in the rat. Relation to drug brain level.243, 275–283.
Squires R.F. and Breastrup C. (1977): Nature (London): Benzodiazepine receptor in rat brain.266, 732–734.
Livingston K.E. and Escobar A. (1971): Arch. Neurol.: Anatomical bias of the limbic system concept. A proposal reorientation.24, 17–21.
Scheibel A.B. (1980): in Advances in Neurology, Vol. 27. Ed.: Glaser G.H., Penry J.K. and Woodbury D.W. p. 49–61, Raven Press, New York.
Möhler H., Okada T. and Enna S.J. (1978): Brain Res.: Benzodiazepine and neurotransmitter receptor binding in rat brain after chronic administration of diazepam or phenobarbital.156, 391–395.
Láznicěk M., Lamka J. and Kvétina J. (1982): Biochem. Pharmacol.: On the interaction of diazepam with human, rat, and mouse plasma proteins and erythrocytes.31, 1455–1458.
Gorodischer R., Jusko W.J. and Yaffe J.J. (1975): Clin. Pharmacol. Ther.: Tissue and erythrocyte distribution of digoxin in infants.19, 256–263.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hariton, C., Jadot, G., Mesdjian, E. et al. Diazepam: Kinetic profiles in various brain areas, plasma and erythrocytes after chronic administration in the rat. European Journal of Drug Metabolism and Pharmacokinetics 10, 105–111 (1985). https://doi.org/10.1007/BF03189703
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF03189703