Summary
The passage of midazolam, a new benzodiazepine derivative with highly water-soluble salts, into cerebrospinal fluid (CSF) was studied after a single oral dose of 15 mg (n=23), a single i.m. injection of 0.075 or 0.150 mg/kg (n=8), or a single i.v. dose of 0.075 mg/kg (n=26). Contrary to previous studies of diazepam and flunitrazepam, the rapid clinical effect of midazolam cannot be explained by rapid passage into human lumbar CSF. In only four cases following intravenous injection was there a measurable amount of drug in lumbar CSF (lower limit of assay sensitivity=2 ng/ml). After both oral (n=10) and intramuscular (n=8) administration, midazolam was rapidly absorbed, with attainment of the peak serum level after about 0.5 h. The pharmacokinetic parameters following i.v. injection of midazolam (n=6) explain its rapid but brief duration of action.
Similar content being viewed by others
References
Aaltonen L, Kanto J, Iisalo E, Koski K, Salo M, Siirtola T (1981) The passage of flunitrazepam into cerebrospinal fluid in man. Acta Pharmacol Toxicol 48: 364–368
Aaltonen L, Kanto J, Salo M (1980) Cerebrospinal fluid concentrations and serum protein binding of lorazepam and its conjugate. Acta Pharmacol Toxicol 46: 156–158
Allonen H, Ziegler G, Klotz U (1981) Midazolam kinetics. Clin Pharmacol Ther 30: 653–661
Amrein R, Cano JP, Eckert M, Coassolo P (1981) Pharmakokinetik von Midazolam nach intravenöser Verabreichung. Arzneimittelforsch (Drug Res) 31 [II]: 2202–2205
Bliding A (1974) Effects of different rates of absorption of two benzodiazepines on subjective and objective parameters. Significance of clinical use and risk of abuse. Eur J Clin Pharmacol 7: 201–211
Bonati M, Kanto J, Tognoni G (1982) Clinical pharmacokinetics of CSF. Clin Pharmacokinet 7: 312–335
Crevoisier E, Eckert M, Heizmann P, Thurneysen DJ, Ziegler WH (1981) Relation entre l'effect clinique et la pharmacocinétique du midazolam aprés administration i.v. et i.m. Arzneimittelforsch (Drug Res) 31 [II]: 2211–2215
Dixon WJ, Brown MB (eds) (1977) BMDP-77. Biomedical computer programs, P-Series. Berkeley, University of California Press
Dundee JW (1979) New i.v. anaesthetics. Br J Anaesth 51: 641–648
Elliott HW (1976) Metabolism of lorazepam. Br J Anaesth 48: 1017–1023
Fragen RJ, Gahl F, Caldwell N (1978) A water-soluble benzodiazepine, Ro 21-3981, for induction of anesthesia. Anesthesiology 49: 41–48
Greenblatt DJ, Locniskar A, Ochs HR, Lauven PM (1981) Automated gas chromatography for studies of midazolam kinetics. Anesthesiology 55: 176–179
Hallström C, Lader MH, Curry SH (1980) Diazepam and N-desmethyldiazepam concentrations in saliva, plasma and CSF. Br J Clin Pharmacol 9: 333–339
Hendel J (1975) Cumulation in cerebrospinal fluid of the N-demethylmetabolite after long-term treatment with diazepam in man. Acta Pharmacol Toxicol 37: 17–22
Himberg J-J (1982) Optimization and validation of gas-chromatographic drug assays for pharmacokinetics studies. A model study with four benzodiazepines. Ph. D. thesis. University of Helsinki
Kangas L, Kanto J, Siirtola T, Pekkarinen A (1977) Cerebrospinal fluid concentrations of nitrazepam in man. Acta Pharmacol Toxicol 41: 74–79
Kanto J, Kangas L, Siirtola T (1975) Cerebrospinal fluid concentrations of diazepam and its metabolites in man. Acta Pharmacol Toxicol 36: 328–334
Klotz U, Kangas L, Kanto J (1980) Clinical pharamcokinetics of benzodiazepines. Progress in Pharmacology, vol 3. Gustav Fischer Verlag, Stuttgart
Leferink JG, Maes RAA (1979) STRIPACT, an interactive curve fit programme for pharmacokinetic analyses. Arzneimittelforsch (Drug Res) 29: 1894–1898
Morel D, Forster A, Gardaz J-P, Suter PM, Gemperle M (1981) Comparative haemodynamic and respiratory effects of midazolam and flunitrazepam as induction agents in cardiac surgery. Arzneimittelforsch (Drug Res) 31 [II]: 2264–2267
Ochs HR, Busse J, Greenblatt DJ, Allen MD (1980) Entry of lorazepam into cerebrospinal fluid. Br J Clin Pharmacol 10: 405–406
Pakkanen A, Kanto J (1982) Midazolam compared with thiopentone as an induction agent. Acta Anaesthesiol Scand 26: 143–146
Pieri L, Schaffner R, Scherschlicht R, Polc P, Sepinvall J, Davidson A, Möhler H, Cumin R, Da Prada M, Burkard WP, Keller HH, Müller PKM, Gerold M, Pieri M, Cook L, Haefely W (1981) Pharmacology of midazolam. Arzneimittelforsch (Drug Res) 31 [II]: 2180–2201
Reves JG, Corssen G, Holcomb C (1978) Comparison of two benzodiazepines for anaesthesia inducation: Midazolam and diazepam. Can Anaesth Soc J 25: 211–214
Smith MT, Eadie MJ, O'Rourke Brophy T (1981) The pharmacokinetics of midazolam in man. Eur J Clin Pharmacol 19: 271–278
Stanski DR, Greenblatt DJ, Selwyn A, Shader RI, Franke K, Koch-Weser J (1976) Plasma and cerebrospinal fluid concentrations of chlordiazepoxide and its metabolites in surgical patients. Clin Pharmacol Ther 20: 571–578
Ziegler WH, Thurneysen JD, Crevoisier C, Eckert M, Amrein R, Dubuis R (1981) Relations entre l'effect clinique et la pharmacocinétique due midazolam aprés administration i.m. et i.v. chez des volontaires. Arzneimittelforsch (Drug Res) 31 [II]: 2206–2210
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Sjövall, S., Kanto, J., Himberg, J.J. et al. CSF penetration and pharmacokinetics of midazolam. Eur J Clin Pharmacol 25, 247–251 (1983). https://doi.org/10.1007/BF00543799
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00543799