The pharmacokinetics of midazolam in man
Midazolam, a new water-soluble benzodiazepine, was administered as: i) 5 mg intravenously, ii) a 10-mg oral solution and iii) a 10-mg oral tablet, to six volunteers whose informed consent had been obtained. Midazolam plasma concentrations were measured using an electron-capture gas-liquid chromatographic assay. After 5-mg intravenous midazolam, subjects fell asleep within 1–2 min and continued to sleep for an average of 1.33 h. After oral midazolam intake (solution or tablets), drowsiness appeared after a average of 0.38 h (range 0.25–0.55 h) and sleep continued for an average of 1.17 h. The time to reach peak plasma midazolam concentration after the 10-mg solution dose (0.37±0.45 h) did not differe significantly (‘t’=2.04, df=10,p>0.05) from the time to reach peak plasma midazolam level after the 10-mg tablet dose (0.74±0.45 h). The terminal half-life, (t1/2), of midazolam in plasma was 1.77±0.83 h and there was no significant difference between the mean terminal half-life values obtained for the three midazolam formulations. The mean total clearance (Cl), of midazolam after 5-mg intravenous administration was 0.383±0.094 l·kg−1·h−1. The first pass effect, F, determined experimentally (0.36±0.09) indicated the substantial first pass metabolism of midazolam. The percentage of the midazolam dose excreted unchanged in urine in four subjects during the 0-8-h urine collection interval was very small (0.011%–0.028%).
Key wordsmidazolam benzodiazepine pharmacokinetics gas-liquid chromatography first-pass metabolism
Unable to display preview. Download preview PDF.
- Archer GA, Sternbach LH (1968) The chemistry of benzodiazepines. Chem Rev 68: 747–784Google Scholar
- Gibaldi M, Perrier D (1975) In: Pharmacokinetics, vol. 1. J. Swarbrick (ed) Drugs and the pharmaceutical sciences. Marcel Dekker, New York, pp 293–296Google Scholar
- Puglisi CV, Meyer JC, D'Arconte L, Brooks MA, de Silva JAF (1978) Determination of water soluble imidazo-1,4-benzodiazepines in blood by electroncapture gas-liquid chromatography and in urine by differential pulse polarography. J Chromatogr 145: 81–96Google Scholar
- Reeves JG, Corssen G, Holcomb C (1978) Comparison of two benzodiazepines for anaesthesia induction: midazolam and diazepam. Can Anaesth Soc J 25: 211–214Google Scholar
- Sedman AJ, Wagner JG (1976) CSTRIP, a fortran IV computer program for obtaining initial polyexponential parameter estimates. J Pharm Sci 65: 1006Google Scholar