Relation between the clinical effect and plasma concentration of midazolam in volunteers

In 12 healthy volunteers, the pharmacological effects of midazolam were investigated following intravenous (0.15 mg X kg-1 and 12.5 mg in 6 subjects each), intramuscular (12.5 mg in 6 subjects) and oral administration (20 mg in 6 subjects and 10 mg in 4 subjects). The findings were correlated with the plasma concentrations of midazolam and its alpha-hydroxy metabolite. The effects were assessed using objective and subjective methods (reaction time, memory test and subjects' self-assessment with an analog scale covering the degree of sedation). Plasma samples were assayed for midazolam and its alpha-hydroxy metabolite by gas chromatography. The results of the memory test showed that mnemonic retention and recall of a number remained intact for the period preceding intravenous or intramuscular administration. The maximum impairment occurred at 30 min after injection for recall of a number presented at the 15th min. The impairment was no longer detectable 4 h after injection. The plasma concentration time course was similar to that of the reaction time after administration of an identical intravenous or intramuscular dose. The maximum effect was attained within 15 min and 30 min after intravenous and intramuscular administration respectively. Within 2 to 4 h after parenteral administration, the reaction time had returned to normal. At identical plasma concentrations of midazolam, the reaction time was slightly longer in the period immediately following oral administration than after parenteral administration. This result suggested that the alpha-hydroxy metabolite contributed actively to the effect of midazolam. After its intravenous injection, this metabolite's sedative effects attained their maximum with 15 min, having disappeared 4 h later.