1 The pharmacokinetic behaviour and the bioavailability of midazolam were investigated in six volunteers after intravenous (0.15 mg/kg) and oral administration (10, 20 and 40 mg). 2 Following rapid intravenous injection of midazolam, the plasma concentration of the substance decreased to approximately 10% within 2 h owing to a rapid rate of distribution. 3 A two compartment model adequately described the kinetics of midazolam in plasma. The following average values were found: elimination half-life, 2.3 h; total clearance, 323 ml/min, and apparent volume of distribution at steady-state (V,s), 50.21. 4 After oral administration, the drug is rapidly absorbed. Maximum plasma levels are reached within 30 min and the drug is rapidly eliminated from plasma with practically the same half-life as determined after i.v. administration. 5 The bioavailability after the ingestion of 10, 20 and 40 mg midazolam in the form of tablets ranged from 31 to 72%, due to the high liver extraction quota of midazolam.

1 In a double-blind, cross-over study in six healthy volunteers, the effects of different oral doses of midazolam (10, 20 and 40 mg), or 0.15 mg kg-'midazolam administered intravenously and of placebo were investigated. Plasma concentrations of midazolam and of its active a-hydroxy metabolite were measured at the same time. 2 The effect was assessed using objective and subjective methods (reaction time, tracing test, subjects' self-assessment and investigator's subjective assessment). 3 The respective time courses of the plasma concentration and of the effect (reaction time, number of errors in the tracing test) were almost identical. Peak plasma levels and maximum effects were attained within 30 min. In general, the effect after intravenous injection of 0.15 mg kg-' and after an oral dose of 10 mg midazolam lasted for 2 h following administration and its duration was doubled (i.e. to 4 h) after the 20 mg oral dose. Between the logarithm of the plasma concentration and the effect, there is a sigmoidal relationship that is virtually time independent. 4 Particularly in the first few hours after oral administration the effect is intensified by the a-hydroxy metabolite of midazolam which is formed by first-pass metabolism. 5 At identical plasma concentrations of midazolam, the oral dose produced more marked effects than did the intravenous administration. 6 Correlation of the measured effects with the total (midazolam + a-hydroxy midazolam) plasma concentration reveals a closer sigmoidal relationship.

The aim of the study was to compare the pharmacological activity and clinical effect after i.v. administration of midazolam, triazolam and their hydroxy metabolites, and, secondly, to compare the clinical effects of midazolam and triazolam in doses yielding the same duration of action (15 mg and 0.25 mg, respectively). 2 In a randomized, cross-over procedure, six healthy volunteers received one of the following in the morning at approximately weekly intervals: 15 mg midazolam; 9 mg a-hydroxy midazolam; 1 mg triazolam; 1 mg a-hydroxy triazolam; 1 mg 4-hydroxy triazolam. Tests of drug effect (investigator's assessment, psychometric testing, and self-rating by subjects) were carried out at different times in the 24-h period following administration. Triazolam 0.25 mg was also studied in four of these six subjects to supplement the findings in the cross-over study. 3 Triazolam mg was shown to have the strongest, most long-lasting'effect. Midazolam 15 mg had almost the same intensity of effect but this was shorter lasting, i.e. 5 h as against 10 h for 1 mg triazolam. The a-hydroxy metabolites had a duration of action about half that of the parent compounds and a less potent effect, and 4-hydroxy triazolam was virtually devoid of effect. The lower 0.25-mg dose of triazolam had about the same duration of action as 15 mg midazolam but did not achieve the same degree of maximum effect as measured by psychometric tests and self-assessment by subjects. 4 The findings of this study indicate that midazolam would be suitable for use in situations in which a brief but intense hypnotic sedative effect is desired.

1 During clinical pharmacology studies with the benzodiazepine antagonist Ro 15-1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. 2 Ro 15-1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 1 kg-l. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.141 min1 resulted in a short elimination half-life of less than 1 h. 3 No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose-proportionality in the areas under plasma concentration-time curves and unchanged distribution characteristics. 4 Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. 5 Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20-90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.

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