Pharmacokinetic-pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite α-hydroxymidazolam in healthy volunteers

Abstract

The pharmacodynamics of midazolam and its main metabolite alpha-hydroxymidazolam were characterized in individual subjects by use of saccadic eye movement and electroencephalographic (EEG) effect measurements. Eight healthy volunteers received 0.1 mg/kg midazolam intravenously in 15 minutes, 0.15 mg/kg alpha-hydroxymidazolam intravenously in 15 minutes, 7.5 mg midazolam orally and placebo in a randomized, double-blind, four-way crossover experiment. Plasma concentrations of midazolam, alpha-hydroxymidazolam and 4-hydroxymidazolam were measured by gas chromatography. The amplitudes in the 11.5 to 30 Hz (beta) frequency band were used as EEG effect measure. The concentration-effect relationships were quantified by the sigmoid maximum effect model. The median effective concentrations of midazolam and alpha-hydroxymidazolam were (mean +/- SE) 77 +/- 15 and 98 +/- 17 ng/ml, respectively, for the EEG effect measure. For peak saccadic velocity the values were 40 +/- 7 ng/ml for midazolam and 49 +/- 10 ng/ml for alpha-hydroxymidazolam. The maximum effect values were similar for both compounds. The effects observed after oral administration of midazolam could not be predicted accurately by an additive and competitive interaction model. It seems that alpha-hydroxymidazolam is highly potent with respect to the measured effects and contributes significantly to those effects of midazolam after oral administration.

Rate of change of blood concentrations is a major determinant of the pharmacodynamics of midazolam in rats

“…However, di erences in metabolic pathways between the two species, rat and man, and the interference of di erent (inter)active metabolites must be considered too. In contrast to the rat, in man metabolites of midazolam were found to contribute to the pharmacological e ects of the drug (Crevoisier et al, 1983;Mandema et al, 1992d). It has been suggested that the apparent acute tolerance to the actions of diazepam in man is due to redistribution of the compound from the central nervous system to the peripheral tissues (Greenblatt & Shader, 1986).…”

Pharmacokinetic‐EEG effect relationship of midazolam in aging BN/BiRij rats

“…In this respect, a large investigation is currently in progress on data obtained in some 150 rats where population analysis is used to identify factors that may be important in this respect. Similar studies are indicated in man and it is of interest that the EEG parameter utilized can also be applied in human studies (Mandema et al, 1992).…”

Midazolam in Spinal Anesthesia — Intrathecal or Intravenous?

“…On the other hand; glucuronidated α-hydroxymidazolam, the main metabolite of midazolam, has a substantial pharmacological effect and can penetrate the intact blood-brain barrier. The elimination half-time of α-hydroxymidazolam is about 70 min [25]. However, it can accumulate in patients with renal failure.…”

“…The α-hydroxymidazolam is as potent as the parent compound and may contribute significantly to the effects of the parent drug when present in sufficiently high concentrations. 4-Hydroxymidazolam is quantitatively unimportant [25]. Both metabolites are rapidly conjugated by glucuronic acid to form products which have been considered to be pharmacologically inactive [14].…”