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Pharmacokinetic‐pharmacodynamic modeling of the central nervous system effects of midazolam and its main metabolite α‐hydroxymidazolam in healthy volunteers
Author(s) -
Mandona Jaap W,
Tuk Bert,
Steveninck Alfred L,
Breimer Douwe D,
Cohen Adam F,
Danhof Meindert
Publication year - 1992
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1992.84
Subject(s) - midazolam , pharmacokinetics , crossover study , metabolite , pharmacodynamics , chemistry , pharmacology , anesthesia , placebo , sedative , oral administration , sedation , medicine , biochemistry , alternative medicine , pathology
The pharmacodynamics of midazolam and its main metabolite α‐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 α‐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, α‐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 α‐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 α‐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 α‐hydroxymidazolam is highly potent with respect to the measured effects and contributes significantly to those effects of midazolam after oral administration. Clinical Pharmacology and Therapeutics (1992) 51 , 715–728; doi: 10.1038/clpt.1992.84