• Harald Ihmsen, Sven Albrecht, Werner Hering, Jürgen Schüttler, and Helmut Schwilden.
• Department of Anaesthesiology, Friedrich-Alexander-University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. harald.ihmsen@kfa.imed.uni-erlangen.de
• Br J Clin Pharmacol. 2004 Feb 1;57(2):153-61.

AimsWe studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791.MethodsNine young (24-28 years) and nine elderly (67-81 years) male volunteers received midazolam and Ro 48-6791 computer-controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml-1 min-1 for midazolam, 3 and 1.5 ng ml-1 min-1 for Ro 48-6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48-6791 and its metabolite Ro 48-6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum.ResultsThe concentration-effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half-maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3-91.6%) and 37% (5.3-69.5%); Ro 48-6791, 22% (-2.8% to 44.6%) and 43% (3.4-82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48-6791, the use of its metabolite Ro 48-6792 as competitive compound also gave appropriate results.ConclusionMidzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.

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