Article date: February 2004
By: Harald Ihmsen, Sven Albrecht, Werner Hering, Jürgen Schüttler, Helmut Schwilden, in Volume 57, Issue 2, pages 153-161
Aims We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48‐6791.
Methods Nine 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.
Results The 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.
Conclusion Midzolam and Ro 48‐6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.
DOI: 10.1046/j.1365-2125.2003.01964.x
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