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

1 The objective of this investigation was to characterize quantitatively th e influence of the rate of increase in blood concentrations on the pharmaco dynamics of midazolam in rats. The pharmacodynamics of midazolam were quant ified by an integrated pharmacokinetic-pharmacodynamic modelling approach. 2 Using a computer controlled infusion technique, a linear increase in bloo d concentrations up to 80 ng ml(-1) was obtained over different time interv als of 1 - 6 h, resulting in rates of rise of the blood concentrations of r espectively, 1.25, 1.00, 0.87, 0.46, 0.34 and 0.20 ng ml(-1) min(-1). In on e group of rats the midazolam concentration was immediately brought to 80 n g ml(-1) and maintained at that level for 4 h. Immediately after the pretre atment an intravenous bolus dose was given to determine the time course of the EEG effect in conjunction with the decline of midazolam concentrations. 3 The increase in beta activity (11.5-30 Hz) of the EEG was used as pharmac odynamic endpoint. For each individual animal the relationship between bloo d concentration and the EEG effect could be described by the sigmoidal E-ma x model. After placebo, the values of the pharmacodynamic parameter estimat es were E-max = 82 +/- 5 mu V, EC50.u = 6.4 +/- 0.8 ng ml(-1) and Hill fact or = 1.4 +/- 0.1. A bell-shaped relationship between the rate of change of midazolam concentration and the value of ECS50.u was observed with a maximu m of 21 +/- 5.0 ng ml(-1) at a rate of change of 0.46 ng ml(-1) min(-1); lo wer values of EC50.u were observed at both higher and lower rates. 4 The findings of this study show that the rate of change in plasma concent rations is an important determinant of the pharmacodynamics of midazolam in rats.