Adaptive changes in the pharmacodynamics of midazolam in different experimental models of epilepsy: kindling, cortical stimulation and genetic absence epilepsy

1 The objective of this investigation was to determine quantitatively whether experimental epilepsy is associated with a change in the pharmacodynamics of benzodiazepines in vivo . For that purpose the pharmacodynamics of midazolam were quantified by an integrated pharmacokinetic‐pharmacodynamic approach in three different models of experimental epilepsy: amygdala kindling, cortical stimulation and genetic absence epilepsy. 2 The time course of the EEG effect was determined in conjunction with the decline of drug concentrations after intravenous administration of 10 mg kg −1 midazolam. The pharmacokinetics of midazolam were most adequately described by a bi‐exponential equation. No influence of epilepsy on the pharmacokinetics of midazolam was observed. 3 The increase in β activity (11.5–30 Hz) of the EEG as derived by Fast Fourier Transformation analysis was used as pharmacodynamic endpoint. For each individual rat the increase in β activity was directly related to the concentration in blood on the basis of the sigmoidal E max pharmacodynamic model. In all three models a significant reduction in the maximal effect was observed, in amygdala kindling 28%, in the cortical stimulation model 49% and in genetic absence epilepsy 37%. No differences in the other pharmacodynamic parameters, E 0 , EC 50,u and Hill factor, were observed. 4 It is inferred that in three different models of epilepsy there is a similar change in GABAergic functioning which is associated with a significant reduction in the intrinsic activity of midazolam in vivo . These models provide therefore a useful basis for further studies on the mechanism of epilepsy‐induced changes in pharmacodynamics of anti‐epileptic drugs.British Journal of Pharmacology (1998) 125 , 615–620; doi: 10.1038/sj.bjp.0702088