PHARMACOKINETIC PHARMACODYNAMIC RELATIONSHIP OF BENZODIAZEPINES IN THE DIRECT CORTICAL STIMULATION MODEL OF ANTICONVULSANT EFFECT/

The in vivo concentration-anticonvulsant effect relationships of six b enzodiazepines, midazolam, clonazepam, oxazepam, flunitrazepam, diazep am and clobazam were quantified in individual rats and correlated with the affinity to the GABA(A)-benzodiazepine receptor complex. Furtherm ore the interaction between midazolam and the benzodiazepine antagonis t flumazenil was characterized. All benzodiazepines exhibited a nonlin ear relationship between concentration and anticonvulsant effect witho ut ceiling of the effect at higher concentration. The potency of most benzodiazepines was similar with values of the EC(250,u) between 0.067 +/- 0.01 mg . l(-1) for midazolam and 0.21 +/- 0.03 mg . l(-1) for di azepam. The EC(250,u) of clobazam was 2.8 +/- 0.9 mg . l(-1). These va lues were considerably larger than the K-i for binding at the GABA(A)- benzodiazepine receptor complex. No correlation was observed between E C(250,u) and K-i. Antagonism of the anticonvulsant effect of midazolam by flumazenil was associated with a remarkable change in the concentr ation-anticonvulsant effect relationship. Analysis of these data on ba sis of a composite model provided evidence for two separate effects of which only one is antagonized by flumazenil. The anticonvulsant effec t at low midazolam concentration was characterized on basis of the sig moid E maximal effect pharmacodynamic model. The value of the EC(50,u) was 0.0086 +/- 0.0013 mg . l(-1) which is similar to the K-i for bind ing at the GABA(A)-benzodiazepine receptor complex. The second more pr onounced anticonvulsant effect occurred at higher concentration and wa s described by an exponential function. The findings of this study ind icate that the effect of benzodiazepines against seizures induced by c ortical stimulation in vivo cannot be fully accounted for by an intera ction at the GABA(A)-benzodiazepine receptor complex.