A. Hoogerkamp et al., PHARMACOKINETIC PHARMACODYNAMIC RELATIONSHIP OF BENZODIAZEPINES IN THE DIRECT CORTICAL STIMULATION MODEL OF ANTICONVULSANT EFFECT/, The Journal of pharmacology and experimental therapeutics, 279(2), 1996, pp. 803-812
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.