ISSN:
1573-904X
Keywords:
flunitrazepam
;
anticonvulsant effect
;
receptor occupancy
;
kinetics-dynamics
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract In this investigation an attempt was made to evaluate quantitatively the relationship between benzo-diazepine receptor occupancy and the anticonvulsant effect of flunitrazepam in rats. A graded measure of anticonvulsant effect was obtained on the basis of an elevation of pentylenetetrazol (PTZ) threshold concentrations. The concentration–anticonvulsant effect relationship could be described by the E max model with an EC50 in cerebrospinal fluid of 2.9 ± 0.8 µg/liter and an E max of 227 ± 22 mg/liter PTZ (mean ± SE). In vitro receptor occupancy was determined in a crude brain homogenate at 0 and 37°C, which yielded K D values of 2.2 ± 0.2 and 26 ± 2 µg/liter, respectively. The results obtained in both experiments were combined by focusing on free flunitrazepam concentrations. This strategy resulted in a nonlinear relationship between receptor occupancy and anticonvulsant effect of flunitrazepam, with 90% of the maximum response achieved at a degree of receptor occupancy of approximately 50% at 37°C.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1015901414495
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