Receptor-mediated model relating anticonvulsant effect to brain levels of camazepam in the presence of its active metabolites

  • Akira Morino
  • Hideki Sasaki
  • Hideya Mukai
  • Makoto Sugiyama
Article

DOI: 10.1007/BF01106709

Cite this article as:
Morino, A., Sasaki, H., Mukai, H. et al. Journal of Pharmacokinetics and Biopharmaceutics (1986) 14: 309. doi:10.1007/BF01106709

Abstract

In a displacement test using3H-diazepam as a radioligand, the in vitro affinities of metabolites of camazepam (CZ) for the benzodiazepine receptors were 1–50 times more potent than that of CZ. In contrast, only three metabolites (temazepam, oxazepam, and hydroxy CZ), as well as CZ itself, exhibited an in vivo affinity parallel to their ability to protect against pentylenetetrazole-induced clonic convulsion in rats. In addition, CZ and these active metabolites displaced the radioligand from their receptor sites in a concentration-dependent saturable manner, indicating the competitive bimolecular interaction of these molecules with their receptors. The percent anticonvulsant effect was a nonlinear, single-valued function of the in vivo percent displacement of specific3H-diazepam binding, independent of these displacers after i.v. dosing; this relationship could be approximated by the Hill equation. On the basis of these findings, a receptor-mediated model, including the Langmuir equation to describe the receptor binding-brain concentration relationship and the Hill equation to accommodate the anticonvulsant effect-receptor binding relationship, was constructed. This model was found to adequately relate the time course values of anticonvulsant effect and of brain levels of CZ and its active metabolites after oral administration. These results demonstrate that CZ and its active metabolites exert anticonvulsant effect by competitive binding to the benzodiazepine receptors.

Key words

camazepam temazepam oxazepam pharmacokinetics anticonvulsant effect radioreceptor assay rat mouse 

Copyright information

© Plenum Publishing Corporation 1986

Authors and Affiliations

  • Akira Morino
    • 1
  • Hideki Sasaki
    • 1
  • Hideya Mukai
    • 1
  • Makoto Sugiyama
    • 1
  1. 1.Research LaboratoriesNippon Shinyaku Co.KyotoJapan

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