Pharmacokinetic-pharmacodynamic modelling of the hypothermic and corticosterone effects of the 5-HT1A receptor agonist flesinoxan

Eur J Pharmacol. 2002 Jun 7;445(1-2):43-54. doi: 10.1016/s0014-2999(02)01665-5.

Abstract

The current investigation describes the pharmacokinetic-pharmacodynamic correlation of the hypothermic and the corticosterone effect of flesinoxan in the rat simultaneously. A specific objective was to determine the influence of handling the animal. The pharmacokinetic-pharmacodynamic correlation was determined following intravenous administration of 3 and 10 mg/kg flesinoxan in 5 or 15 min. Serial blood samples were obtained for determination of the time course of the flesinoxan and corticosterone concentrations by high performance liquid chromatography. Body temperature was monitored using a telemetric probe. The pharmacokinetics of flesinoxan were described using a three-compartment model. Both the hypothermic and the corticosterone response were successfully described using a physiological indirect response model. It is shown that customizing the animal prior to the experiment has no influence on the pharmacokinetic-pharmacodynamic parameter estimates. Furthermore, the similarity in potency between the hypothermic and corticosterone effects suggests that both are mediated via tissues with a similar receptor-effector coupling efficiency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Temperature / drug effects
  • Body Temperature / physiology
  • Corticosterone / blood*
  • Handling, Psychological
  • Hypothermia / blood
  • Hypothermia / chemically induced*
  • Male
  • Piperazines / blood
  • Piperazines / pharmacokinetics
  • Piperazines / pharmacology*
  • Rats
  • Rats, Wistar
  • Receptors, Serotonin / physiology*
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists / blood
  • Serotonin Receptor Agonists / pharmacokinetics
  • Serotonin Receptor Agonists / pharmacology*

Substances

  • Piperazines
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Serotonin Receptor Agonists
  • flesinoxan
  • Corticosterone