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

Publication Type:

Journal Article

Authors:

Zuideveld, K.P.; van Gestel, A.; Peletier, L.A.; Van der Graaf, P.H.; Danhof, M.

Source:

Eur J Pharmacol, Volume 445, Number 1-2, p.43-54 (2002)

ISBN:

0014-2999 (Print)

DOI Name (links to online publication)

Keywords:

Animals; Body Temperature/drug effects/physiology; Corticosterone/*blood; Handling (Psychology); Hypothermia/blood/*chemically induced; Male; Piperazines/blood/pharmacokinetics/*pharmacology; Rats; Rats; Wistar; Receptors; Serotonin/*physiology; Receptors

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.