Pharmacokinetic-pharmacodynamic modelling of the hypothermic and corticosterone effects of the 5-HT1A receptor agonist flesinoxan.
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.
Zuideveld
Klaas P
KP
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratory, P.O. Box 9502, 2300 RA, Leiden, The Netherlands.
van Gestel
Aukje
A
Peletier
Lambertus A
LA
Van der Graaf
Piet H
PH
Danhof
Meindert
M
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D003345:Corticosterone / Q000097:blood*; D006234:Handling, Psychological; D007035:Hypothermia / Q000097:blood / Q000139:chemically induced*; D008297:Male; D010879:Piperazines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; C056895:flesinoxan; D003345:Corticosterone