A set-point model with oscillatory behavior predicts the time course of 8-OH-DPAT-induced hypothermia

Abstract

Agonists for the 5-hydroxytryptamine (HT)(1A) receptor induce a hypothermic response that is believed to occur by lowering of the body's set-point temperature. We have developed a physiological model that can be used to predict the complex time course of the hypothermic response after administration of 5-HT(1A) agonists to rats. In the model, 5-HT(1A) agonists exert their effect by changing heat loss through a control mechanism with a thermostat signal that is proportional to the difference between measured and set-point temperature. Agonists exert their effect in a direct concentration-dependent manner, with saturation occurring at higher concentrations. On the basis of simulations, it is shown that, depending on the concentration and the intrinsic efficacy of a 5-HT(1A) agonist, the model shows oscillatory behavior. The model was successfully applied to characterize the complex hypothermic response profiles after administration of the reference 5-HT(1A) agonists R-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT) and S-8-OH-DPAT. This analysis revealed that the observed difference in effect vs. time profile for these two reference agonists could be explained by a difference in in vivo intrinsic efficacy.

Allometric Scaling of Pharmacodynamic Responses: Application to 5-Ht1A Receptor Mediated Responses from Rat to Man

“…The pharmacokinetic and pharmacodynamic models and their analyses have been published previously (9)(10)(11). Briefly 2-and 3-compartment pharmacokinetic models were used for the pharmacokinetics of buspirone and flesinoxan, respectively.…”

“…The pharmacokinetic profiles were used to quantify the relationship between the time profile of the agonist blood concentration and the time course of the hypothermic and corticosterone response. For this purpose, the previously described mechanistic PK-PD model (9) was fitted to the data on the time course of the hypothermic effect for each individual rat. In this model the hypothermic effect by the 5-HT 1A -receptor agonists is considered to be the result of the attenuation of a set-point control by the drug receptor interaction.…”

“…3 is high and this may lead to parameter identifiability problems. It has been shown that one parameter can be eliminated in a procedure involving the introduction of dimensionless variables (9). The procedure results in the establishment of the parameters A and B defined by,…”

“…Recent work by Lepist and Jusko (7) has shown that using a relatively simple physiological model it was possible to scale both PK and PD parameters across four species. The aim of the present report was to explore the allometric scaling of the hypothermic response and the increase in corticosterone following the administration of 5-HT 1A receptor agonists using two previously developed mechanism-based PK-PD models (9).…”

Biomarkers and Therapeutic Drug Monitoring in Psychiatry

“…As well as, the recent increase in the number of publications about PK-PD models in journals of Clinical Pharmacology and Clinical Pharmacy, concerning to theoretical models and their implementation. Despite the continued increase in the number of articles, there are still, a large number of publications that contain pharmacokinetic and pharmacodynamic data without PK-PD modeling studies (Francheteau 1993;Geldof 2007;Mandem & Wada 1995;Zuideveld 2001). …”