A Competitive Interaction Model Predicts the Effect of WAY-100,635 on the Time Course of R -(+)-8-Hydroxy-2-(di-n-propylamino)tetralin-Induced Hypothermia

Abstract

The objective of this investigation was to characterize quantitatively the pharmacodynamic interaction between N-[2-[4-(2-The 8-OH-DPATinduced change in body temperature was used as a pharmacodynamic endpoint. Four groups of rats each received 1 mg/kg 8-OH-DPAT in 5 min during computer-controlled infusions of physiological saline or WAY-100,635, targeted at steady-state concentrations of 20, 85, and 170 ng/ml. Body temperature was monitored continuously with a telemetric system, and frequent blood samples were obtained to determine the pharmacokinetics of both drugs. Large differences in pharmacokinetics were observed between WAY-100,635 and R-8-OH-DPAT, reflected in values of the terminal elimination half-life of 33 and 143 min, respectively. Infusion of WAY-100,635 had no influence on the pharmacokinetics of R-8-OH-DPAT. With regard to the pharmacodynamics, clear antagonism of the R-8-OH-DPAT-induced hypothermia was observed. The complex pharmacological effect versus time profiles of R-8-OH-DPAT were analyzed on the basis of an indirect physiological response model with set point control coupled to a competitive interaction model for an agonist and antagonist acting at a common receptor. This model converged, yielding precise estimates of the pharmacodynamic parameters of both WAY-100,635 and R-8-OH-DPAT, which were independent of the infusion rate of WAY-100,635. The estimated in vivo binding constant of WAY-100,635 was 0.98 ng/ml (2.3 nM), which is very similar to the reported value from in vitro receptor binding assays. The findings of this investigation show that, in contrast to earlier reports in the literature, WAY 100,635 behaves as a pure competitive antagonist at the 5-hydroxytryptamine 1A receptor in vivo.Over the years, several, more or less, stable agonists at the 5-HT 1A receptor have been developed that differ in both affinity and intrinsic efficacy. Of these 5-HT 1A ligands,

Pharmacokinetic-Pharmacodynamic Modeling of Buspirone and Its Metabolite 1-(2-Pyrimidinyl)-piperazine in Rats

“…Recently, a reduced version of this model has been applied successfully to characterize the interaction between R-8-OH-DPAT and the competitive antagonist WAY-100,635 (Zuideveld et al, 2002a). The pharmacodynamic parameters found for buspirone with eqs.…”

“…[4-(2-methoxyphenyl)-1-piperzinyl]ethyl]-n-2-pyridinyl-cyclohexanecarboxamide (WAY-100,635), and Flesinoxan (Zuideveld et al, 2001(Zuideveld et al, , 2002a(Zuideveld et al, , 2002b. In the present investigation we apply this model to determine the relative in vivo potency and intrinsic activity of buspirone and its metabolite 1-PP, taking into consideration the potential pharmacodynamic interaction between the two.…”

“…The hypothermic response is considered a robust marker of 5-HT 1A activity (Millan et al, 1993;Cryan et al, 1999). It has been shown that the PK-PD model allows for the estimation of the in vivo potency and intrinsic activity of a wide array of different 5-HT 1A agonists such as R-8- -100,635), and Flesinoxan (Zuideveld et al, 2001, 2002a, 2002b. In the present investigation we apply this model to determine the relative in vivo potency and intrinsic activity of buspirone and its metabolite 1-PP, taking into consideration the potential pharmacodynamic interaction between the two.…”

“…At present there is limited quantitative information on the magnitude of this effect. In theory the contribution of the metabolite to the effect is determined by the relative concentrations of buspirone and 1-PP, their relative in vivo potency and intrinsic activity, and the nature of the pharmacodynamic interaction between the two.Recently we have developed a physiological pharmacokinetic-pharmacodynamic (PK-PD) model to quantitatively characterize the pharmacodynamics of 5-HT 1A receptor agonists in vivo using the hypothermic effect as a pharmacodynamic endpoint (Zuideveld et al, 2001(Zuideveld et al, , 2002a. The hypothermic response is considered a robust marker of 5-HT 1A activity (Millan et al, 1993;Cryan et al, 1999).…”

“…Recently we have developed a physiological pharmacokinetic-pharmacodynamic (PK-PD) model to quantitatively characterize the pharmacodynamics of 5-HT 1A receptor agonists in vivo using the hypothermic effect as a pharmacodynamic endpoint (Zuideveld et al, 2001(Zuideveld et al, , 2002a. The hypothermic response is considered a robust marker of 5-HT 1A activity (Millan et al, 1993;Cryan et al, 1999).…”