Vol. 283, Issue 3, 1051-1058, 1997

Pharmacokinetic-Pharmacodynamic Characterization of the Cardiovascular, Hypnotic, EEG and Ventilatory Responses to Dexmedetomidine in the Rat¹

Cornelis J.J.G. Bol² , Meindert Danhof, Donald R. Stanski and Jaap W. Mandema³

Departments of Anesthesia, Stanford University School of Medicine, Stanford, CA (C.J.J.G.B., J.W.M., D.R.S.) and Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands (C.J.J.G.B., M.D.)

This study characterizes the pharmacokinetic-pharmacodynamic (PK-PD) relationships of the cardiovascular, EEG, hypnotic and ventilatory effects of the alpha-2 adrenergic agonist dexmedetomidine in rats. Dexmedetomidine was administered by a single rapid infusion (n = 6) and by an infusion regimen of gradually increasing rate (n = 8). HR, mean arterial pressure (MAP) and EEG signals were recorded continuously, as was the time at which the rats woke up spontaneously from drug-induced sleep, a measure of hypnosis. Arterial concentrations of dexmedetomidine and blood gases were determined regularly. A sigmoidal E_max model was used to describe the HR, MAP and EEG concentration-effect relationships, with the EEG effect (activity in 0.5-3.5-Hz frequency band) linked to an effect-site model. The PK of dexmedetomidine could be described by a two-compartment model, with similar PK parameters for both infusion regimens. Plasma protein binding was 84.1[0.7]%. Because of complex cardiovascular homeostatic reflex mechanisms, HR and MAP could only be analyzed during gradually increasing infusions. The maximal decrease in HR was 35(2)%, and the maximal increase in MAP was 37(2)%. For both infusion regimens, similar PD parameters were found for the EEG and the hypnotic measure. These data suggest the absence of active metabolites or tolerance of the EEG and hypnotic effects. Judging on the basis of concentrations of dexmedetomidine (mean (S.E.M.)), HR decrease was the most sensitive response [EC₅₀ of 0.65(0.09) ng/ml], followed by increase in MAP [EC₅₀ of 2.01(0.14) ng/ml], change in EEG activity [EC₅₀ of 2.24(0.16) ng/ml] and the hypnotic measure [C_wake-up of 2.64(0.10) ng/ml]. Ventilatory effects were minor.