PHARMACOKINETIC-PHARMACODYNAMIC CHARACTERIZATION OF THE CARDIOVASCULAR, HYPNOTIC, EEG AND VENTILATORY RESPONSES TO DEXMEDETOMIDINE IN THE RAT

This study characterizes the pharmacokinetic-pharmacodynamic (PK-PD) r elationships of the cardiovascular, EEG, hypnotic and ventilatory effe cts of the alpha-2 adrenergic agonist dexmedetomidine in rats. Dexmede tomidine was administered by a single rapid infusion (n = 6) and by an infusion regimen of gradually increasing rate (n = 8). HR, mean arter ial pressure (MAP) and EEG signals were recorded continuously, as was the time at which the rats woke up spontaneously from drug-induced sle ep, 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 relationshi ps, 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 infus ion regimens. Plasma protein binding was 84.1[0.7]%. Because of comple x cardiovascular homeostatic reflex mechanisms, HR and MAP could only be analyzed during gradually increasing infusions. The maximal decreas e in HR was 35(2)%, and the maximal increase in MAP was 37(2)%. For bo th infusion regimens, similar PD parameters were found for the EEG and the hypnotic measure. These data suggest the absence of active metabo lites or tolerance of the EEG and hypnotic effects. Judging on the bas is of concentrations of dexmedetomidine (mean (S.E.M.)), HR decrease w as 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 [E C50 of 2.24(0.16) ng/ml] and the hypnotic measure [Cwake-up Of 2.64(0. 10) ng/ml]. Ventilatory effects were minor.