Influence of biophase distribution and P-glycoprotein interaction on pharmacokinetic-pharmacodynamic modelling of the effects of morphine on the EEG

Background and purpose: The aim was to investigate the influence of biophase distribution including P- glycoprotein ( Pgp) function on the pharmacokinetic- pharmacodynamic correlations of morphine's actions in rat brain. Experimental approach: Male rats received a 10- min infusion of morphine as 4mg kg(-1), combined with a continuous infusion of the Pgp inhibitor GF120918 or vehicle, 10 or 40 mg kg(-1). EEG signals were recorded continuously and blood samples were collected. Key results: Profound hysteresis was observed between morphine blood concentrations and effects on the EEG. Only the termination of the EEG effect was influenced by GF120918. Biophase distribution was best described with an extended catenary biophase distribution model, with a sequential transfer and effect compartment. The rate constant for transport through the transfer compartment ( k(1e)) was 0.038 min(-1), being unaffected by GF120918. In contrast, the rate constant for the loss from the effect compartment ( k(eo)) decreased 60% after GF120918. The EEG effect was directly related to concentrations in the effect compartment using the sigmoidal E-max model. The values of the pharmacodynamic parameters E-o, E-max, EC50 and Hill factor were 45.0 mu V, 44.5 mu V, 451 ng ml(-1) and 2.3, respectively. Conclusions and implications: The effects of GF120918 on the distribution kinetics of morphine in the effect compartment were consistent with the distribution in brain extracellular fluid ( ECF) as estimated by intracerebral microdialysis. However, the time- course of morphine concentrations at the site of action in the brain, as deduced from the biophase model, is distinctly different from the brain ECF concentrations.