Background and purpose: Biophase equilibration must be considered to gain insight into the mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) correlations of opioids. The objective was to characterise in a quantitative manner the non-linear distribution kinetics of morphine in brain. Experimental approach: Male rats received a 10-min infusion of 4 mg kg À1 of morphine, combined with a continuous infusion of the P-glycoprotein (Pgp) inhibitor GF120918 or vehicle, or 40 mg kg À1 morphine alone. Unbound extracellular fluid (ECF) concentrations obtained by intracerebral microdialysis and total blood concentrations were analysed using a population modelling approach. Key results: Blood pharmacokinetics of morphine was best described with a three-compartment model and was not influenced by GF120918. Non-linear distribution kinetics in brain ECF was observed with increasing dose. A one compartment distribution model was developed, with separate expressions for passive diffusion, active saturable influx and active efflux by Pgp. The passive diffusion rate constant was 0.0014 min À1 . The active efflux rate constant decreased from 0.0195 min À1 to 0.0113 min À1 in the presence of GF120918. The active influx was insensitive to GF120918 and had a maximum transport (N max /V ecf ) of 0.66 ng min À1 ml À1 and was saturated at low concentrations of morphine (C 50 ¼ 9.9 ng ml À1 ). Conclusions and implications: Brain distribution of morphine is determined by three factors: limited passive diffusion; active efflux, reduced by 42% by Pgp inhibition; low capacity active uptake. This implies blood concentration-dependency and sensitivity to drug-drug interactions. These factors should be taken into account in further investigations on PK-PD correlations of morphine.

Our ultimate goal is to develop mechanism-based pharmacokinetic (PK)-pharmacodynamic (PD) models to characterize and to predict CNS drug responses in both physiologic and pathologic conditions. To this end, it is essential to have information on the biophase pharmacokinetics, because these may significantly differ from plasma pharmacokinetics. It is anticipated that biophase kinetics of CNS drugs are strongly influenced by transport across the blood-brain barrier (BBB). The special role of microdialysis in PK/PD modeling of CNS drugs lies in the fact that it enables the determination of free-drug concentrations as a function of time in plasma and in extracellular fluid of the brain, thereby providing important data to determine BBB transport characteristics of drugs. Also, the concentrations of (potential) extracellular biomarkers of drug effects or disease can be monitored with this technique. Here we describe our studies including microdialysis on the following: (1) the evaluation of the free drug hypothesis; (2) the role of BBB transport on the central effects of opioids; (3) changes in BBB transport and biophase equilibration of anti-epileptic drugs; and (4) the relation among neurodegeneration, BBB transport, and drug effects in ParkinsonÕs disease progression.

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