Population pharmacokinetic modelling of non-linear brain distribution of morphine: influence of active saturable influx and P-glycoprotein mediated efflux

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(-1) of morphine, combined with a continuous infusion of the P- glycoprotein ( Pgp) inhibitor GF120918 or vehicle, or 40 mg kg(-1) 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(-1). The active efflux rate constant decreased from 0.0195 min(-1) to 0.0113 min(-1) 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(-1) ml(-1) and was saturated at low concentrations of morphine ( C-50= 9.9 ng ml(-1)). 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.