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. British Journal of Pharmacology (2007) 151 , 701–712; doi: 10.1038/sj.bjp.0707257