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

Abstract

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.

Morphine Brain Pharmacokinetics at Very Low Concentrations Studied with Accelerator Mass Spectrometry and Liquid Chromatography-Tandem Mass Spectrometry

“…Oral pretreatment of rats with the specific P-glycoprotein (Pgp) inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) caused a prolonged morphine-associated antinociceptive effect due to morphine's prolonged half-life in the brain (Letrent et al, 1999). The involvement of Pgp in the efflux of morphine at the BBB is also supported by the results of modeling to describe the transport of morphine, as proposed by Groenendaal et al (2007), where the efflux rate constant value decreased from 0.0195 to 0.0113 min Ϫ1 , to provide the best fit after the addition of Pgp inhibitor GF120918. In a study of Pgp-deficient mice, the influx clearance for morphine was 24% higher than that for wild-type mice, which indicates that Pgp accounts for only part of the efflux from the BBB (Dagenais et al, 2004).…”

“…The discrepancy between the studies might be due to species differences in the experimental models used. However, although the inclusion of active influx increased the fit of the model proposed by Groenendaal et al (2007), there was no concrete evidence suggesting the presence of such a process in their study. In our experimental setup, we used a 25-fold lower concentration than the C 50 described by Groenendaal et al (2007), but no active influx of morphine was seen.…”

“…However, although the inclusion of active influx increased the fit of the model proposed by Groenendaal et al (2007), there was no concrete evidence suggesting the presence of such a process in their study. In our experimental setup, we used a 25-fold lower concentration than the C 50 described by Groenendaal et al (2007), but no active influx of morphine was seen. This result does not necessarily mean that there is no active influx of morphine at the BBB, but rather that the evidence indicated that it could not, based on concentration, be differentiated from the more efficient efflux.…”

“…Because the active uptake transporter has not yet been characterized (Okura et al, 2008), the uptake process could not be studied by blocking it with a specific blocker, and saturating efflux transport is not achievable in vivo. There has consequently been conjecture that it might be possible to separate the influx and efflux processes in vivo by decreasing the concentrations of morphine (Xie et al, 1999;Groenendaal et al, 2007).…”

“…This result indicates that the transport of morphine into the human brain might occur not only by passive diffusion but also by active influx. It has been suggested that the mechanism for active uptake of morphine into the brain could involve low-capacity active influx, which is saturated at low concentrations and therefore results in a net efflux across the BBB at higher morphine concentrations (Groenendaal et al, 2007). The influx transporter of oxycodone and morphine is likely to be the same, but because it has not yet been characterized (Okura et al, 2008), there is neither a specific inhibitor nor a knockout animal for use in studies.…”