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


METHODS
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.


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
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.
Groenendaal
D
D
Leiden Amsterdam Center for Drug Research, Leiden University, Division of Pharmacology, Leiden, The Netherlands.
Freijer
J
J
de Mik
D
D
Bouw
M R
MR
Danhof
M
M
de Lange
E C M
EC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000166:Acridines / Q000494:pharmacology; D000465:Algorithms; D000701:Analgesics, Opioid / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001784:Blood Gas Analysis; D001921:Brain / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000097:blood; D008297:Male; D017551:Microdialysis; D008874:Midazolam / Q000097:blood; D009020:Morphine / Q000493:pharmacokinetics* / Q000494:pharmacology; D017711:Nonlinear Dynamics; D011153:Population; D051381:Rats; D017208:Rats, Wistar; D012121:Respiration, Artificial; D044005:Tetrahydroisoquinolines / Q000097:blood / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D044005:Tetrahydroisoquinolines; D009020:Morphine; C083501:Elacridar; D008874:Midazolam