BLOOD-BRAIN-BARRIER EQUILIBRATION OF CODEINE IN RATS STUDIED WITH MICRODIALYSIS

Purpose, The purpose of the study was to investigate the distribution of codeine across the blood-brain barrier (BBB) in rats by microdialys is (MD). Methods. Rats were administered intravenous infusion of codei ne in doses of (1) 10 mg/kg, (2) 20 mg/kg for 10 min, and (3) an expon ential infusion for 2 h aiming at a plasma concentration of 2500 ng/ml , in a crossover design (n = 6). Microdialysis was used to determine c odeine unbound concentrations in blood and brain extracellular fluid ( ECF). Total brain tissue and plasma concentrations were also determine d. Nalorphine was used as a calibrator for measurement of in vivo reco very. Results. Relative recovery and retrodialysis loss of codeine and nalorphine were similar both in vitro and in vivo. Codeine was rapidl y transported into the brain ECF with identical influx and efflux clea rance across the BBB. The AUC ratios of brain to blood were 0.99 +/- 0 .25 and 0.95 +/- 0.16 for Dose 1 and 2, respectively. The C-ss ratio o f brain to blood was 1.06 +/- 0.12 for the exponential infusion. The h alf-lives were 25 +/- 4 min, 22 +/- 2 min in blood and 27 +/- 5 min, 2 5 +/- 5 min in brain for Dose 1 and Dose 2, respectively. Total brain tissue concentrations were 3.6 +/- 1.2-fold higher than the unbound co ncentrations in brain. Codeine was demethylated to morphine with an un bound AUC(blood,morphine)/AUC(blood,codeine) ratio of 7.7 +/- 5.1% in blood. No morphine was detected in brain MD, but total concentrations were possible to measure. Conclusions. Codeine rapidly reached a distr ibutional equilibrium with equal unbound concentrations in blood and b rain. The brain transport of codeine did not show any dose-dependency.