Purpose: The purpose of the study was to investigate the distribution of codeine across the blood-brain barrier (BBB) in rats by microdialysis (MD).
Methods: Rats were administered intravenous infusion of codeine in doses of (1) 10 mg/kg, (2) 20 mg/kg for 10 min, and (3) an exponential infusion for 2 h aiming at a plasma concentration of 2500 ng/ml, in a crossover design (n = 6). Microdialysis was used to determine codeine unbound concentrations in blood and brain extracellular fluid (ECF). Total brain tissue and plasma concentrations were also determined. Nalorphine was used as a calibrator for measurement of in vivo recovery.
Results: Relative recovery and retrodialysis loss of codeine and nalorphine were similar both in vitro and in vivo. Codeine was rapidly transported into the brain ECF with identical influx and efflux clearance 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 Css ratio of brain to blood was 1.06 +/- 0.12 for the exponential infusion. The half-lives were 25 +/- 4 min, 22 +/- 2 min in blood and 27 +/- 5 min, 25 +/- 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 concentrations in brain. Codeine was demethylated to morphine with an unbound AUCblood,morphine/AUCblood,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 distributional equilibrium with equal unbound concentrations in blood and brain. The brain transport of codeine did not show any dose-dependency.