Xie R, Hammarlund-Udenaes M
Department of Pharmacy, Faculty of Pharmacy, Uppsala University, Sweden.
Pharm Res. 1998 Apr;15(4):570-5. doi: 10.1023/a:1011929910782.
The purpose of the study was to investigate the distribution of codeine across the blood-brain barrier (BBB) in rats by microdialysis (MD).
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.
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.
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.
本研究旨在通过微透析（MD）研究大鼠体内可待因在血脑屏障（BBB）中的分布情况。
采用交叉设计（n = 6），给大鼠静脉输注可待因，剂量分别为：（1）10 mg/kg，（2）20 mg/kg，持续10分钟，（3）以指数方式输注2小时，目标血浆浓度为2500 ng/ml。使用微透析法测定血液和脑细胞外液（ECF）中游离的可待因浓度。同时还测定了脑组织和血浆的总浓度。纳洛啡用作体内回收率测量的校准剂。
可待因和纳洛啡在体外和体内的相对回收率及反透析损失相似。可待因迅速转运至脑细胞外液，通过血脑屏障的流入和流出清除率相同。剂量1和剂量2时，脑血药浓度时间曲线下面积（AUC）比值分别为0.99±0.25和0.95±0.16。指数输注时，脑血稳态浓度（Css）比值为1.06±0.12。剂量1和剂量2时，血液中的半衰期分别为25±4分钟、22±2分钟，脑内半衰期分别为27±5分钟、25±5分钟。脑组织总浓度比脑内游离浓度高3.6±1.2倍。可待因脱甲基代谢为吗啡，血液中游离的吗啡AUC与可待因AUC的比值为7.7±5.1%。在脑微透析中未检测到吗啡，但可测量总浓度。
可待因迅速达到分布平衡，血液和脑内游离浓度相等。可待因的脑转运未显示出任何剂量依赖性。
