Yuan J, Dunnick J K, Barnes E R, Findlay J W
Drug Metab Dispos. 1994 Jan-Feb;22(1):14-20.
Codeine toxicokinetics in F344 rats of both sexes were determined during a 2-year chronic toxicology study using dosed feed as the exposure route with a 12-hr light/dark cycle starting at 7:00 a.m. Rats were allowed to access to dosed feed formulations ad libitum with codeine concentrations at 0, 400, 800, and 1600 ppm. Blood samples were collected from individual rat on days 7, 21, and 90 at 7:00 p.m., 11:00 p.m., 3:00 a.m., and 7:00 a.m. Additional samples were collected at 16 and 24 months between 6:00-8:00 a.m. Plasma concentrations of codeine and morphine were determined directly by radioimmunoassay. Concentrations of their conjugates were determined indirectly by measuring the total amount of free codeine and morphine released after samples were treated with beta-glucuronidase. Results indicated that plasma concentrations of both codeine and morphine steadily decreased from day 7 to 16 months and then rebounded at 24 months. Results also indicated that plasma concentrations of both codeine and morphine correlated well with the amounts of codeine added to the feed. Bioavailability of codeine using the dosed feed route increased with dose, varying from 10% to 25%, which was somewhat higher than the previously reported approximately 8% bioavailability using the gavage route. Concentrations of conjugated codeine were very low, whereas concentrations of conjugated morphine were very high. These results suggested that demethylation of codeine to morphine in rats is the main metabolic pathway and was maintained over the course of the study.
在一项为期两年的慢性毒理学研究中，以喂食给药作为暴露途径，于上午7:00开始12小时光照/黑暗循环，测定了F344雌雄大鼠体内可待因的毒代动力学。大鼠可随意获取含可待因浓度分别为0、400、800和1600 ppm的给药饲料配方。在第7、21和90天的晚上7:00、晚上11:00、凌晨3:00和上午7:00从每只大鼠采集血样。在16和24个月的上午6:00 - 8:00采集额外的血样。通过放射免疫分析法直接测定血浆中可待因和吗啡的浓度。通过测量样品用β-葡萄糖醛酸酶处理后释放的游离可待因和吗啡的总量间接测定其结合物的浓度。结果表明，可待因和吗啡的血浆浓度从第7天到16个月稳步下降，然后在24个月时反弹。结果还表明，可待因和吗啡的血浆浓度与饲料中添加的可待因量密切相关。采用给药饲料途径时，可待因的生物利用度随剂量增加，从10%到25%不等，略高于先前报道的采用灌胃途径约8%的生物利用度。结合型可待因的浓度非常低，而结合型吗啡的浓度非常高。这些结果表明，大鼠体内可待因脱甲基转化为吗啡是主要代谢途径，且在研究过程中持续存在。
