Bodd E, Drevon C A, Kveseth N, Olsen H, Mørland J
J Pharmacol Exp Ther. 1986 Apr;237(1):260-4.
Suspensions of isolated hepatocytes from male Wistar rats were prepared according to a two step Ca++-free collagenase perfusion method. Codeine, morphine or norcodeine were incubated with hepatocytes at 37 degrees C for up to 90 min in the absence and presence of ethanol. The elimination rate constant (Kel) of codeine and morphine was reduced with approximately one-third and one-fourth, respectively, in the presence of 60 mM ethanol, whereas the presence of ethanol did not alter the Kel of norcodeine significantly. The inhibition of codeine metabolism was dose-dependent, extending from approximately 15% at 10 mM ethanol to 40 to 50% at 100 mM. A 3-fold increase in the ratio of morphine concentration (formed from codeine) to the amount of codeine metabolized was observed in the presence of ethanol as compared to control cells. The mean morphine concentration was 170% higher in the ethanol-treated suspensions than in the controls. The ratio of norcodeine concentration to codeine metabolized was unchanged. The inhibition of morphine metabolism was accompanied by a similar reduction of morphine-3-glucuronide formation. The accumulation of morphine observed in the cell medium in the presence of ethanol might be due to inhibition of other metabolic pathways from codeine, thus shunting to morphine formation, combined with the inhibitory effect of ethanol on morphine metabolism per se.
按照两步无钙胶原酶灌注法制备雄性Wistar大鼠的分离肝细胞悬液。在有无乙醇存在的情况下，将可待因、吗啡或去甲可待因与肝细胞在37℃孵育长达90分钟。在60 mM乙醇存在时，可待因和吗啡的消除速率常数（Kel）分别降低了约三分之一和四分之一，而乙醇的存在并未显著改变去甲可待因的Kel。可待因代谢的抑制呈剂量依赖性，从10 mM乙醇时的约15%延伸至100 mM乙醇时的40%至50%。与对照细胞相比，在乙醇存在下观察到由可待因形成的吗啡浓度与代谢的可待因量之比增加了3倍。乙醇处理的悬液中吗啡的平均浓度比对照高170%。去甲可待因浓度与代谢的可待因之比未改变。吗啡代谢的抑制伴随着吗啡-3-葡萄糖醛酸苷形成的类似减少。在乙醇存在下细胞培养基中观察到的吗啡积累可能是由于可待因其他代谢途径的抑制，从而转向吗啡形成，再加上乙醇本身对吗啡代谢的抑制作用。
