Bodd E, Green M H, Drevon C A, Mørland J
Eur J Drug Metab Pharmacokinet. 1986 Jul-Sep;11(3):239-43. doi: 10.1007/BF03189852.
A multicompartmental pharmacokinetic model is presented, which based upon data from a previous study, describes the effects of ethanol (60 mM) on the metabolism of codeine (10 microM) in isolated rat hepatocytes. According to this model, about one third of codeine metabolized was transformed to morphine (13%) and norcodeine (18%), and two-thirds to unknown metabolites in the absence of ethanol. In the presence of ethanol, the apparent first order fractional rate of total codeine metabolism was reduced by 66% (0.0783 vs 0.0271 min-1). There was no alteration in the portion of codeine metabolized to norcodeine, but there was a 44% decrease in the fraction transformed to unknown metabolites and a tripling in the portion transformed to morphine. The fractional rate of codeine O-demethylation to morphine was apparently not sensitive to ethanol. In the absence of ethanol, about two-thirds of morphine was metabolized to morphine-3-glucuronide and the other third to unidentified metabolites. Only the glucuronidation process seemed to be inhibited by ethanol. The fractional rate of further metabolism of norcodeine to normorphine was similar in the absence or presence of ethanol. In conclusion ethanol co-incubation with codeine resulted in an inhibition of codeine conversion to unknown metabolites and norcodeine, and with morphine to morphine-3-glucuronide, but no inhibition in morphine production.
本文提出了一种多室药代动力学模型，该模型基于先前一项研究的数据，描述了乙醇（60 mM）对分离的大鼠肝细胞中可待因（10 microM）代谢的影响。根据该模型，在无乙醇的情况下，约三分之一代谢的可待因转化为吗啡（13%）和去甲可待因（18%），三分之二转化为未知代谢物。在有乙醇存在的情况下，可待因总代谢的表观一级分数速率降低了66%（0.0783对0.0271 min-1）。转化为去甲可待因的可待因部分没有改变，但转化为未知代谢物的部分减少了44%，而转化为吗啡的部分增加了两倍。可待因O-去甲基化生成吗啡的分数速率显然对乙醇不敏感。在无乙醇的情况下，约三分之二的吗啡代谢为吗啡-3-葡萄糖醛酸苷，另外三分之一代谢为未鉴定的代谢物。似乎只有葡萄糖醛酸化过程受到乙醇的抑制。在有无乙醇的情况下，去甲可待因进一步代谢为去甲吗啡的分数速率相似。总之，乙醇与可待因共同孵育导致可待因转化为未知代谢物和去甲可待因受到抑制，以及吗啡转化为吗啡-3-葡萄糖醛酸苷受到抑制，但对吗啡生成没有抑制作用。
