Codeine and morphine metabolism

The principal pathways for the metabolism of codeine occur in the liver, although some metabolism occurs in the intestine and brain. Approximately 50-70% of codeine is converted to codeine-6-glucuronide by UGT2B7. Codeine-6-glucuronide has a similar affinity to codeine for the mu-opioid receptor, coded for by the OPRM1 gene. Approximately 10-15% of codeine is N-demethylated to norcodeine by CYP3A4. Norcodeine also has a similar affinity to codeine for the mu-opioid receptor. Between 0-15% of codeine is O-demethylated to morphine, the most active metabolite, which has a 200 fold greater affinity for the mu-opioid receptor compared to codeine. This metabolic reaction is performed by CYP2D6. Approximately 60% of morphine is glucuronidated to morphine-3-glucuronide (M3G) while 5-10% is glucuronidated to morphine-6-glucuronide (M6G). These reactions are principally catalyzed by UGT2B7 in the liver. UGT1A1 may have a minor role in the formation of M3G, and UGT1A1 and UGT1A8 are capable of catalyzing the formation of M6G in vitro and so contribute to this pathway, although UGT1A8 is minimally expressed in the liver and so is not depicted here. M6G has a higher affinity for OPRM1 than morphine and M3G and so the ratio of morphine to M6G is considered an important indicator of analgesic effect. Transporters are also depicted in this pathway, as they influence the clearance of codeine, morphine, and their metabolites. Some of the evidence for the involvement of these transporters was derived from experiments done in mice and may or may not be translatable to human pharmacokinetics. The transporters present at the blood-brain barrier, not depicted in this pathway, as well as metabolic enzymes and transporters in the brain and GI tract, likely also play an important role in the pharmacokinetics of codeine and morphine. A disease linked to this pathway is Gilbert syndrome (visualised in pink), which is characterized by impaired glucuronidation due to a polymorphism in the gene encoding UGT1A1.

可待因的代谢主要途径存在于肝脏中，尽管部分代谢过程亦发生在肠道和大脑。约50%-70%的可待因经UGT2B7转化为可待因-6-葡萄糖苷酸。可待因-6-葡萄糖苷酸与可待因对μ-阿片受体的亲和力相似，该受体由OPRM1基因编码。约10%-15%的可待因经CYP3A4去甲基化转化为去甲可待因。去甲可待因对μ-阿片受体的亲和力亦与可待因相似。0%-15%的可待因经CYP2D6去甲基化转化为吗啡，即活性最强的代谢产物，其对μ-阿片受体的亲和力是可待因的200倍。此代谢反应由CYP2D6完成。约60%的吗啡转化为吗啡-3-葡萄糖苷酸（M3G），而5%-10%转化为吗啡-6-葡萄糖苷酸（M6G）。这些反应主要由肝脏中的UGT2B7催化。UGT1A1可能在M3G的形成中扮演次要角色，且UGT1A1和UGT1A8能够在体外催化M6G的形成，从而参与此代谢途径，尽管UGT1A8在肝脏中的表达量极低，因此在此图中未显示。M6G对OPRM1的亲和力高于吗啡和M3G，因此吗啡与M6G的比率被视为镇痛效果的重要指标。运输蛋白也在此代谢途径中有所体现，因为它们影响可待因、吗啡及其代谢物的清除。部分关于这些运输蛋白参与的证据来源于小鼠实验，其结果可能或可能不适用于人类药代动力学。图中未显示的位于血脑屏障的运输蛋白，以及大脑和胃肠道中的代谢酶和运输蛋白，可能在可待因和吗啡的药代动力学中也扮演着重要角色。与该代谢途径相关的一种疾病是吉尔伯特综合征（以粉红色标示），其特征为由于编码UGT1A1基因的多态性导致的葡萄糖苷化功能受损。