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. b66 a66 cd3 e96 df0 N-demethylation a16 O-dealkylation bfc a16 d03 Conjugation b36 abc bbd c58 f03 major enzyme involved Iinactive metabolite, a.k.a. M3G major enzyme involved d03 b2a b66 N-demethylation, major protein d03 conjugation d03 d03 dac a2f a8d d03 d49 e96 f80 d03 deb f90 d03 f1a dbd b6b b74 f58 hepatocyte CL:0000182 Cell Type 18781855 PubMed Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Pharmacogenomics 2008 Madadi P Koren G 10516633 PubMed The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice. 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