Codeine and morphine metabolism (Homo sapiens)
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Description
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.Quality Tags
Ontology Terms
Bibliography
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- Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ; ''Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother.''; Lancet, 2006 PubMed Europe PMC Scholia
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- Court MH, Krishnaswamy S, Hao Q, Duan SX, Patten CJ, Von Moltke LL, Greenblatt DJ; ''Evaluation of 3'-azido-3'-deoxythymidine, morphine, and codeine as probe substrates for UDP-glucuronosyltransferase 2B7 (UGT2B7) in human liver microsomes: specificity and influence of the UGT2B7*2 polymorphism.''; Drug Metab Dispos, 2003 PubMed Europe PMC Scholia
- Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, Desmeules J; ''Codeine intoxication associated with ultrarapid CYP2D6 metabolism.''; N Engl J Med, 2004 PubMed Europe PMC Scholia
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History
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External references
DataNodes
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Name | Type | Database reference | Comment |
---|---|---|---|
ABCB1 | GeneProduct | 5243 (Entrez Gene) | |
ABCC2 | GeneProduct | 1244 (Entrez Gene) | |
ABCC3 | GeneProduct | 8714 (Entrez Gene) | |
CYP2C8 | Protein | ENSG00000138115 (Ensembl) | |
CYP2D6 | GeneProduct | 1565 (Entrez Gene) | O-dealkylation |
CYP2D7P1 | GeneProduct | ENSG00000205702 (Ensembl) | |
CYP3A4 | GeneProduct | 1576 (Entrez Gene) | N-demethylation |
CYP3A4 | Protein | ENSG00000160868 (Ensembl) | N-demethylation, major protein |
Codeine-6-glucuronide | Metabolite | 5489029 (PubChem-compound) | |
Codeine | Metabolite | HMDB0004995 (HMDB) | |
Elimination via bile | Pathway | ||
Morphine-3-glucuronide | Metabolite | HMDB0041936 (HMDB) | |
Morphine-6-glucuronide | Metabolite | 5360621 (PubChem-compound) | |
Morphine | Metabolite | HMDB0014440 (HMDB) | |
Norcodeine | Metabolite | 9925873 (PubChem-compound) | |
Normorphine | Metabolite | HMDB0041959 (HMDB) | |
SLCO1B1 | GeneProduct | 10599 (Entrez Gene) | |
UGT1A10 | GeneProduct | ENSG00000242515 (Ensembl) | |
UGT1A1 | GeneProduct | 54658 (Entrez Gene) | |
UGT1A3 | GeneProduct | ENSG00000243135 (Ensembl) | |
UGT1A6 | Protein | ENSG00000167165 (Ensembl) | |
UGT1A8 | GeneProduct | ENSG00000242366 (Ensembl) | |
UGT1A9 | GeneProduct | ENSG00000241119 (Ensembl) | |
UGT2B4 | Protein | ENSG00000156096 (Ensembl) | conjugation |
UGT2B7 | GeneProduct | 7364 (Entrez Gene) | major enzyme involved |
Annotated Interactions
No annotated interactions