Codeine and Morphine Metabolism (Homo sapiens)

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3, 13, 14, 18, 19241, 16, 20, 22, 239125, 17, 21, 242424, 1824Elimination via bileLiver cellGilbert syndromeUGT1A1CYP3A4NorcodeineCodeine-6-glucuronideUGT1A1UGT2B7ABCB1CYP2D6Morphine-6-glucuronideCodeineMorphineCYP2D7P1Morphine-3-glucuronideMorphine-6-glucuronideABCC2NormorphineABCC3Morphine-3-glucuronideUGT2B7SLCO1B1Codeine-6-glucuronideUGT2B786, 7, 11, 25, 2726243CYP3A410, 24, 26CYP2C824UGT1A3UGT1A6UGT1A8UGT1A9UGT1A10UGT2B424


The principal pathways for 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 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 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 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.

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110711view14:49, 28 May 2020Fehrhartchanged node to label for Gilbert syndrome
106699view13:09, 17 September 2019MaintBotHMDB identifier normalization
98130view08:58, 25 July 2018DeSlAdded stereochemically correct ID for Norcodeine; changed layout slightly due to overlapping references on nodes.
98129view07:56, 25 July 2018DeSlOntology Term : 'Gilbert syndrome' added !
95222view18:21, 26 November 2017DeSlRemoved licence number
95221view18:19, 26 November 2017DeSlConnected unconnected line.
95202view14:47, 22 November 2017DeSlModified description
95201view14:37, 22 November 2017DeSlModified description
95200view14:34, 22 November 2017DeSlAdded OMIM IDs for diseases
95199view14:34, 22 November 2017DeSlModified description
95198view14:32, 22 November 2017DeSlAdded additional enzym information from new literature source.
89511view10:44, 16 September 2016Mkutmonontology tag fix
89468view13:39, 15 September 2016Mkutmonremove space from ontology term id
74317view13:50, 12 April 2014EgonwFixed a character encoding issue.
69899view19:27, 11 July 2013AlexanderPicoCleaned up interactions
69895view19:18, 11 July 2013AlexanderPicoModified title
67120view10:09, 26 June 2013Christine ChichesterOntology Term : 'codeine and morphine drug pathway' added !
63436view15:40, 10 May 2013EgonwAdded other missing metabolite identifiers (from HMDB and PubChem)
63435view15:08, 10 May 2013EgonwAdded a HMDB id for morphine.
63165view20:24, 8 May 2013MaintBotUpdating gpml version
59205view19:45, 22 February 2013MaintBotUpdated Ensembl data source
44994view14:37, 6 October 2011MartijnVanIerselOntology Term : 'xenobiotics biodegradation pathway' added !
44993view14:37, 6 October 2011MartijnVanIerselOntology Term : 'drug pathway' added !
41197view23:43, 1 March 2011MaintBotRemoved redundant pathway information and comments
38483view18:24, 17 September 2010AlexanderPicoModified description
38351view22:51, 1 September 2010KhanspersModified categories
38350view22:51, 1 September 2010KhanspersChanged literature references
38349view22:47, 1 September 2010KhanspersModified description
38348view22:39, 1 September 2010KhanspersNew pathway

External references


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NameTypeDatabase referenceComment
ABCB1GeneProduct5243 (Entrez Gene)
ABCC2GeneProduct1244 (Entrez Gene)
ABCC3GeneProduct8714 (Entrez Gene)
CYP2C8ProteinENSG00000138115 (Ensembl)
CYP2D6GeneProduct1565 (Entrez Gene) O-dealkylation
CYP2D7P1GeneProductENSG00000205702 (Ensembl)
CYP3A4GeneProduct1576 (Entrez Gene) N-demethylation
CYP3A4ProteinENSG00000160868 (Ensembl) N-demethylation, major protein
Codeine-6-glucuronideMetabolite5489029 (PubChem-compound)
CodeineMetaboliteHMDB0004995 (HMDB)
Morphine-3-glucuronideMetaboliteHMDB0041936 (HMDB)
Morphine-6-glucuronideMetabolite5360621 (PubChem-compound)
MorphineMetaboliteHMDB0014440 (HMDB)
NorcodeineMetabolite9925873 (PubChem-compound)
NormorphineMetaboliteHMDB0041959 (HMDB)
SLCO1B1GeneProduct10599 (Entrez Gene)
UGT1A10GeneProductENSG00000242515 (Ensembl)
UGT1A1GeneProduct54658 (Entrez Gene)
UGT1A3GeneProductENSG00000243135 (Ensembl)
UGT1A6ProteinENSG00000167165 (Ensembl)
UGT1A8GeneProductENSG00000242366 (Ensembl)
UGT1A9GeneProductENSG00000241119 (Ensembl)
UGT2B4ProteinENSG00000156096 (Ensembl) conjugation
UGT2B7GeneProduct7364 (Entrez Gene) major enzyme involved

Annotated Interactions

No annotated interactions

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