Codeine and morphine metabolism (WP1604)

Homo sapiens

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.


Kristina Hanspers , Alex Pico , Martijn Van Iersel , Egon Willighagen , Christine Chichester , Martina Summer-Kutmon , Denise Slenter , Friederike Ehrhart , and Eric Weitz


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Homo sapiens



Cell Type Ontology


Pathway Ontology

codeine and morphine drug pathway xenobiotics biodegradation pathway drug pathway

Disease Ontology

Gilbert syndrome


Label Type Compact URI Comment
Codeine Metabolite hmdb:HMDB0004995
Normorphine Metabolite hmdb:HMDB0041959
Morphine-3-glucuronide Metabolite hmdb:HMDB0041936 Iinactive metabolite, a.k.a. M3G
Codeine-6-glucuronide Metabolite pubchem.compound:5489029
Morphine Metabolite hmdb:HMDB0014440
Morphine-3-glucuronide Metabolite hmdb:HMDB0041936
Morphine-6-glucuronide Metabolite pubchem.compound:5360621
Morphine-6-glucuronide Metabolite pubchem.compound:5360621
Norcodeine Metabolite pubchem.compound:9925873
Codeine-6-glucuronide Metabolite pubchem.compound:5489029
CYP3A4 GeneProduct ncbigene:1576 N-demethylation
CYP2D6 GeneProduct ncbigene:1565 O-dealkylation
UGT2B7 GeneProduct ncbigene:7364 Conjugation
UGT2B7 GeneProduct ncbigene:7364 major enzyme involved
SLCO1B1 GeneProduct ncbigene:10599
UGT2B7 GeneProduct ncbigene:7364 major enzyme involved
UGT1A1 GeneProduct ncbigene:54658
ABCC2 GeneProduct ncbigene:1244
ABCB1 GeneProduct ncbigene:5243
UGT1A1 GeneProduct ncbigene:54658
CYP2D7P1 GeneProduct ensembl:ENSG00000205702
ABCC3 GeneProduct ncbigene:8714
UGT1A3 GeneProduct ensembl:ENSG00000243135
UGT1A8 GeneProduct ensembl:ENSG00000242366
UGT1A9 GeneProduct ensembl:ENSG00000241119
UGT1A10 GeneProduct ensembl:ENSG00000242515
CYP3A4 Protein ensembl:ENSG00000160868 N-demethylation, major protein
CYP2C8 Protein ensembl:ENSG00000138115
UGT1A6 Protein ensembl:ENSG00000167165
UGT2B4 Protein ensembl:ENSG00000156096 conjugation


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