Codeine and morphine metabolism (WP3270)

Bos taurus

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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. Sources: [http://www.pharmgkb.org/do/serve?objId=PA146123006&objCls=Pathway PharmGKB:Codeine and Morphine metabolism], [http://en.wikipedia.org/wiki/Codeine Codeine at Wikipedia], [http://en.wikipedia.org/wiki/Morphine Morphine at Wikipedia].

Authors

Martina Summer-Kutmon and Eric Weitz

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

drug pathway xenobiotics biodegradation pathway codeine and morphine drug pathway

Participants

Label Type Compact URI Comment
Codeine Metabolite hmdb:HMDB0004995
Normorphine Metabolite hmdb:HMDB0041959
Morphine-3-glucuronide Metabolite hmdb:HMDB0041936
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:5359402
Codeine-6-glucuronide Metabolite pubchem.compound:5489029
CYP3A4 GeneProduct ensembl:ENSBTAG00000047379 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1576
MGC127055 GeneProduct ensembl:ENSBTAG00000026501 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1565
UGT2B7 GeneProduct ensembl:ENSBTAG00000040337 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7364
UGT2B7 GeneProduct ensembl:ENSBTAG00000040337 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7364
SLCO1B1 GeneProduct ensembl:ENSBTAG00000022329 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10599
UGT2B7 GeneProduct ensembl:ENSBTAG00000040337 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7364
UGT1A1 GeneProduct ensembl:ENSBTAG00000026181 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54658
ABCB1 GeneProduct ensembl:ENSBTAG00000005997 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5243
UGT1A1 GeneProduct ensembl:ENSBTAG00000026181 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54658
MGC127055 GeneProduct ensembl:ENSBTAG00000026501 HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000205702

References

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