Codeine and morphine metabolism (Bos taurus)

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2, 5, 13, 18, 231, 12, 21, 24, 251610, 134, 7, 1419Liver cellElimination via bileMGC127055UGT1A1Codeine-6-glucuronideMorphineUGT1A1Morphine-3-glucuronideMorphine-6-glucuronideABCB1SLCO1B1NorcodeineUGT2B7ABCC2CodeineMorphine-6-glucuronideMGC127055NormorphineCodeine-6-glucuronideUGT2B7UGT2B7ABCC3Morphine-3-glucuronideCYP3A439, 15, 17, 20, 225118, 11


Description

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: PharmGKB:Codeine and Morphine metabolism, Codeine at Wikipedia, Morphine at Wikipedia.

Comments

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This pathway was inferred from Homo sapiens pathway WP1604(74317) with a 83.0% conversion rate.

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Bibliography

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  5. Pai HV, Kommaddi RP, Chinta SJ, Mori T, Boyd MR, Ravindranath V; ''A frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine.''; J Biol Chem, 2004 PubMed Europe PMC Scholia
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History

CompareRevisionActionTimeUserComment
117488view11:01, 21 May 2021EweitzModified title
106006view11:53, 16 August 2019MaintBotHMDB identifier normalization
89454view13:04, 15 September 2016Mkutmonremove space in ontology term id
80919view15:31, 30 June 2015MkutmonNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ABCB1GeneProductENSBTAG00000005997 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5243
ABCC2GeneProduct
ABCC3GeneProduct
CYP3A4GeneProductENSBTAG00000047379 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1576
Codeine-6-glucuronideMetabolite5489029 (PubChem-compound)
CodeineMetaboliteHMDB0004995 (HMDB)
MGC127055GeneProductENSBTAG00000026501 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = En:ENSG00000205702
Morphine-3-glucuronideMetaboliteHMDB0041936 (HMDB)
Morphine-6-glucuronideMetabolite5360621 (PubChem-compound)
MorphineMetaboliteHMDB0014440 (HMDB)
NorcodeineMetabolite5359402 (PubChem-compound)
NormorphineMetaboliteHMDB0041959 (HMDB)
SLCO1B1GeneProductENSBTAG00000022329 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10599
UGT1A1GeneProductENSBTAG00000026181 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:54658
UGT2B7GeneProductENSBTAG00000040337 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7364

Annotated Interactions

No annotated interactions
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