Codeine and Morphine Metabolism (Bos taurus)

From WikiPathways

Jump to: navigation, search
2, 5, 13, 18, 231, 12, 21, 24, 25191610, 134, 7, 14Elimination via bileLiver cellSLCO1B1ABCB1Morphine-3-glucuronideNorcodeineUGT2B7Morphine-6-glucuronideCodeineABCC2Codeine-6-glucuronideMorphine-6-glucuronideNormorphineMorphine-3-glucuronideUGT1A1Codeine-6-glucuronideCYP3A4UGT2B7MorphineMGC127055UGT1A1UGT2B7ABCC3MGC12705553119, 15, 17, 20, 228, 11


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.


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

Quality Tags

Ontology Terms



View all...
  1. Lötsch J, Skarke C, Liefhold J, Geisslinger G; ''Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives.''; Clin Pharmacokinet, 2004 PubMed Europe PMC Scholia
  2. Milne RW, Nation RL, Somogyi AA; ''The disposition of morphine and its 3- and 6-glucuronide metabolites in humans and animals, and the importance of the metabolites to the pharmacological effects of morphine.''; Drug Metab Rev, 1996 PubMed Europe PMC Scholia
  3. Caraco Y, Tateishi T, Guengerich FP, Wood AJ; ''Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity.''; Drug Metab Dispos, 1996 PubMed Europe PMC Scholia
  4. Yue QY, Hasselström J, Svensson JO, Säwe J; ''Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine.''; Br J Clin Pharmacol, 1991 PubMed Europe PMC Scholia
  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
  6. Pelletier M, Hinglais N, Bach JF; ''Characteristic immunohistochemical and ultrastructural glomerular lesions in Nude mice.''; Lab Invest, 1975 PubMed Europe PMC Scholia
  7. Madadi P, Koren G; ''Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use.''; Pharmacogenomics, 2008 PubMed Europe PMC Scholia
  8. Desmeules J, Gascon MP, Dayer P, Magistris M; ''Impact of environmental and genetic factors on codeine analgesia.''; Eur J Clin Pharmacol, 1991 PubMed Europe PMC Scholia
  9. Innocenti F, Liu W, Fackenthal D, Ramírez J, Chen P, Ye X, Wu X, Zhang W, Mirkov S, Das S, Cook E Jr, Ratain MJ; ''Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene.''; Pharmacogenet Genomics, 2008 PubMed Europe PMC Scholia
  10. Lötsch J, Stockmann A, Kobal G, Brune K, Waibel R, Schmidt N, Geisslinger G; ''Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers.''; Clin Pharmacol Ther, 1996 PubMed Europe PMC Scholia
  11. 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
  12. Bourasset F, Cisternino S, Temsamani J, Scherrmann JM; ''Evidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier.''; J Neurochem, 2003 PubMed Europe PMC Scholia
  13. Ohno S, Kawana K, Nakajin S; ''Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties.''; Drug Metab Dispos, 2008 PubMed Europe PMC Scholia
  14. Chen ZR, Somogyi AA, Reynolds G, Bochner F; ''Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.''; Br J Clin Pharmacol, 1991 PubMed Europe PMC Scholia
  15. Darbari DS, van Schaik RH, Capparelli EV, Rana S, McCarter R, van den Anker J; ''UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease.''; Am J Hematol, 2008 PubMed Europe PMC Scholia
  16. Holthe M, Klepstad P, Zahlsen K, Borchgrevink PC, Hagen L, Dale O, Kaasa S, Krokan HE, Skorpen F; ''Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy.''; Eur J Clin Pharmacol, 2002 PubMed Europe PMC Scholia
  17. Sawyer MB, Innocenti F, Das S, Cheng C, Ramírez J, Pantle-Fisher FH, Wright C, Badner J, Pei D, Boyett JM, Cook E Jr, Ratain MJ; ''A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine.''; Clin Pharmacol Ther, 2003 PubMed Europe PMC Scholia
  18. Madadi P, Ross CJ, Hayden MR, Carleton BC, Gaedigk A, Leeder JS, Koren G; ''Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study.''; Clin Pharmacol Ther, 2009 PubMed Europe PMC Scholia
  19. Coffman BL, Rios GR, King CD, Tephly TR; ''Human UGT2B7 catalyzes morphine glucuronidation.''; Drug Metab Dispos, 1997 PubMed Europe PMC Scholia
  20. 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
  21. Zelcer N, van de Wetering K, Hillebrand M, Sarton E, Kuil A, Wielinga PR, Tephly T, Dahan A, Beijnen JH, Borst P; ''Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception.''; Proc Natl Acad Sci U S A, 2005 PubMed Europe PMC Scholia
  22. Bhasker CR, McKinnon W, Stone A, Lo AC, Kubota T, Ishizaki T, Miners JO; ''Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance.''; Pharmacogenetics, 2000 PubMed Europe PMC Scholia
  23. 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
  24. Xie R, Hammarlund-Udenaes M, de Boer AG, de Lange EC; ''The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice.''; Br J Pharmacol, 1999 PubMed Europe PMC Scholia
  25. Meineke I, Freudenthaler S, Hofmann U, Schaeffeler E, Mikus G, Schwab M, Prange HW, Gleiter CH, Brockmöller J; ''Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine.''; Br J Clin Pharmacol, 2002 PubMed Europe PMC Scholia


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


View all...
NameTypeDatabase referenceComment
ABCB1GeneProductENSBTAG00000005997 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5243
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
Personal tools