Codeine and morphine metabolism (WP3270)

Bos taurus

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].


Martina Summer-Kutmon and Eric Weitz


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Bos taurus



Pathway Ontology

drug pathway xenobiotics biodegradation pathway codeine and morphine drug pathway


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


  1. Impact of environmental and genetic factors on codeine analgesia. Desmeules J, Gascon MP, Dayer P, Magistris M. Eur J Clin Pharmacol. 1991;41(1):23–6. PubMed Europe PMC Scholia
  2. Pharmacokinetics of codeine and its metabolites in Caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine. Yue QY, Hasselström J, Svensson JO, Säwe J. Br J Clin Pharmacol. 1991 Jun;31(6):635–42. PubMed Europe PMC Scholia
  3. Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers. Chen ZR, Somogyi AA, Reynolds G, Bochner F. Br J Clin Pharmacol. 1991 Apr;31(4):381–90. PubMed Europe PMC Scholia
  4. Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity. Caraco Y, Tateishi T, Guengerich FP, Wood AJ. Drug Metab Dispos. 1996 Jul;24(7):761–4. PubMed Europe PMC Scholia
  5. Pharmacokinetics of morphine and its glucuronides after intravenous infusion of morphine and morphine-6-glucuronide in healthy volunteers. Lötsch J, Stockmann A, Kobal G, Brune K, Waibel R, Schmidt N, et al. Clin Pharmacol Ther. 1996 Sep;60(3):316–25. PubMed Europe PMC Scholia
  6. 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. Milne RW, Nation RL, Somogyi AA. Drug Metab Rev. 1996 Aug;28(3):345–472. PubMed Europe PMC Scholia
  7. Human UGT2B7 catalyzes morphine glucuronidation. Coffman BL, Rios GR, King CD, Tephly TR. Drug Metab Dispos. 1997 Jan;25(1):1–4. PubMed Europe PMC Scholia
  8. The role of P-glycoprotein in blood-brain barrier transport of morphine: transcortical microdialysis studies in mdr1a (-/-) and mdr1a (+/+) mice. Xie R, Hammarlund-Udenaes M, de Boer AG, de Lange EC. Br J Pharmacol. 1999 Oct;128(3):563–8. PubMed Europe PMC Scholia
  9. Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance. Bhasker CR, McKinnon W, Stone A, Lo AC, Kubota T, Ishizaki T, et al. Pharmacogenetics. 2000 Nov;10(8):679–85. PubMed Europe PMC Scholia
  10. Morphine glucuronide-to-morphine plasma ratios are unaffected by the UGT2B7 H268Y and UGT1A1*28 polymorphisms in cancer patients on chronic morphine therapy. Holthe M, Klepstad P, Zahlsen K, Borchgrevink PC, Hagen L, Dale O, et al. Eur J Clin Pharmacol. 2002 Aug;58(5):353–6. PubMed Europe PMC Scholia
  11. 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. Meineke I, Freudenthaler S, Hofmann U, Schaeffeler E, Mikus G, Schwab M, et al. Br J Clin Pharmacol. 2002 Dec;54(6):592–603. PubMed Europe PMC Scholia
  12. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Sawyer MB, Innocenti F, Das S, Cheng C, Ramírez J, Pantle-Fisher FH, et al. Clin Pharmacol Ther. 2003 Jun;73(6):566–74. PubMed Europe PMC Scholia
  13. 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. Court MH, Krishnaswamy S, Hao Q, Duan SX, Patten CJ, Von Moltke LL, et al. Drug Metab Dispos. 2003 Sep;31(9):1125–33. PubMed Europe PMC Scholia
  14. Evidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier. Bourasset F, Cisternino S, Temsamani J, Scherrmann JM. J Neurochem. 2003 Sep;86(6):1564–7. PubMed Europe PMC Scholia
  15. A frameshift mutation and alternate splicing in human brain generate a functional form of the pseudogene cytochrome P4502D7 that demethylates codeine to morphine. Pai HV, Kommaddi RP, Chinta SJ, Mori T, Boyd MR, Ravindranath V. J Biol Chem. 2004 Jun 25;279(26):27383–9. PubMed Europe PMC Scholia
  16. Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Lötsch J, Skarke C, Liefhold J, Geisslinger G. Clin Pharmacokinet. 2004;43(14):983–1013. PubMed Europe PMC Scholia
  17. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. Gasche Y, Daali Y, Fathi M, Chiappe A, Cottini S, Dayer P, et al. N Engl J Med. 2004 Dec 30;351(27):2827–31. PubMed Europe PMC Scholia
  18. Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Zelcer N, van de Wetering K, Hillebrand M, Sarton E, Kuil A, Wielinga PR, et al. Proc Natl Acad Sci U S A. 2005 May 17;102(20):7274–9. PubMed Europe PMC Scholia
  19. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Lancet. 2006 Aug 19;368(9536):704. PubMed Europe PMC Scholia
  20. UGT2B7 promoter variant -840G>A contributes to the variability in hepatic clearance of morphine in patients with sickle cell disease. Darbari DS, van Schaik RHN, Capparelli EV, Rana S, McCarter R, van den Anker J. Am J Hematol. 2008 Mar;83(3):200–2. PubMed Europe PMC Scholia
  21. Contribution of UDP-glucuronosyltransferase 1A1 and 1A8 to morphine-6-glucuronidation and its kinetic properties. Ohno S, Kawana K, Nakajin S. Drug Metab Dispos. 2008 Apr;36(4):688–94. PubMed Europe PMC Scholia
  22. Single nucleotide polymorphism discovery and functional assessment of variation in the UDP-glucuronosyltransferase 2B7 gene. Innocenti F, Liu W, Fackenthal D, Ramírez J, Chen P, Ye X, et al. Pharmacogenet Genomics. 2008 Aug;18(8):683–97. PubMed Europe PMC Scholia
  23. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a case-control study. Madadi P, Ross CJD, Hayden MR, Carleton BC, Gaedigk A, Leeder JS, et al. Clin Pharmacol Ther. 2009 Jan;85(1):31–5. PubMed Europe PMC Scholia
  24. Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Madadi P, Koren G. Pharmacogenomics. 2008 Sep;9(9):1267–84. PubMed Europe PMC Scholia