Codeine and morphine metabolism (Homo sapiens)

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7, 8, 14, 21, 235, 10, 15, 19, 2421, 2532211, 17, 20Liver cellElimination via bileUGT2B7NormorphineUGT1A1Codeine-6-glucuronideUGT1A1ABCB1CodeineMorphineUGT2B7Morphine-6-glucuronideCYP2D6ABCC2ABCC3Morphine-3-glucuronideCYP3A4NorcodeineSLCO1B1UGT2B7Codeine-6-glucuronideCYP2D7P1Morphine-6-glucuronideMorphine-3-glucuronide9, 13131, 2, 4, 12, 16718


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.

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Bibliography

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  1. Loetsch 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
  2. Maurer HH, Sauer C, Theobald DS; ''Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine.''; Ther Drug Monit, 2006 PubMed Europe PMC Scholia
  3. 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
  4. Coffman BL, Rios GR, King CD, Tephly TR; ''Human UGT2B7 catalyzes morphine glucuronidation.''; Drug Metab Dispos, 1997 PubMed Europe PMC Scholia
  5. Sawyer MB, Innocenti F, Das S, Cheng C, Ramirez 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
  6. Meineke I, Freudenthaler S, Hofmann U, Schaeffeler E, Mikus G, Schwab M, Prange HW, Gleiter CH, Brockmoeller 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
  7. Yue QY, Hasselstroem J, Svensson JO, Saewe 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
  8. 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
  9. 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
  10. 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
  11. Madadi P, Koren G; ''Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use.''; Pharmacogenomics, 2008 PubMed Europe PMC Scholia
  12. 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
  13. 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
  14. 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
  15. 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
  16. Innocenti F, Liu W, Fackenthal D, Ramirez 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
  17. 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
  18. Skarke C, Schmidt H, Geisslinger G, Darimont J, Loetsch J; ''Pharmacokinetics of morphine are not altered in subjects with Gilbert's syndrome.''; Br J Clin Pharmacol, 2003 PubMed Europe PMC Scholia
  19. 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
  20. 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
  21. 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
  22. 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
  23. 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
  24. 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
  25. 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
  26. Loetsch 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

History

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CompareRevisionActionTimeUserComment
128156view16:57, 28 January 2024EweitzEconomize layout
128155view16:54, 28 January 2024EweitzImprove alignment, economize layout
128154view16:48, 28 January 2024EweitzStandardize shapes
128153view16:45, 28 January 2024EweitzOntology Term : 'hepatocyte' added !
125609view10:33, 4 March 2023EgonwMinor updates to modern drawing standards.
118374view13:50, 27 May 2021Mkutmonfix references
116814view10:12, 14 May 2021EweitzModified title
110711view14:49, 28 May 2020Fehrhartchanged node to label for Gilbert syndrome
106699view13:09, 17 September 2019MaintBotHMDB identifier normalization
98130view08:58, 25 July 2018DeSlAdded stereochemically correct ID for Norcodeine; changed layout slightly due to overlapping references on nodes.
98129view07:56, 25 July 2018DeSlOntology Term : 'Gilbert syndrome' added !
95222view18:21, 26 November 2017DeSlRemoved licence number
95221view18:19, 26 November 2017DeSlConnected unconnected line.
95202view14:47, 22 November 2017DeSlModified description
95201view14:37, 22 November 2017DeSlModified description
95200view14:34, 22 November 2017DeSlAdded OMIM IDs for diseases
95199view14:34, 22 November 2017DeSlModified description
95198view14:32, 22 November 2017DeSlAdded additional enzym information from new literature source.
89511view10:44, 16 September 2016Mkutmonontology tag fix
89468view13:39, 15 September 2016Mkutmonremove space from ontology term id
74317view13:50, 12 April 2014EgonwFixed a character encoding issue.
69899view19:27, 11 July 2013AlexanderPicoCleaned up interactions
69895view19:18, 11 July 2013AlexanderPicoModified title
67120view10:09, 26 June 2013Christine ChichesterOntology Term : 'codeine and morphine drug pathway' added !
63436view15:40, 10 May 2013EgonwAdded other missing metabolite identifiers (from HMDB and PubChem)
63435view15:08, 10 May 2013EgonwAdded a HMDB id for morphine.
63165view20:24, 8 May 2013MaintBotUpdating gpml version
59205view19:45, 22 February 2013MaintBotUpdated Ensembl data source
44994view14:37, 6 October 2011MartijnVanIerselOntology Term : 'xenobiotics biodegradation pathway' added !
44993view14:37, 6 October 2011MartijnVanIerselOntology Term : 'drug pathway' added !
41197view23:43, 1 March 2011MaintBotRemoved redundant pathway information and comments
38483view18:24, 17 September 2010AlexanderPicoModified description
38351view22:51, 1 September 2010KhanspersModified categories
38350view22:51, 1 September 2010KhanspersChanged literature references
38349view22:47, 1 September 2010KhanspersModified description
38348view22:39, 1 September 2010KhanspersNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ABCB1GeneProduct5243 (Entrez Gene)
ABCC2GeneProduct1244 (Entrez Gene)
ABCC3GeneProduct8714 (Entrez Gene)
CYP2D6GeneProduct1565 (Entrez Gene)
CYP2D7P1GeneProductENSG00000205702 (Ensembl)
CYP3A4GeneProduct1576 (Entrez Gene)
Codeine-6-glucuronideMetabolite5489029 (PubChem-compound)
CodeineMetaboliteHMDB04995 (HMDB)
Morphine-3-glucuronideMetaboliteHMDB41936 (HMDB)
Morphine-6-glucuronideMetabolite5360621 (PubChem-compound)
MorphineMetaboliteHMDB14440 (HMDB)
NorcodeineMetabolite5359402 (PubChem-compound)
NormorphineMetaboliteHMDB41959 (HMDB)
SLCO1B1GeneProduct10599 (Entrez Gene)
UGT1A1GeneProduct54658 (Entrez Gene)
UGT2B7GeneProduct7364 (Entrez Gene)

Annotated Interactions

No annotated interactions

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