Molecular Diagnosis & Therapy

, Volume 16, Issue 1, pp 43–53 | Cite as

Pharmacogenomics of Codeine, Morphine, and Morphine-6-Glucuronide

Model-Based Analysis of the Influence of CYP2D6 Activity, UGT2B7 Activity, Renal Impairment, and CYP3A4 Inhibition
Original Research Article


Background and Objective: The analgesic effect of codeine depends on the formation of the opioid metabolites morphine and morphine-6-glucuronide. Different factors have been shown or suspected to affect the safety and efficacy of codeine treatment. The objective of the current study is to assess and quantify the impact of important pharmacokinetic factors, using a mechanistic modeling approach.

Methods: By means of a generic modeling approach integrating prior physiologic knowledge, we systematically investigated the complex dependence of opioid exposure on cytochrome P450 2D6 and 3A4 (CYP2D6 and CYP3A4), and uridine diphosphate glucuronosyltransferase 2B7 (UGT2B7) activity, as well as renal function, by means of a virtual clinical trial.

Results: First, the known dominant role of CYP2D6 activity for morphine exposure was reproduced. Second, the model demonstrated that mild and moderate renal impairment and co-administration of CYP3A4 inhibitors have only minor influences on opioid exposure. Third, the model showed — in contrast to current opinion — that increased UGT2B7 activity is associated with a decrease in active opioid exposure.

Conclusion: Overall, the model-based analysis predicts a wide range of morphine levels after codeine administration and supports recent doubts about safe and efficacious use of codeine for analgesia in non-genotyped individuals.



The authors acknowledge financial support by the Virtual Liver Initiative ( <>), QuantPro Initiative ( <>), FORSYS-Partner Initiative ( <>), and Services@MediGrid Initiative ( <>), partly funded by the German Federal Ministry of Research and Education (BmBF).

T.E., J.L., and S.W. are employees of Bayer Technology Services GmbH, the company that owns and commercializes the software platform used for the simulations described in the manuscript (PK-Sim® and MoBi®), as well as parent company stock owners.


  1. 1.
    Madadi P, Koren G, Cairns J, et al. Safety of codeine during breastfeeding: fatal morphine poisoning in the breastfed neonate of a mother prescribed codeine. Can Fam Physician 2007 Jan; 53(1): 33–5PubMedGoogle Scholar
  2. 2.
    Koren G, Cairns J, Chitayat D, et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006 Aug 19; 368(9536): 704PubMedCrossRefGoogle Scholar
  3. 3.
    Magnani B, Evans R. Codeine intoxication in the neonate. Pediatrics 1999 Dec; 104(6): e75PubMedCrossRefGoogle Scholar
  4. 4.
    Ferreiros N, Dresen S, Hermanns-Clausen M, et al. Fatal and severe codeine intoxication in 3-year-old twins: interpretation of drug and metabolite concentrations. Int J Legal Med 2009 Sep; 123(5): 387–94PubMedCrossRefGoogle Scholar
  5. 5.
    Hermanns-Clausen M, Weinmann W, Auwarter V, et al. Drug dosing error with drops: severe clinical course of codeine intoxication in twins. Eur J Pediatr 2009 Jul; 168(7): 819–24PubMedCrossRefGoogle Scholar
  6. 6.
    Ciszkowski C, Madadi P, Phillips MS, et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med 2009 Aug 20; 361(8): 827–8PubMedCrossRefGoogle Scholar
  7. 7.
    Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant — an ultra-rapid metabolizer. Paediatr Anaesth 2007 Jul; 17(7): 684–7PubMedCrossRefGoogle Scholar
  8. 8.
    Lee AC, Chan R, So KT. A case of probable codeine poisoning in a young infant after the use of a proprietary cough and cold medicine. Hong Kong Med J 2004 Aug; 10(4): 285–7PubMedGoogle Scholar
  9. 9.
    Frei MY, Nielsen S, Dobbin MD, et al. Serious morbidity associated with misuse of over-the-counter codeine-ibuprofen analgesics: a series of 27 cases. Med J Aust 2010 Sep 6; 193(5): 294–6PubMedGoogle Scholar
  10. 10.
    Dalen P, Frengell C, Dahl ML, et al. Quick onset of severe abdominal pain after codeine in an ultrarapid metabolizer of debrisoquine. Ther Drug Monit 1997 Oct; 19(5): 543–4PubMedCrossRefGoogle Scholar
  11. 11.
    Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med 2004 Dec 30; 351(27): 2827–31PubMedCrossRefGoogle Scholar
  12. 12.
    Lötsch J, Rohrbacher M, Schmidt H, et al. Can extremely low or high morphine formation from codeine be predicted prior to therapy initiation? Pain 2009 Jul; 144(1–2): 119–24PubMedCrossRefGoogle Scholar
  13. 13.
    Desmeules J, Gascon MP, Dayer P, et al. Impact of environmental and genetic factors on codeine analgesia. Eur J Clin Pharmacol 1991; 41(1): 23–6PubMedCrossRefGoogle Scholar
  14. 14.
    Persson K, Sjöström S, Sigurdardottir I, et al. Patient-controlled analgesia (PC A) with codeine for postoperative pain relief in ten extensive metabolisers and one poor metaboliser of dextromethorphan. Br J Clin Pharmacol 1995; 39(2): 182–6PubMedCrossRefGoogle Scholar
  15. 15.
    Sindrup SH, Poulsen L, Brøsen K, et al. Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers? Pain 1993; 53(3): 335–9PubMedCrossRefGoogle Scholar
  16. 16.
    Sindrup SH, Brøsen K. The pharmacogenetics of codeine hypoalgesia. Pharmacogenetics 1995; 5(6): 335–46PubMedCrossRefGoogle Scholar
  17. 17.
    Eissing T, Kuepfer L, Becker C, et al. A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Front Physiol 2011; 2: 4PubMedCrossRefGoogle Scholar
  18. 18.
    Willmann S, Edginton AN, Coboeken K, et al. Risk to the breast-fed neonate from codeine treatment to the mother: a quantitative mechanistic modeling study. Clin Pharmacol Ther 2009 Dec; 86(6): 634–43PubMedCrossRefGoogle Scholar
  19. 19.
    Zanger UM, Fischer J, Raimundo S, et al. Comprehensive analysis of the genetic factors determining expression and function of hepatic CYP2D6. Pharmacogenetics 2001 Oct; 11(7): 573–85PubMedCrossRefGoogle Scholar
  20. 20.
    Court MH, Krishnaswamy S, Hao Q, et al. Evaluation of 3−azido-3′-deoxy-thymidine, 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 Sep; 31(9): 1125–33PubMedCrossRefGoogle Scholar
  21. 21.
    Raungrut P, Uchaipichat V, Elliot DJ, et al. In vitro-in vivo extrapolation predicts drug-drug interactions arising from inhibition of codeine glucuronidation by dextropropoxyphene, fluconazole, ketoconazole and methadone in humans. J Pharmacol Exp Ther 2010 May 18; 334(2): 609–18PubMedCrossRefGoogle Scholar
  22. 22.
    Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J 2007 Aug; 7(4): 257–65PubMedCrossRefGoogle Scholar
  23. 23.
    Yue QY, Alm C, Svensson JO, et al. Quantification of the O- and N-demethylated and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid, and poor debrisoquine hydroxylators. Ther Drug Monit 1997 Oct; 19(5): 539–42PubMedCrossRefGoogle Scholar
  24. 24.
    Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996 Sep; 278(3): 1165–74PubMedGoogle Scholar
  25. 25.
    Kenworthy KE, Bloomer JC, Clarke SE, et al. CYP3A4 drug interactions: correlation of 10 in vitro probe substrates. Br J Clin Pharmacol 1999 Nov; 48(5): 716–27PubMedCrossRefGoogle Scholar
  26. 26.
    Willmann S, Hohn K, Edginton A, et al. Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. J Pharmacokinet Pharmacodyn 2007 Jun; 34(3): 401–31PubMedCrossRefGoogle Scholar
  27. 27.
    Valentin J. Basic anatomical and physiological data for use in radiological protection: reference values. Annals of the ICRP 2002; 32(3): 1–277CrossRefGoogle Scholar
  28. 28.
    Paris P, Yealy D. Pain management. In: Marx JA, editor. Rosen’s emergency medicine: concepts and clinical practice. St Louis (MO): Mosby, 2002: 2555–77Google Scholar
  29. 29.
    Zimmer G. Acute pain management. In: Tintinalli J, Kelen G, Stapczynski J, editors. Emergency medicine: a comprehensive study guide. New York: McGraw-Hill, 2004: 257–64Google Scholar
  30. 30.
    Osborne R, Thompson P, Joel S, et al. The analgesic activity of morphine-6-glucuronide. Br J Clin Pharmacol 1992 Aug; 34(2): 130–8PubMedCrossRefGoogle Scholar
  31. 31.
    Smith TW, Binning AR, Dahan A. Efficacy and safety of morphine-6-glucuronide (M6G) for postoperative pain relief: a randomized, double-blind study. Eur J Pain 2009 Mar; 13(3): 293–9PubMedCrossRefGoogle Scholar
  32. 32.
    Vossen M, Sevestre M, Niederalt C, et al. Dynamically simulating the interaction of midazolam and the CYP3A4 inhibitor itraconazole using individual coupled whole-body physiologically-based pharmacokinetic (WB-PBPK) models. Theor Biol Med Model 2007; 4: 13PubMedCrossRefGoogle Scholar
  33. 33.
    Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determinants of codeine induction by rifampin: the impact on codeine’s respiratory, psychomotor and miotic effects. J Pharmacol Exp Ther 1997 Apr; 281(1): 330–6PubMedGoogle Scholar
  34. 34.
    Vevelstad M, Pettersen S, Tallaksen C, et al. O-demethylation of codeine to morphine inhibited by low-dose levomepromazine. Eur J Clin Pharmacol 2009 Aug; 65(8): 795–801PubMedCrossRefGoogle Scholar
  35. 35.
    Aitkenhead AR, Vater M, Achola K, et al. Pharmacokinetics of single-dose i.v. morphine in normal volunteers and patients with end-stage renal failure. Br J Anaesth 1984 Aug; 56(8): 813–9PubMedCrossRefGoogle Scholar
  36. 36.
    Sawe J, Svensson JO, Odar-Cederlof I. Kinetics of morphine in patients with renal failure. Lancet 1985 Jul 27; 2(8448): 211PubMedCrossRefGoogle Scholar
  37. 37.
    Woolner DF, Winter D, Frendin TJ, et al. Renal failure does not impair the metabolism of morphine. Br J Clin Pharmacol 1986 Jul; 22(1): 55–9PubMedCrossRefGoogle Scholar
  38. 38.
    Hanna MH, D’Costa F, Peat SJ, et al. Morphine-6-glucuronide disposition in renal impairment. Br J Anaesth 1993 May; 70(5): 511–4PubMedCrossRefGoogle Scholar
  39. 39.
    Court MH. Interindividual variability in hepatic drug glucuronidation: studies into the role of age, sex, enzyme inducers, and genetic polymorphism using the human liver bank as a model system. Drug Metab Rev 2010 Feb; 42(1): 209–24PubMedCrossRefGoogle Scholar
  40. 40.
    Kwara A, Lartey M, Boamah I, et al. Interindividual variability in pharmacokinetics of generic nucleoside reverse transcriptase inhibitors in TB/HIV-coinfected Ghanaian patients: UGT2B7*1c is associated with faster zidovudine clearance and glucuronidation. J Clin Pharmacol 2009 Sep; 49(9): 1079–90PubMedCrossRefGoogle Scholar
  41. 41.
    Holthe M, Rakvag TN, Klepstad P, et al. Sequence variations in the UDP-glucuronosyltransferase 2B7 (UGT2B7) gene: identification of 10 novel single nucleotide polymorphisms (SNPs) and analysis of their relevance to morphine glucuronidation in cancer patients. Pharmacogenomics J 2003; 3(1): 17–26PubMedCrossRefGoogle Scholar
  42. 42.
    Madadi P, Ross CJ, Hayden MR, et al. Pharmacogenetics of neonatal opioid toxicity following maternal use of codeine during breastfeeding: a casecontrol study. Clin Pharmacol Ther 2009 Jan; 85(1): 31–5PubMedCrossRefGoogle Scholar
  43. 43.
    Sawyer MB, Innocenti F, Das S, et al. A pharmacogenetic study of uridine diphosphate-glucuronosyltransferase 2B7 in patients receiving morphine. Clin Pharmacol Ther 2003 Jun; 73(6): 566–74PubMedCrossRefGoogle Scholar
  44. 44.
    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 Apr; 36(4): 688–94PubMedCrossRefGoogle Scholar
  45. 45.
    Nagano E, Yamada H, Oguri K. Characteristic glucuronidation pattern of physiologic concentration of morphine in rat brain. Life Sci 2000 Oct 6; 67(20): 2453–64PubMedCrossRefGoogle Scholar
  46. 46.
    Madadi P, Koren G. Pharmacogenetic insights into codeine analgesia: implications to pediatric codeine use. Pharmacogenomics 2008 Sep; 9(9): 1267–84PubMedCrossRefGoogle Scholar
  47. 47.
    Quiding H, Anderson P, Bondesson U, et al. Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration. Eur J Clin Pharmacol 1986; 30(6): 673–7PubMedCrossRefGoogle Scholar
  48. 48.
    Lötsch J, Skarke C, Liefhold J, et al. Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet 2004; 43(14): 983–1013PubMedCrossRefGoogle Scholar
  49. 49.
    Poulsen L, Brøsen K, Arendt-Nielsen L, et al. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 1996; 51(3–4): 289–95PubMedCrossRefGoogle Scholar
  50. 50.
    Sistonen J, Sajantila A, Lao O, et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics 2007 Feb; 17(2): 93–101PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2012

Authors and Affiliations

  • Thomas Eissing
    • 1
  • Jörg Lippert
    • 1
  • Stefan Willmann
    • 1
  1. 1.Competence Center Systems Biology and Computational SolutionsBayer Technology Services GmbHLeverkusenGermany

Personalised recommendations