Molecular Diagnosis & Therapy

, Volume 12, Issue 2, pp 109–124 | Cite as

Interindividual Variability of Methadone Response

Impact of Genetic Polymorphism
  • Yongfang Li
  • Jean-Pierre Kantelip
  • Pauline Gerritsen-van Schieveen
  • Siamak DavaniEmail author


Methadone, an opioid analgesic, is used clinically in pain therapy as well as for substitution therapy in opioid addiction. It has a large interindividual variability in response and a narrow therapeutic index. Genetic polymorphisms in genes coding for methadone-metabolizing enzymes, transporter proteins (p-glycoprotein; P-gp), and μ-opioid receptors may explain part of the observed interindividual variation in the pharmacokinetics and pharmacodynamics of methadone. Cytochrome P450 (CYP) 3A4 and 2B6 have been identified as the main CYP isoforms involved in methadone metabolism. Methadone is a P-gp substrate, and, although there are inconsistent reports, ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics and influence dose requirements. Genetic polymorphism is the cause of high interindividual variability of methadone blood concentrations for a given dose; for example, in order to obtain methadone plasma concentrations of 250 ng/mL, doses of racemic methadone as low as 55 mg/day or as high as 921 mg/day can be required in a 70-kg patient without any co-medication.

The clinician must be aware of the pharmacokinetic properties and pharmacological interactions of methadone in order to personalize methadone administration. In the future, pharmacogenetics, at a limited level, can also be expected to facilitate individualized methadone therapy.


Interindividual Variability Methadone Maintenance Treatment Opioid Dependence Dezocine Large Interindividual Variability 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Bertschy G. Methadone maintenance treatment: an update. Eur Arch Psychiatry Clin Neurosci 1995; 245(2): 114–24PubMedCrossRefGoogle Scholar
  2. 2.
    Farrell M, Ward J, Mattick R, et al. Methadone maintenance treatment in opiate dependence: a review. BMJ 1994 Oct 15; 309(6960): 997–1001PubMedCrossRefGoogle Scholar
  3. 3.
    Connor PD, Sampson PD, Bookstein FL, et al. Direct and indirect effects of prenatal alcohol damage on executive function. Dev Neuropsychol 2000; 18(3): 331–54PubMedCrossRefGoogle Scholar
  4. 4.
    Conversation with Vincent Dole. Addiction 1994; 89 (1): 23–9Google Scholar
  5. 5.
    Olsen GD. Methadone binding to human plasma proteins. Clin Pharmacol Ther 1973 May–Jun; 14(3): 338–43PubMedGoogle Scholar
  6. 6.
    Austrialian Government, National Drug Strategy. Clinical guidelines and procedures for the use of methadone in the maintenance treatment of opioid dependence [online]. Available from URL: [Accessed 2008 Mar 25]
  7. 7.
    Gourlay GK, Cherry DA, Cousins MJ. A comparative study of the efficacy and pharmacokinetics of oral methadone and morphine in the treatment of severe pain in patients with cancer. Pain 1986 Jun; 25(3): 297–312PubMedCrossRefGoogle Scholar
  8. 8.
    Manfredi PL, Borsook D, Chandler SW, et al. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain 1997 Mar; 70(1): 99–101PubMedCrossRefGoogle Scholar
  9. 9.
    Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone for cancer pain. Pain 1997 Apr; 70(2–3): 109–15PubMedCrossRefGoogle Scholar
  10. 10.
    Bruera E, Pereira J, Watanabe S, et al. Opioid rotation in patients with cancer pain: a retrospective comparison of dose ratios between methadone, hydromorphone, and morphine. Cancer 1996 Aug 15; 78(4): 852–7PubMedCrossRefGoogle Scholar
  11. 11.
    Mitchell TB, Dyer KR, Newcombe D, et al. Subjective and physiological responses among racemic-methadone maintenance patients in relation to relative (S)-vs. (R)-methadone exposure. Br J Clin Pharmacol 2004; 58(6): 609–17PubMedCrossRefGoogle Scholar
  12. 12.
    Eap CB, Buclin T, Baumann P. Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence. Clin Pharmacokinet 2002; 41(14): 1153–93PubMedCrossRefGoogle Scholar
  13. 13.
    Garrido MJ, Troconiz IF. Methadone: a review of its pharmacokinetic/pharmacodynamic properties. J Pharmacol Toxicol Methods 1999 Oct; 42(2): 61–6PubMedCrossRefGoogle Scholar
  14. 14.
    Inturrisi CE, Verebely K. Disposition of methadone in man after a single oral dose. Clin Pharmacol Ther 1972 Nov–Dec; 13(6): 923–30PubMedGoogle Scholar
  15. 15.
    Oda Y, Kharasch ED. Metabolism of methadone and levo-alpha-acetylmethadol (LAAM) by human intestinal cytochrome P450 3A4 (CYP3A4): potential contribution of intestinal metabolism to presystemic clearance and bioactivation. J Pharmacol Exp Ther 2001 Sep 1; 298(3): 1021–32PubMedGoogle Scholar
  16. 16.
    Inturrisi CE. Clinical pharmacology of opioids for pain. Clin J Pain 2002 Jul–Aug; 18(4 Suppl.): S3–13PubMedCrossRefGoogle Scholar
  17. 17.
    Meresaar U, Nilsson MI, Holmstrand J, et al. Single dose pharmacokinetics and bioavailability of methadone in man studied with a stable isotope method. Eur J Clin Pharmacol 1981; 20(6): 473–8PubMedCrossRefGoogle Scholar
  18. 18.
    Boulton DW, Arnaud P, DeVane CL. Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate. Clin Pharmacol Ther 2001 Jul; 70(1): 48–57PubMedCrossRefGoogle Scholar
  19. 19.
    Nilsson MI, Anggard E, Holmstrand J, et al. Pharmacokinetics of methadone during maintenance treatment: adaptive changes during the induction phase. Eur J Clin Pharmacol 1982; 22(4): 343–9PubMedCrossRefGoogle Scholar
  20. 20.
    Moody DE, Alburges ME, Parker RJ, et al. The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norLAAM, and methadone. Drug Metab Dispos 1997 Dec; 25(12): 1347–53PubMedGoogle Scholar
  21. 21.
    Vaupel DB, Jasinski DR. l-Alpha-acetylmethadol, l-alpha-acetyl-N-normethadol and l-alpha-acetyl-N,N-dinormethadol: comparisons with morphine and metha-done in suppression of the opioid withdrawal syndrome in the dog. J Pharmacol Exp Ther 1997 Nov 1; 283(2): 833–42PubMedGoogle Scholar
  22. 22.
    Anggard E, Gunne LM, Homstrand J, et al. Disposition of methadone in methadone maintenance. Clin Pharmacol Ther 1975 Mar; 17(3): 258–66PubMedGoogle Scholar
  23. 23.
    Kreek MJ, Bencsath FA, Field FH. Effects of liver disease on urinary excretion of methadone and metabolites in maintenance patients: quantitation by direct probe chemical ionization mass spectrometry. Biomed Mass Spectrom 1980 Sep; 7(9): 385–95PubMedCrossRefGoogle Scholar
  24. 24.
    Kreek MJ, Bencsath FA, Fanizza A, et al. Effects of liver disease on fecal excretion of methadone and its unconjugated metabolites in maintenance patients: quantitation by direct probe chemical ionization mass spectrometry. Biomed Mass Spectrom 1983 Oct; 10(10): 544–9PubMedCrossRefGoogle Scholar
  25. 25.
    Furlan V, Hafi A, Dessalles M, et al. Methadone is poorly removed by haemodialysis. Nephrol Dial Transplant 1999 Jan 1; 14(1): 254–5PubMedCrossRefGoogle Scholar
  26. 26.
    Reisine T, Law SF, Blake A, et al. Molecular mechanisms of opiate receptor coupling to G proteins and effector systems. Ann N Y Acad Sci 1996 Mar 22; 780: 168–75PubMedCrossRefGoogle Scholar
  27. 27.
    Ehret GB, Voide C, Gex-Fabry M, et al. Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med 2006 Jun 26; 166(12): 1280–7PubMedCrossRefGoogle Scholar
  28. 28.
    Iskandar SB, Abi-Saleh BS, Mechleb BK, et al. Methadone and torsade de pointes: case report and review of the literature. Tenn Med 2007 Feb; 100(2): 35–7, 42PubMedGoogle Scholar
  29. 29.
    Nilsson MI, Meresaar U, Anggard E. Clinical pharmacokinetics of methadone. Acta Anaesthesiol Scand Suppl 1982; 74: 66–9PubMedCrossRefGoogle Scholar
  30. 30.
    Rebbeck TR, Jaffe JM, Walker AH, et al. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1998 Aug 19; 90(16): 1225–9PubMedCrossRefGoogle Scholar
  31. 31.
    Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality 2004 Jan; 16(1): 36–44PubMedCrossRefGoogle Scholar
  32. 32.
    Wang JS, DeVane CL. Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos 2003 Jun; 31(6): 742–7PubMedCrossRefGoogle Scholar
  33. 33.
    Begre S, von Bardeleben U, Ladewig D, et al. Paroxetine increases steady-state concentrations of (R)-methadone in CYP2D6 extensive but not poor metabolizers. J Clin Psychopharmacol 2002 Apr; 22(2): 211–5PubMedCrossRefGoogle Scholar
  34. 34.
    Eap CB, Broly F, Mino A, et al. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol 2001 Apr; 21(2): 229–34PubMedCrossRefGoogle Scholar
  35. 35.
    Crettol S, Deglon JJ, Besson J, et al. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther 2005 Dec; 78(6): 593–604PubMedCrossRefGoogle Scholar
  36. 36.
    Foster DJ, Somogyi AA, Bochner F. Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol 1999 Apr; 47(4): 403–12PubMedCrossRefGoogle Scholar
  37. 37.
    Iribarne C, Berthou F, Baird S, et al. Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol 1996; 9(2): 365–73PubMedCrossRefGoogle Scholar
  38. 38.
    Shinderman M, Maxwell S, Brawand-Amey M, et al. Cytochrome P4503A4 metabolic activity, methadone blood concentrations, and methadone doses. Drug Alcohol Depend 2003 Mar 1; 69(2): 205–11PubMedCrossRefGoogle Scholar
  39. 39.
    Kharasch ED, Hoffer C, Whittington D, et al. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther 2004 Sep; 76(3): 250–69PubMedCrossRefGoogle Scholar
  40. 40.
    Shimada T, Yamazaki H, Mimura M, et al. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994 Jul; 270(1): 414–23PubMedGoogle Scholar
  41. 41.
    Westlind A, Lofberg L, Tindberg N, et al. Interindividual differences in hepatic expression of CYP3A4: relationship to genetic polymorphism in the 5t?-up-stream regulatory region. Biochem Biophys Res Commun 1999 May 27; 259(1): 201–5PubMedCrossRefGoogle Scholar
  42. 42.
    Wojnowski L. Genetics of the variable expression of CYP3A in humans. Ther Drug Monit 2004 Apr; 26(2): 192–9PubMedCrossRefGoogle Scholar
  43. 43.
    Eiselt R, Domanski TL, Zibat A, et al. Identification and functional characterization of eight CYP3A4 protein variants. Pharmacogenetics 2001 Jul; 11(5): 447–58PubMedCrossRefGoogle Scholar
  44. 44.
    van Schaik RH. Cancer treatment and pharmacogenetics of cytochrome P450 enzymes. Invest New Drugs 2005 Dec; 23(6): 513–22PubMedCrossRefGoogle Scholar
  45. 45.
    Tayeb MT, Clark C, Sharp L, et al. CYP3A4 promoter variant is associated with prostate cancer risk in men with benign prostate hyperplasia. Oncol Rep 2002 May–Jun; 9(3): 653–5PubMedGoogle Scholar
  46. 46.
    Lamba JK, Lin YS, Thummel K, et al. Common allelic variants of cytochrome P4503A4 and their prevalence in different populations. Pharmacogenetics 2002 Mar; 12(2): 121–32PubMedCrossRefGoogle Scholar
  47. 47.
    Walker AH, Jaffe JM, Gunasegaram S, et al. Characterization of an allelic variant in the nifedipine-specific element of CYP3A4: ethnic distribution and implications for prostate cancer risk. Mutations in brief no. 191. Hum Mutat 1998; 12(4): 289PubMedGoogle Scholar
  48. 48.
    Amirimani B, Walker AH, Weber BL, et al. Response RE: modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1999 Sep 15; 91(18): 1588–90PubMedCrossRefGoogle Scholar
  49. 49.
    Spurdle AB, Goodwin B, Hodgson E, et al. The CYP3A4*1B polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer. Pharmacogenetics 2002 Jul; 12(5): 355–66PubMedCrossRefGoogle Scholar
  50. 50.
    Crettol S, Deglon JJ, Besson J, et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006 Dec; 80(6): 668–81PubMedCrossRefGoogle Scholar
  51. 51.
    Sata F, Sapone A, Elizondo G, et al. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: evidence for an allelic variant with altered catalytic activity. Clin Pharmacol Ther 2000 Jan; 67(1): 48–56PubMedCrossRefGoogle Scholar
  52. 52.
    Dai D, Tang J, Rose R, et al. Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos. J Pharmacol Exp Ther 2001 Dec; 299(3): 825–31PubMedGoogle Scholar
  53. 53.
    Hsieh KP, Lin YY, Cheng CL, et al. Novel mutations of CYP3 A4 in Chinese. Drug Metab Dispos 2001 Mar; 29(3): 268–73PubMedGoogle Scholar
  54. 54.
    Kharasch ED, Hoffer C, Whittington D. The effect of quinidine, used as a probe for the involvement of P-glycoprotein, on the intestinal absorption and pharmaco-dynamics of methadone. Br J Clin Pharmacol 2004 May; 57(5): 600–10PubMedCrossRefGoogle Scholar
  55. 55.
    Totah RA, Allen KE, Sheffels P, et al. Enantiomeric metabolic interactions and stereoselective human methadone metabolism. J Pharmacol Exp Ther 2007 Apr 1; 321(1): 389–99PubMedCrossRefGoogle Scholar
  56. 56.
    Lang T, Klein K, Fischer J, et al. Extensive genetic polymorphism in the human CYP2B6 gene with impact on expression and function in human liver. Pharmacogenetics 2001 Jul; 11(5): 399–415PubMedCrossRefGoogle Scholar
  57. 57.
    Ariyoshi N, Sawamura Y, Kamataki T. A novel single nucleotide polymorphism altering stability and activity of CYP2a6. Biochem Biophys Res Commun 2001 Mar 2; 281(3): 810–4PubMedCrossRefGoogle Scholar
  58. 58.
    Jinno H, Tanaka-Kagawa T, Ohno A, et al. Functional characterization of cytochrome P450 2B6 allelic variants. Drug Metab Dispos 2003 Apr; 31(4): 398–403PubMedCrossRefGoogle Scholar
  59. 59.
    Lamba V, Lamba J, Yasuda K, et al. Hepatic CYP2B6 expression: gender and ethnic differences and relationship to CYP2B6 genotype and CAR (constitutive androstane receptor) expression. J Pharmacol Exp Ther 2003 Dec; 307(3): 906–22PubMedCrossRefGoogle Scholar
  60. 60.
    Xie HJ, Yasar U, Lundgren S, et al. Role of polymorphic human CYP2B6 in cyclophosphamide bioactivation. Pharmacogenomics J 2003; 3(1): 53–61PubMedCrossRefGoogle Scholar
  61. 61.
    Hiratsuka M, Takekuma Y, Endo N, et al. Allele and genotype frequencies of CYP2B6 and CYP3A5 in the Japanese population. Eur J Clin Pharmacol 2002 Sep; 58(6): 417–21PubMedCrossRefGoogle Scholar
  62. 62.
    Tsuchiya K, Gatanaga H, Tachikawa N, et al. Homozygous CYP2B6 *6 (Q172H and K262R) correlates with high plasma efavirenz concentrations in HIV-1 patients treated with standard efavirenz-containing regimens. Biochem Biophys Res Commun 2004 Jul 9; 319(4): 1322–6PubMedCrossRefGoogle Scholar
  63. 63.
    Kirchheiner J, Klein C, Meineke I, et al. Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics 2003 Oct; 13(10): 619–26PubMedCrossRefGoogle Scholar
  64. 64.
    Eap CB, Crettol S, Rougier JS, et al. Stereoselective block of hERG channel by (S)- methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clin Pharmacol Ther 2007 May; 81(5): 719–28PubMedCrossRefGoogle Scholar
  65. 65.
    Eap CB, Bertschy G, Powell K, et al. Fluvoxamine and fluoxetine do not interact in the same way with the metabolism of the enantiomers of methadone. J Clin Psychopharmacol 1997 Apr; 17(2): 113–7PubMedCrossRefGoogle Scholar
  66. 66.
    Sim SC, Ingelman-Sundberg M. The human cytochrome P450 allele nomenclature committee website: submission criteria, procedures, and objectives. Methods Mol Biol 2006; 320: 183–91PubMedGoogle Scholar
  67. 67.
    Somogyi AA, Barratt DT, Coller JK. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007 Mar; 81(3): 429–44PubMedCrossRefGoogle Scholar
  68. 68.
    Nakamura K, Goto F, Ray WA, et al. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985 Oct; 38(4): 402–8PubMedCrossRefGoogle Scholar
  69. 69.
    Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics 2002 Mar; 3(2): 229–43PubMedCrossRefGoogle Scholar
  70. 70.
    Lotsch J, Skarke C, Wieting J, et al. Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action. Clin Pharmacol Ther 2006 Jan; 79(1): 72–89PubMedCrossRefGoogle Scholar
  71. 71.
    Perez de Los Cobos J, Sinol N, Trujols J, et al. Association of CYP2D6 ultrarapid metabolizer genotype with deficient patient satisfaction regarding methadone maintenance treatment. Drug Alcohol Depend 2007 Jul 10; 89(2–3): 190–4CrossRefGoogle Scholar
  72. 72.
    Shiran MR, Chowdry J, Rostami-Hodjegan A, et al. A discordance between cytochrome P450 2D6 genotype and phenotype in patients undergoing methadone maintenance treatment. Br J Clin Pharmacol 2003 Aug; 56(2): 220–4PubMedCrossRefGoogle Scholar
  73. 73.
    Schweikl H, Taylor JA, Kitareewan S, et al. Expression of CYP1 A1 and CYP1A2 genes in human liver. Pharmacogenetics 1993 Oct; 3(5): 239–49PubMedCrossRefGoogle Scholar
  74. 74.
    Ingelman-Sundberg M, Oscarson M, McLellan RA. Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. Trends Pharmacol Sci 1999 Aug; 20(8): 342–9PubMedCrossRefGoogle Scholar
  75. 75.
    Ieiri I, Tainaka H, Morita T, et al. Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis. Ther Drug Monit 2000 Jun; 22(3): 237–44PubMedCrossRefGoogle Scholar
  76. 76.
    Stubbins MJ, Harries LW, Smith G, et al. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996 Oct; 6(5): 429–39PubMedCrossRefGoogle Scholar
  77. 77.
    Sullivan-Klose TH, Ghanayem BI, Bell DA, et al. The role of the CYP2C9-Leu359 allelic variant in the tolbutamide polymorphism. Pharmacogenetics 1996 Aug; 6(4): 341–9PubMedCrossRefGoogle Scholar
  78. 78.
    Kirchheiner J, Roots I, Goldammer M, et al. Effect of genetic polymorphisms in cytochrome p450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin Pharmacokinet 2005; 44(12): 1209–25PubMedCrossRefGoogle Scholar
  79. 79.
    De Morais SM, Wilkinson GR, Blaisdell J, et al. Identification of a new genetic defect responsible for the polymorphism of (S)-mephenytoin metabolism in Japanese. Mol Pharmacol 1994 Oct; 46(4): 594–8PubMedGoogle Scholar
  80. 80.
    de Morais SM, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem 1994 Jun 3; 269(22): 15419–22PubMedGoogle Scholar
  81. 81.
    Xie HG, Stein CM, Kim RB, et al. Allelic, genotypic and phenotypic distributions of S-mephenytoin 4t?-hydroxylase (CYP2C19) in healthy Caucasian populations of European descent throughout the world. Pharmacogenetics 1999 Oct; 9(5): 539–49PubMedCrossRefGoogle Scholar
  82. 82.
    Bouer R, Barthe L, Philibert C, et al. The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac. Fundam Clin Pharmacol 1999; 13(4): 494–500PubMedCrossRefGoogle Scholar
  83. 83.
    Nanovskaya T, Nekhayeva I, Karunaratne N, et al. Role of P-glycoprotein in transplacental transfer of methadone. Biochem Pharmacol 2005 Jun 15; 69(12): 1869–78PubMedCrossRefGoogle Scholar
  84. 84.
    Wang JS, Ruan Y, Taylor RM, et al. Brain penetration of methadone (R)- and (S)- enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of ABCB1a gene knockout mice. Psychopharmacology (Berl) 2004 Apr; 173(1–2): 132–8CrossRefGoogle Scholar
  85. 85.
    Marzolini C, Paus E, Buclin T, et al. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 2004 Jan; 75(1): 13–33PubMedCrossRefGoogle Scholar
  86. 86.
    Dietrich CG, Geier A, Oude Elferink RP. ABC of oral bioavailability: transporters as gatekeepers in the gut. Gut 2003 Dec; 52(12): 1788–95PubMedCrossRefGoogle Scholar
  87. 87.
    Chan LM, Lowes S, Hirst BH. The ABCs of drug transport in intestine and liver: efflux proteins limiting drug absorption and bioavailability. Eur J Pharm Sci 2004 Jan; 21(1): 25–51PubMedCrossRefGoogle Scholar
  88. 88.
    Shitara Y, Horie T, Sugiyama Y. Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci 2006 Apr; 27(5): 425–46PubMedCrossRefGoogle Scholar
  89. 89.
    Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine. Pharmacol Ther 2006 Jan; 109(1–2): 137–61PubMedCrossRefGoogle Scholar
  90. 90.
    Thompson SJ, Koszdin K, Bernards CM. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein. Anesthesiology 2000 May; 92(5): 1392–9PubMedCrossRefGoogle Scholar
  91. 91.
    Owen A, Goldring C, Morgan P, et al. Relationship between the C3435T and G2677T(A) polymorphisms in the ABCB1 gene and P-glycoprotein expression in human liver. Br J Clin Pharmacol 2005 Mar; 59(3): 365–70PubMedCrossRefGoogle Scholar
  92. 92.
    Meier Y, Pauli-Magnus C, Zanger UM, et al. Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology 2006 Jul; 44(1): 62–74PubMedCrossRefGoogle Scholar
  93. 93.
    Thorn M, Finnstrom N, Lundgren S, et al. Cytochromes P450 and MDR1 mRNA expression along the human gastrointestinal tract. Br J Clin Pharmacol 2005 Jul; 60(1): 54–60PubMedCrossRefGoogle Scholar
  94. 94.
    Kerb R. Implications of genetic polymorphisms in drug transporters for pharmaco-therapy. Cancer Lett 2006 Mar 8; 234(1): 4–33PubMedCrossRefGoogle Scholar
  95. 95.
    Ameyaw MM, Regateiro F, Li T, et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 2001 Apr; 11(3): 217–21PubMedCrossRefGoogle Scholar
  96. 96.
    Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 2000 Mar 28; 97(7): 3473–8PubMedCrossRefGoogle Scholar
  97. 97.
    Song P, Lamba JK, Zhang L, et al. G2677T and C3435T genotype and haplotype are associated with hepatic ABCB1 (MDR1) expression. J Clin Pharmacol 2006 Mar; 46(3): 373–9PubMedCrossRefGoogle Scholar
  98. 98.
    Wang D, Sadee W. Searching for polymorphisms that affect gene expression and mRNA processing: example ABCB1 (MDR1). AAPS J 2006; 8(3): E515–20PubMedCrossRefGoogle Scholar
  99. 99.
    Kim RB, Leake BF, Choo EF, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther 2001 Aug; 70(2): 189–99PubMedCrossRefGoogle Scholar
  100. 100.
    Coller JK, Barratt DT, Dahlen K, et al. ABCB1 genetic variability and methadone dosage requirements in opioid-dependent individuals. Clin Pharmacol Ther 2006 Dec; 80(6): 682–90PubMedCrossRefGoogle Scholar
  101. 101.
    Schaeffeler E, Eichelbaum M, Brinkmann U, et al. Frequency of C3435T polymorphism of MDR1 gene in African people. Lancet 2001 Aug 4; 358(9279): 383–4PubMedCrossRefGoogle Scholar
  102. 102.
    Inturrisi CE, Colburn WA, Kaiko RF, et al. Pharmacokinetics and pharmacodynamics of methadone in patients with chronic pain. Clin Pharmacol Ther 1987 Apr; 41(4): 392–401PubMedCrossRefGoogle Scholar
  103. 103.
    Gourlay GK, Wilson PR, Glynn CJ. Pharmacodynamics and pharmacokinetics of methadone during the perioperative period. Anesthesiology 1982 Dec; 57(6): 458–67PubMedCrossRefGoogle Scholar
  104. 104.
    Gourlay GK, Willis RJ, Wilson PR. Postoperative pain control with methadone: influence of supplementary methadone doses and blood concentration-response relationships. Anesthesiology 1984 Jul; 61(1): 19–26PubMedGoogle Scholar
  105. 105.
    Inturrisi CE, Portenoy RK, Max MB, et al. Pharmacokinetic-pharmacodynamic relationships of methadone infusions in patients with cancer pain. Clin Pharmacol Ther 1990 May; 47(5): 565–77PubMedCrossRefGoogle Scholar
  106. 106.
    Hiltunen AJ, Beck O, Hjemdahl P, et al. Rated well-being in relation to plasma concentrations of l- and d-methadone in satisfied and dissatisfied patients on methadone maintenance treatment. Psychopharmacology (Berl) 1999 Apr; 143(4): 385–93CrossRefGoogle Scholar
  107. 107.
    Dyer KR, Foster DJ, White JM, et al. Steady-state pharmacokinetics and pharmacodynamics in methadone maintenance patients: comparison of those who do and do not experience withdrawal and concentration-effect relationships. Clin Pharmacol Ther 1999 Jun; 65(6): 685–94PubMedCrossRefGoogle Scholar
  108. 108.
    Dyer KR, White JM, Foster DJ, et al. The relationship between mood state and plasma methadone concentration in maintenance patients. J Clin Psychopharmacol 2001 Feb; 21(1): 78–84PubMedCrossRefGoogle Scholar
  109. 109.
    Ikeda K, Ide S, Han W, et al. How individual sensitivity to opiates can be predicted by gene analyses. Trends Pharmacol Sci 2005 Jun; 26(6): 311–7PubMedCrossRefGoogle Scholar
  110. 110.
    Lotsch J, Geisslinger G. Are mu-opioid receptor polymorphisms important for clinical opioid therapy? Trends Mol Med 2005 Feb; 11(2): 82–9PubMedCrossRefGoogle Scholar
  111. 111.
    Bond C, LaForge KS, Tian M, et al. Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: possible implications for opiate addiction. Proc Natl Acad Sci USA 1998 Aug 4; 95(16): 9608–13PubMedCrossRefGoogle Scholar
  112. 112.
    Beyer A, Koch T, Schroder H, et al. Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor. J Neurochem 2004 May; 89(3): 553–60PubMedCrossRefGoogle Scholar
  113. 113.
    Befort K, Filliol D, Decaillot FM, et al. A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signaling. J Biol Chem 2001 Feb 2; 276(5): 3130–7PubMedCrossRefGoogle Scholar
  114. 114.
    Zhang Y, Wang D, Johnson AD, et al. Allelic expression imbalance of human mu opioid receptor (OPRM1) caused by variant A1 18G. J Biol Chem 2005 Sep 23; 280(38): 32618–24PubMedCrossRefGoogle Scholar
  115. 115.
    Lotsch J, Skarke C, Grosch S, et al. The polymorphism A118G of the human mu-opioid receptor gene decreases the pupil constrictory effect of morphine-6-glucuronide but not that of morphine. Pharmacogenetics 2002 Jan; 12(1): 3–9PubMedCrossRefGoogle Scholar
  116. 116.
    Romberg RR, Olofsen E, Bijl H, et al. Polymorphism of mu-opioid receptor gene (OPRM1:c.118A>G) does not protect against opioid-induced respiratory depression despite reduced analgesic response. Anesthesiology 2005 Mar; 102(3): 522–30PubMedCrossRefGoogle Scholar
  117. 117.
    Skarke C, Darimont J, Schmidt H, et al. Analgesic effects of morphine and morphine-6-glucuronide in a transcutaneous electrical pain model in healthy volunteers. Clin Pharmacol Ther 2003 Jan; 73(1): 107–21PubMedCrossRefGoogle Scholar
  118. 118.
    Oertel BG, Schmidt R, Schneider A, et al. The mu-opioid receptor gene polymorphism 118A>G depletes alfentanil-induced analgesia and protects against respiratory depression in homozygous carriers. Pharmacogenet Genomics 2006 Sep; 16(9): 625–36PubMedCrossRefGoogle Scholar
  119. 119.
    Klepstad P, Rakvag TT, Kaasa S, et al. The 118 A>G polymorphism in the human micro-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease. Acta Anaesthesiol Scand 2004 Nov; 48(10): 1232–9PubMedCrossRefGoogle Scholar
  120. 120.
    Lotsch J, Zimmermann M, Darimont J, et al. Does the A1 18G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity? Anesthesiology 2002 Oct; 97(4): 814–9PubMedCrossRefGoogle Scholar
  121. 121.
    Koch T, Kroslak T, Averbeck M, et al. Allelic variation S268P of the human mu-opioid receptor affects both desensitization and G protein coupling. Mol Pharmacol 2000 Aug; 58(2): 328–34PubMedGoogle Scholar
  122. 122.
    Wang D, Raehal KM, Bilsky EJ, et al. Inverse agonists and neutral antagonists at mu opioid receptor (MOR): possible role of basal receptor signaling in narcotic dependence. J Neurochem 2001 Jun; 77(6): 1590–600PubMedCrossRefGoogle Scholar
  123. 123.
    Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett 1997 Feb 14; 223(1): 5–8PubMedCrossRefGoogle Scholar
  124. 124.
    Bulka A, Wiesenfeld-Hallin Z, Xu XJ. Differential antinociception by morphine and methadone in two sub-strains of Sprague-Dawley rats and its potentiation by dextromethorphan. Brain Res 2002 Jun 28; 942(1–2): 95–100PubMedCrossRefGoogle Scholar
  125. 125.
    Shimoyama N, Shimoyama M, Elliott KJ, et al. d-Methadone is antinociceptive in the rat formalin test. J Pharmacol Exp Ther 1997 Nov; 283(2): 648–52PubMedGoogle Scholar
  126. 126.
    Williams NM, Bowen T, Spurlock G, et al. Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate receptor. Mol Psychiatry 2002; 7(5): 508–14PubMedCrossRefGoogle Scholar
  127. 127.
    Ohtsuki T, Sakurai K, Dou H, et al. Mutation analysis of the NMDAR2B (GRIN2B) gene in schizophrenia. Mol Psychiatry 2001 Mar; 6(2): 211–6PubMedCrossRefGoogle Scholar
  128. 128.
    Codd EE, Shank RP, Schupsky JJ, et al. Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 1995 Sep; 274(3): 1263–70PubMedGoogle Scholar
  129. 129.
    Kreek MJ, Garfield JW, Gutjahr CL, et al. Rifampin-induced methadone withdrawal. N Engl J Med 1976 May 13; 294(20): 1104–6PubMedCrossRefGoogle Scholar
  130. 130.
    Baciewicz AM, Self TH. Rifampin drug interactions. Arch Intern Med 1984 Aug; 144(8): 1667–71PubMedCrossRefGoogle Scholar
  131. 131.
    Niemi M, Backman JT, Fromm MF, et al. Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet 2003; 42(9): 819–50PubMedCrossRefGoogle Scholar
  132. 132.
    Preston KL, Griffiths RR, Stitzer ML, et al. Diazepam and methadone interactions in methadone maintenance. Clin Pharmacol Ther 1984 Oct; 36(4): 534–41PubMedCrossRefGoogle Scholar
  133. 133.
    Tong TG, Pond SM, Kreek MJ, et al. Phenytoin-induced methadone withdrawal. Ann Intern Med 1981 Mar; 94(3): 349–51PubMedGoogle Scholar
  134. 134.
    Markowitz JS, Wells BG, Carson WH. Interactions between antipsychotic and antihypertensive drugs. Ann Pharmacother 1995 Jun; 29(6): 603–9PubMedGoogle Scholar
  135. 135.
    Tarumi Y, Pereira J, Watanabe S. Methadone and fluconazole: respiratory depression by drug interaction. J Pain Symptom Manage 2002 Feb; 23(2): 148–53PubMedCrossRefGoogle Scholar
  136. 136.
    Katz HI. Drug interactions of the newer oral antifungal agents. Br J Dermatol 1999 Nov; 141Suppl. 56: 26–32PubMedCrossRefGoogle Scholar
  137. 137.
    Eich-Hochli D, Oppliger R, Golay KP, et al. Methadone maintenance treatment and St. John’s Wort: a case report. Pharmacopsychiatry 2003 Jan; 36(1): 35–7PubMedCrossRefGoogle Scholar
  138. 138.
    Ortega I, Rodriguez M, Suarez E, et al. Modeling methadone pharmacokinetics in rats in presence of p-glycoprotein inhibitor valspodar. Pharm Res 2007 Jul; 24(7): 1299–308PubMedCrossRefGoogle Scholar
  139. 139.
    Iribarne C, Picart D, Dreano Y, et al. In vitro interactions between fluoxetine or fluvoxamine and methadone or buprenorphine. Fundam Clin Pharmacol 1998; 12(2): 194–9PubMedCrossRefGoogle Scholar
  140. 140.
    Liu SJ, Wang RI. Case report of barbiturate-induced enhancement of methadone metabolism and withdrawal syndrome. Am J Psychiatry 1984 Oct; 141(10): 1287–8PubMedGoogle Scholar
  141. 141.
    Moody DE, Walsh SL, Rollins DE, et al. Ketoconazole, a cytochrome P450 3A4 inhibitor, markedly increases concentrations of levo-acetyl-alpha-methadol in opioid-naive individuals. Clin Pharmacol Ther 2004 Aug; 76(2): 154–66PubMedCrossRefGoogle Scholar
  142. 142.
    Cobb MN, Desai J, Brown Jr LS, et al. The effect of fluconazole on the clinical pharmacokinetics of methadone. Clin Pharmacol Ther 1998 Jun; 63(6): 655–62PubMedCrossRefGoogle Scholar
  143. 143.
    Iribarne C, Picart D, Dreano Y, et al. Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver microsomes. Life Sci 1997; 60(22): 1953–64PubMedCrossRefGoogle Scholar
  144. 144.
    Bart PA, Rizzardi PG, Gallant S, et al. Methadone blood concentrations are decreased by the administration of abacavir plus amprenavir. Ther Drug Monit 2001 Oct; 23(5): 553–5PubMedCrossRefGoogle Scholar
  145. 145.
    Clarke SM, Mulcahy FM, Tjia J, et al. The pharmacokinetics of methadone in HIV-positive patients receiving the non-nucleoside reverse transcriptase inhibitor efavirenz. Br J Clin Pharmacol 2001 Mar; 51(3): 213–7PubMedCrossRefGoogle Scholar
  146. 146.
    Marzolini C, Troillet N, Telenti A, et al. Efavirenz decreases methadone blood concentrations. AIDS 2000 Jun 16; 14(9): 1291–2PubMedCrossRefGoogle Scholar
  147. 147.
    Barry M, Gibbons S, Back D, et al. Protease inhibitors in patients with HIV disease: clinically important pharmacokinetic considerations. Clin Pharmacokinet 1997 Mar; 32(3): 194–209PubMedCrossRefGoogle Scholar
  148. 148.
    Beauverie P, Taburet AM, Dessalles MC, et al. Therapeutic drug monitoring of methadone in HIV-infected patients receiving protease inhibitors. AIDS 1998 Dec 24; 12(18): 2510–1PubMedGoogle Scholar
  149. 149.
    Geletko SM, Erickson AD. Decreased methadone effect after ritonavir initiation. Pharmacotherapy 2000 Jan; 20(1): 93–4PubMedCrossRefGoogle Scholar
  150. 150.
    Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS 1999 May 28; 13(8): 957–62PubMedCrossRefGoogle Scholar
  151. 151.
    Otero MJ, Fuertes A, Sanchez R, et al. Nevirapine-induced withdrawal symptoms in HIV patients on methadone maintenance programme: an alert. AIDS 1999 May 28; 13(8): 1004–5PubMedCrossRefGoogle Scholar
  152. 152.
    Dole VP, Warner A. Selected bibliography on narcotic addiction treatment, 1960–1966: reports of treatment programs. Am J Public Health Nations Health 1967 Nov; 57(11): 2005–8PubMedCrossRefGoogle Scholar
  153. 153.
    Mannino R, Coyne P, Swainey C, et al. Methadone for cancer-related neuropathic pain: a review of the literature. J Opioid Manag 2006 Sep–Oct; 2(5): 269–76PubMedGoogle Scholar
  154. 154.
    Boglione-Kerrien C, Furet Y, Bachellier J, et al. Methadone blood assay by the FPIA technique: application to the monitoring of patients in maintenance treatment to opiates [in French]. Ann Biol Clin (Paris) 2007 Jan–Feb; 65(1): 51–7Google Scholar
  155. 155.
    Eap CB, Bourquin M, Martin J, et al. Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend 2000 Dec 22; 61(1): 47–54PubMedCrossRefGoogle Scholar
  156. 156.
    Maxwell S, Shinderman M. Optimizing response to methadone maintenance treatment: use of higher-dose methadone. J Psychoactive Drugs 1999 Apr–Jun; 31(2): 95–102PubMedCrossRefGoogle Scholar
  157. 157.
    Krantz MJ, Lewkowiez L, Hays H, et al. Torsade de pointes associated with very-high-dose methadone. Ann Intern Med 2002 Sep 17; 137(6): 501–4PubMedGoogle Scholar
  158. 158.
    Terpening CM, Johnson WM. Methadone as an analgesic: a review of the risks and benefits. W V Med J 2007 Jan–Feb; 103(1): 14–8PubMedGoogle Scholar
  159. 159.
    Kornick CA, Kilborn MJ, Santiago-Palma J, et al. QTc interval prolongation associated with intravenous methadone. Pain 2003 Oct; 105(3): 499–506PubMedCrossRefGoogle Scholar
  160. 160.
    Bryson J, Tamber A, Seccareccia D, et al. Methadone for treatment of cancer pain. Curr Oncol Rep 2006 Jul; 8(4): 282–8PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Yongfang Li
    • 1
    • 2
  • Jean-Pierre Kantelip
    • 1
  • Pauline Gerritsen-van Schieveen
    • 1
  • Siamak Davani
    • 1
    Email author
  1. 1.Department of Clinical Pharmacology and ToxicologyUniversity Hospital BesançonBesançonFrance
  2. 2.Department of PharmacologyQinghai University Medical CollegeXiningChina

Personalised recommendations