Skip to main content
SpringerLink
Log in

An in vitro approach to potential methadone metabolic-inhibition interactions

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

The aim of this study was to assess the drug interaction potential of psychotropic medication on methadone N-demethylation using cDNA-expressed cytochrome P450 CYP enzymes.

Methods

Methadone was incubated with various drugs (n = 10) and cDNA-expressed CYP3A4, CYP2D6, CYP2B6, CYP2C19 and CYP1A2 enzymes to screen for their inhibition potency. The nature of enzyme selective activity for inhibition was further investigated for potent inhibitors. To test for a mechanism-based component in inhibition, all substances were tested with preincubation and without. 2-Ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) concentration was determined by liquid chromatography/tandem mass spectrometry following liquid/liquid extraction.

Results

Formation of EDDP was catalysed by CYP3A4, CYP2D6 and CYP2C19. The N-demethylation of methadone was preferentially inhibited by amitriptyline, buprenorphine, methylenedioxymethamphetamine (MDMA) and zolpidem. Both amitriptyline and buprenorphine were strong, reversible inhibitors of CYP3A4. Similarly, amitriptyline and MDMA were identified as inhibitors of CYP2D6. Zolpidem revealed a mechanism-based inhibition of CYP3A4.

Conclusion

Amitriptyline, MDMA and zolpidem are likely to slow down conversion of methadone and to increase its area under the curve (AUC). A consideration of the in vitro evidence of drug-methadone interactions should help to improve patient care during methadone maintenance treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Shah N, Lathrop SL, Landen MG (2005) Unintentional methadone-related overdose death in New Mexico (USA) and implications for surveillance, 1998–2002. Addiction 100:176–188

    Article  PubMed  Google Scholar 

  2. Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J (2003) Increase in deaths due to methadone in North Carolina. JAMA 290:40

    Article  PubMed  Google Scholar 

  3. Cairns A, Roberts IS, Benbow EW (1996) Characteristics of fatal methadone overdose in Manchester, 1985–1994. BMJ 313:264–265

    PubMed  CAS  Google Scholar 

  4. Brugal MT, Domingo-Salvany R, Barrio G, Garcia de Olalla P, de la Fuente L (2005) Evaluating the impact of methadone maintenance programmes on mortality due to overdose and AIDS in a cohort of heroin users in Spain. Addiction 100:981–989

    Article  PubMed  CAS  Google Scholar 

  5. Buster MC, van Brussel GH, van den Brink W (2002) An increase in overdose mortality during the first 2 weeks after entering or re-entering methadone treatment in Amsterdam. Addiction 97:993–1001

    Article  PubMed  Google Scholar 

  6. Gölz J (2000) Nebenkonsum und Beendigung der Substitution, Behandlungsabbruch und Konsequenzen. In: Jellinek C, Westermann B, Bellmann GU (eds) Beigebrauch. Deutscher Studien Verlag, Weinheim, pp 43–49

    Google Scholar 

  7. Iribarne C, Berthou F, Baird S, Dreano Y, Picart D, Bail JP, Beaune P, Menez JF (1996) Involvement of cytochrome P450 3A4 enzyme in the N-demethylation of methadone in human liver microsomes. Chem Res Toxicol 9:365–373

    Article  PubMed  CAS  Google Scholar 

  8. Moody DE, Alburges ME, Parker RJ, Collins JM, Strong JM (1997) The involvement of cytochrome P450 3A4 in the N-demethylation of L-alpha-acetylmethadol (LAAM), norLAAM, and methadone. Drug Metab Dispos 25:1347–1353

    PubMed  CAS  Google Scholar 

  9. Foster DJR, Somogyi AA, Coccia CP (1999) Methadone N-demethylation in human liver microsomes: lack of stereoselectivity and involvement of CYP3A4. Br J Clin Pharmacol 47:403–412

    Article  PubMed  CAS  Google Scholar 

  10. Gerber JG, Rhodes RJ, Gal J (2004) Stereoselective metabolism of methadone N-demethylation by cytochrome P450 2B6 and 2C19. Chirality 16:36–44

    Article  PubMed  CAS  Google Scholar 

  11. Oda Y, Kharasch ED (2001) 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 298:1021–1032

    PubMed  CAS  Google Scholar 

  12. Wang JS, De Vane CL (2003) Involvement of CYP3A4, CYP2C8, and CYP2D6 in the metabolism of (R)- and (S)-methadone in vitro. Drug Metab Dispos 31:742–747

    Article  PubMed  CAS  Google Scholar 

  13. Wu D, Otton SV, Sproule BA, Busto U, Inaba T, Kalow W, Sellers EM (1993) Inhibition of human cytochrome P450 2D6 (CYP2D6) by methadone. Br J Clin Pharmacol 35:30–34

    PubMed  CAS  Google Scholar 

  14. Bomsien S (2006) In vitro Untersuchungen zur Wechselwirkung psychotroper Substanzen mit Methadon und Buprenorphin. PhD Thesis, University of Heidelberg, Heidelberg, Germany

  15. University of Washington (2005) Metabolism and transport drug interaction database. http://www.druginteractioninfo.org. 12 July 2005

  16. FDA (2005) U.S. Food and Drug Administration. http://www.fda.gov. 10 March 2005

  17. Dixon M (1953) The determination of enzyme inhibitor constants. Biochem J 55:170–171

    PubMed  CAS  Google Scholar 

  18. Kitz R, Wilson IB (1962) Esters of methanesulfonic acid as irreversible inhibitors of acetylcholinesterase. J Biol Chem 237:3245–3246

    PubMed  CAS  Google Scholar 

  19. Venkatakrishnan K, von Moltke LL, Obach RS, Greenblatt DJ (2003) Drug metabolism and drug interactions: applications and clinical value of in vitro models. Curr Drug Metab 4:423–459

    Article  PubMed  CAS  Google Scholar 

  20. Silverman RB (1995) Mechanism based enzyme inactivators. In: Abelson JN, Simon MJ, Purich PL (eds) Methods in enzymology. Academic, San Diego, pp 240–283

    Google Scholar 

  21. Maurer ST, Tabrizi-Fard MA, Fung HL (2000) Impact of mechanism-based enzyme inactivation on inhibitor potency: implications for rational drug discovery. J Pharm Sci 89:1404–1414

    Article  PubMed  CAS  Google Scholar 

  22. Mayhew BS, Jones DR, Hall SD (2000) An in vitro model for predicting in vivo inhibition of cytochrome P450 3A4 by metabolic intermediate complex formation. Drug Metab Dispos 28:1031–1037

    PubMed  CAS  Google Scholar 

  23. Chan GM, Stajic M, Marker EK, Hoffman RS, Nelson LS (2006) Testing positive for methadone and either a tricyclic antidepressant or a benzodiazepine is associated with an accidental overdose death: analysis of medical examiner data. Acad Emerg Med 13:543–547

    Article  PubMed  Google Scholar 

  24. Plummer JL, Gourlay GK, Cherry DA, Cousins MJ (1988) Estimation of methadone clearance: application in the management of cancer pain. Pain 33:313–322

    Article  PubMed  CAS  Google Scholar 

  25. Milroy CM, Forrest AR (2000) Methadone deaths: a toxicological analysis. J Clin Pathol 53:277–281

    Article  PubMed  CAS  Google Scholar 

  26. Pirnay S, Borron SW, Giudicelli CP, Tourneau J, Baud FJ, Ricordel I (2004) A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths. Addiction 99:978–988

    Article  PubMed  CAS  Google Scholar 

  27. Bjornsson TD, Callaghan JT, Einolf HJ, Fischer V, Gan L, Grimm S, Kao J, King P, Miwa G, Ni L, Kumar G, McLeod J, Obach RS, Roberts S, Roe A, Shah A, Snikeris F, Sullivan JT, Tweedie D, Vega JM, Walsh J, Wrighton SA (2001) The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab Dispos 31:815–832

    Article  Google Scholar 

Download references

Acknowledgements

We appreciate the kind assistance of Ms. Hoenekopp and her team from a local maintenance treatment centre in Mannheim, Germany.

Author information

Authors and Affiliations

  1. Institute of Legal Medicine and Traffic Medicine, Ruprecht-Karls University, Voßstr. 2, 69115, Heidelberg, Germany

    Stephanie Bomsien & Gisela Skopp

Authors
  1. Stephanie Bomsien
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gisela Skopp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gisela Skopp.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bomsien, S., Skopp, G. An in vitro approach to potential methadone metabolic-inhibition interactions. Eur J Clin Pharmacol 63, 821–827 (2007). https://doi.org/10.1007/s00228-007-0327-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-007-0327-z

Keywords

Search

Navigation