An in vitro approach to potential methadone metabolic-inhibition interactions
- 316 Downloads
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.
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.
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.
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.
KeywordsMethadone metabolism In vitro interaction Psychotropic co-medication CYP3A4 CYP2D6
We appreciate the kind assistance of Ms. Hoenekopp and her team from a local maintenance treatment centre in Mannheim, Germany.
- 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 43–49Google Scholar
- 14.Bomsien S (2006) In vitro Untersuchungen zur Wechselwirkung psychotroper Substanzen mit Methadon und Buprenorphin. PhD Thesis, University of Heidelberg, Heidelberg, GermanyGoogle Scholar
- 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
- 20.Silverman RB (1995) Mechanism based enzyme inactivators. In: Abelson JN, Simon MJ, Purich PL (eds) Methods in enzymology. Academic, San Diego, pp 240–283Google 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 31:815–832CrossRefGoogle Scholar