Desperate for a Drink

Fatal Forty DDI: amitriptyline, CYP2D6 poor metabolizer
  • Erica D. Wittwer
  • Juraj Sprung
  • Wayne T. Nicholson


This case discusses a drug–gene interaction involving the poor metabolism of amitriptyline by the cytochrome P450 2D6 enzyme pathway, leading to toxicity.


Drug-gene interaction Pharmacogenomic CYP2D6 Poor metabolizer Amitriptyline Tricyclic antidepressant Genetic variant 10-OH-nortriptyline Nortriptyline Toxicity Therapeutic window Anticholinergic QRS prolongation QTc prolongation Ventricular tachycardia Seizures CYP Cytochrome P450 2D6 


  1. 1.
    Steimer W, Zopf K, von Amelunxen S, et al. Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy. Clin Chem. 2005;51(2):376–85. Epub 2004 Dec 8.PubMedCrossRefGoogle Scholar
  2. 2.
    Shimoda K, Someya T, Yokono A, et al. The impact of CYP2C19 and CYP2D6 genotypes on metabolism of amitriptyline in Japanese psychiatric patients. J Clin Psychopharmacol. 2002;22(4):371–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Poolsup N, Li Wan Po A, Knight TL. Pharmacogenetics and psychopharmacotherapy. J Clin Pharm Ther. 2000;25(3):197–220.PubMedCrossRefGoogle Scholar
  4. 4.
    Billups SJ, Delate T, Dugan D. Evaluation of risk factors for elevated tricyclic antidepressant plasma concentrations. Pharmacoepidemiol Drug Saf. 2009;18(3):253–7.PubMedCrossRefGoogle Scholar
  5. 5.
    Martinez C, Albet C, Agundez JA, et al. Comparative in vitro and in vivo inhibition of cytochrome P450 CYP1A2, CYP2D6, and CYP3A by H2-receptor antagonists. Clin Pharmacol Ther. 1999;65(4):369–76.PubMedCrossRefGoogle Scholar
  6. 6.
    Desta Z, Wu GM, Morocho AM, et al. The gastroprokinetic and antiemetic drug metoclopramide is a substrate and inhibitor of cytochrome P450 2D6. Drug Metab Dispos. 2002;30(3):336–43.PubMedCrossRefGoogle Scholar
  7. 7.
    He N, Zhang WQ, Shockley D, et al. Inhibitory effects of H1-antihistamines on CYP2D6- and CYP2C9-mediated drug metabolic reactions in human liver microsomes. Eur J Clin Pharmacol. 2002;57(12):847–51.PubMedCrossRefGoogle Scholar
  8. 8.
    Downs JM, Downs AD, Rosenthal TL, et al. Increased plasma tricyclic antidepressant concentrations in two patients concurrently treated with fluoxetine. J Clin Psychiatry. 1989;50(6):226–7.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Erica D. Wittwer
    • 1
  • Juraj Sprung
    • 1
  • Wayne T. Nicholson
    • 1
  1. 1.Department of AnesthesiologyMayo ClinicRochesterUSA

Personalised recommendations