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Paradoxical Excitation on Diphenhydramine May Be Associated with Being a CYP2D6 Ultrarapid Metabolizer: Three Case Reports

Published online by Cambridge University Press:  07 November 2014

Jose de Leon  and
D. Michele Nikoloff
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Abstract

Diphenhydramine is a widely used antihistaminic that is frequently included in over-the-counter medications. Due to its sedating properties, diphenhydramine is used in some hypnotic preparations. Occasionally, patients respond to diphenhydramine with paradoxical excitation. There are no studies on the prevalence of paradoxical excitation in healthy subjects. Diphenhydramine appears to cause mild inhibition of the cytochrome P450 (CYP) 2D6 enzyme. This can be interpreted as competitive inhibition, suggesting that diphenhydramine may be a CYP2D6 substrate. When subjects have at least three active copies of the CYP2D6 gene, they are called ultrarapid metabolizers (UMs) and present high metabolic capacity for CYP2D6 substrates. In the United States, CYP2D6 UMs may account for ∼1 % to 2% of the population. We describe three CYP2D6 UMs who reported paradoxical excitation on diphenhydramine. These cases suggest that in CYP2D6 UMs, diphenhydramine may be converted to a compound that causes excitation due to the abnormally high CYP2D6 activity. Therefore, such individuals may be at higher risk for excitation. Although these are onl y three anecdotal cases of paradoxical excitation from three CYP2D6 UMs, the reports illustrate the need for larger, more formal studies of diphenhydramine responses in CYP2D6 UMs and of diphenhydramine metabolism.

Type
Case Report
Information
CNS Spectrums , Volume 13 , Issue 2 , February 2008 , pp. 133 - 135
Copyright
Copyright © Cambridge University Press 2008

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References

REFERENCES

1. Scharman, EJ, Erdman, AR, Wax, PM, et al. Diphenhydramine and dimenhydrinate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44:205–223.CrossRefGoogle ScholarPubMed
2. Cheng, KL, Dwyer, PN, Amsden, GW. Paradoxic excitation with diphenhydramine in an adult. Pharmacotherapy. 1997;17:1311–1314.Google Scholar
3. Ohio Historical Society Web site. Benadryi. Available at: http://www.ohiohistorycentral.org/entry.php?rec=2591. Accessed on October 6, 2007.Google Scholar
4. Hamelin, BA, Bouayad, A, Méthot, J, et al. Significant interaction between the non-prescription antihistamine diphenhydramine and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6 activity. Clin Pharmacol Ther. 2000;67:466–477.Google Scholar
5. Hamelin, BA, Bouayad, A, Drolet, B, Gravel, A, Turgeon, J. In vitro characterization of cytochrome P450 2D6 inhibition by classic histamine H1 receptor antagonists. Drug Metab Dispos. 1998;26:536–539.Google Scholar
6. Armstrong, SC, Cozza, KL. Antihistamines. Psychosomatics. 2003;44:430–434.Google Scholar
7. Johansson, I, Lundqvist, E, Bertilsson, L, Dahl, ML, Sjoqvist, F, Ingelmann-Sundberg, M. Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. Proc Nat Acad Sci U S A. 1993;90:11825–11829.CrossRefGoogle ScholarPubMed
8. Johnson, M, Markham-Abedi, C, Susce, MT, Murray-Carmichael, E, McCollum, S, de Leon, J. A poor metabolizer for both cytochrome P450 2D6 and 2C19 (CYP2D6 and CYP2C19): a case report on antidepressant treatment. CNS Spectr. 2006;11:757–760.Google Scholar
9. Dahl, ML, Johansson, I, Bertilsson, L, Ingelmann-Sundberg, M, Sjoqvist, F. Ultrarapid hydroxylation of debrisoquine in a Swedish population. Analysis of the molecular genetic basis. J Pharmacol Exper Ther. 1995;274:516–520.Google Scholar
10. Aklillu, E, Persson, I, Bertilsson, L, et al. Frequent distribution of ultrarapid metabolizers of debrisoquine in an Ethiopian population carrying duplicated and multiduplicated functional CYP2D6 alleles. J Clin Pharmacol Exp Ther. 1996;278:441–446.Google Scholar
11. McLellan, RA, Oscarson, M, Seidegard, J. et al. Frequent occurrence of CYP2D6 gene duplication in Saudi Arabians. Pharmacogenetics. 1997;7:187–191.CrossRefGoogle ScholarPubMed
12. de Leon, J. The AmpliChip CYP450 Test: personalized medicine has arrived in psychiatry. Expert Rev Mol Diagn. 2006;6:277–286.Google Scholar
13. Mrazek, DA, Smoller, JW, de Leon, J. Incorporating pharmacogenetics into clinical practice: reality of a new tool in psychiatry. CNS Spectr. 2006;11(3 suppl 3):1–16.Google Scholar
14. de Leon, J. The crucial role of the therapeutic window in understanding the clinical relevance of the poor versus the ultrarapid metabolizer phenotypes in subjects taking drugs metabolized by CYP2D6 and CYP2C19. J Clin Psychopharmacol. 2007;27:241–245.Google Scholar
15. de Leon, J, Susce, MT, Pan, R-M, Fairchild, M, Koch, W, Wedlund, PJ. The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry. 2005;66:15–27.CrossRefGoogle ScholarPubMed
16. Candiotti, KA, Birnbach, DJ, Lubarsky, DA, et al. The impact of pharmacogenomics on postoperative nausea and vomiting: do CYP2D6 allele copy number and polymorphisms affect the success or failure of ondansetron prophylaxis? Anesthesiology. 2005;102:543–549.Google Scholar
17. Susce, MT, Murray-Carmichael, E, de Leon, J. Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer. Prog Neuro-Psychopharmacol Biol Psychiatry. 2006;30:1356–1358.Google Scholar
18. de Leon, J, Dinsmore, L, Wedlund, PJ. Adverse drug reactions to oxycodone and hydrocodone in CYP2D6 ultrarapid metabolizers [letter], J Clin Psychopharmacol. 2003;23:420–421.Google Scholar
19. de Leon, J, Armstrong, SC, Cozza, KL. Clinical guidelines for using pharmacogenetic testing of CYP450 2D6 and CYP450 2C19 in psychiatry. Psychosomatics. 2006;47:75–85.Google Scholar