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Pharmacogenomic evaluation of a pediatric dextromethorphan fatality following cold medication therapy: the role of cytochrome P450 2D6 polymorphisms
Author(s) -
Tobin Ann A,
Little Colleen,
Schneider Randal J,
Thompson Victoria M,
Jannetto Paul J,
Wong Steven H,
Gummin David D
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1134.6
Subject(s) - dextromethorphan , dextrorphan , cyp2d6 , medicine , pharmacogenomics , genotyping , pharmacology , adverse effect , pharmacogenetics , genotype , cytochrome p450 , biology , genetics , metabolism , gene
Cold medications are commonly used to alleviate respiratory viral symptoms in children under two years of age, but pose a risk of adverse effects and overdose. Though side effects may be enhanced by immature drug metabolizing enzymes, they may even become lethal when combined with mutations that compromise enzyme function. We identify the role of pharmacogenomic variants of cytochrome P450 (CYP) in a pediatric cold medication fatality. Postmortem toxicological analysis of the infant's blood showed elevated levels of the cough suppressant, dextromethorphan (29.2 ng/ml; adult therapeutic range: 10–40 ng/ml). Genotyping was used to identify mutations in CYP enzymes that metabolize dextromethorphan to dextrorphan (CYP2D6 *2, 3, 4, 5, 6, 7, 8) and 3‐methoxymorphinan (CYP3A4 *1B and CYP3A5 *3) using pyrosequencing. As a confirmatory test, 27 allelic variations of CYP2D6 were genotyped using a Roche CYP450 microarray. The decedent's genotype was CYP2D6 *1/*4 and CYP2D6 *4/*9, respectively. Overall, genotyping identified the child as an intermediate metabolizer of dextromethorphan, a probable cause of the high drug level and death. Genotyping may improve respiratory infection therapy in the neonate by predicting efficacious cold medication doses while minimizing potentially lethal side effects. Supported by grants from the Medical College of Wisconsin, Roche Diagnostics, Abbott Diagnostics and GE Healthcare.