Discrepancy between CYP2D6 phenotype and genotype derived from post-mortem dextromethorphan blood level.
OBJECTIVE
To describe the death of a toddler after a therapeutic dose of dextromethorphan and its investigation.


METHODS
Case report, cytochrome P450 phenotype and genotype determination in the victim and post-mortem drug redistribution study performed in rats.


RESULTS
A 20-month Asian male who received 3 mg of dextromethorphan once at 09:00 h and again at 22:00 h was found dead at 04:35 h. Post-mortem examination showed signs of early bronchopneumonia (bacterial cultures were negative); dextromethorphan and dextrorphan blood concentrations taken from the heart cavity were 500 ng/ml (1. 84 micromol/l) and 200 ng/ml (0.78 micromol/l), respectively. Despite the dextromethorphan level being almost 100-fold higher than expected after therapeutic doses, intentional or unintentional overdose was extremely unlikely; other potential causes were investigated. Post-mortem drug redistribution study performed in rats showed that dextromethorphan does not undergo extensive redistribution after death (6+/-5-fold increase) and could not explain the observed dextromethorphan level. The dextromethorphan/dextrorphan concentration ratio of 2.5 found in this toddler was compatible with a slow CYP2D6 metabolizer phenotype. However, the toddler exhibited a fast metabolizer genotype. Potential reasons for this discrepancy are discussed.


CONCLUSIONS
CYP450 phenotypes derived from post-mortem blood levels should be interpreted with caution and preferably confirmed by a genotype analysis.
Bailey
B
B
Department of Pediatrics, Division of Clinical Pharmacology and Toxicology, H¿opital Ste-Justine, 3175 Cote St. Catherine, Montr¿eal, Qu¿ebec, Canada. baileyb@med.umontreal.ca
Daneman
R
R
Daneman
N
N
Mayer
J M
JM
Koren
G
G
D000818:Animals; D000996:Antitussive Agents / Q000009:adverse effects / Q000097:blood*; D002423:Cause of Death; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D003915:Dextromethorphan / Q000009:adverse effects / Q000097:blood*; D003917:Dextrorphan / Q000097:blood; D018691:Excitatory Amino Acid Antagonists / Q000097:blood; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D010641:Phenotype; D011014:Pneumonia / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000996:Antitussive Agents; D018691:Excitatory Amino Acid Antagonists; D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6