Case report
Discrepancy between CYP2D6 phenotype and genotype derived from post-mortem dextromethorphan blood level

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Abstract

Objective: To describe the death of a toddler after a therapeutic dose of dextromethorphan and its investigation. Study design: 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 μmol/l) and 200 ng/ml (0.78 μmol/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. Conclusion: CYP450 phenotypes derived from post-mortem blood levels should be interpreted with caution and preferably confirmed by a genotype analysis.

Introduction

Dextromethorphan is the dextrogyre isomer of the codeine analog levorphanol [1]. While exhibiting cough suppressant activity equivalent to opioid drugs, dextromethorphan has no analgesic or addictive properties probably because it does not act through opioid receptors [1]. Thus, dextromethorphan is considered a non-opioid antitussive drug with low toxicity, although at extremely high doses it may produce CNS depression [1]. Despite dextromethorphan’s wide use since the 1950s, there are very few published reports of adverse effects associated with its therapeutic use. Most reports published up to now, have involved accidental or intentional overdosages, or abuse [2], [3], [4], [5], [6], [7], [8], [9].

Genetic polymorphism of the cytochrome P-450 isoenzyme involved in dextromethorphan metabolism, CYP2D6, has been described and explains the observed wide interindividual variation with respect to blood concentrations [10]. Due to its safety, dextromethorphan has become a widely used substrate in characterizing slow and fast CYP2D6 metabolizers. In most situations, CYP2D6 phenotype is evaluated on a urine sample after dextromethorphan administration. However, in cases of death, urine may not be available and thus post-mortem blood concentrations must be examined. We report the case of a toddler who died after an alleged therapeutic dose of dextromethorphan in which a discrepancy between CYP2D6 genotype and phenotype based on post-mortem blood concentrations was found.

Section snippets

Case-report

A 20-month 10-kg Asian male was found dead in bed at 04:35 h. That night the toddler had been cared for by his adult babysitter at her family home. Due to his cough, associated with an upper respiratory tract infection, the babysitter reported to have given him 1 ml of her daughter’s cough syrup (dextromethorphan 3 mg/ml) once at 09:00 hand once at 22:00 h the day prior to death (dextromethorphan therapeutic dosage is 1–2 mg/kg per day every 6–8 h). The toddler had no evidence of abuse,

Dextromethorphan post-mortem redistribution studies

Male Albino Wistar rats weighing 250–350 g (Charles River Canada, Quebec) were housed in well-ventilated cages and were allowed free access to food and water until the day of the experiment. Twelve rats were administered 1.5 mg/kg of dextromethorphan hydrobromide subcutaneously (Sigma, St. Louis, MO) in 0.9% sodium chloride that was sterilized before administration via suction-filtration through a 0.22-μm filter (Millipore, MA).

Ante-mortem blood samples were drawn from the rats by cardiac

Dextromethorphan post-mortem redistribution studies

In rats given 1.5 mg/kg of dextromethorphan subcutaneously and sacrificed after 2.5 h, all ante-mortem concentrations were below the limit of detection. Conversely, post-mortem levels were measurable in most animals (Table 1). The mean increase in dextromethorphan concentrations in rats with post-mortem concentrations done 8, 24 and 48 h after sacrifice were 73±45, 40±26 and 42±35 ng/ml, respectively. These values were ascertained by assuming all undetectable ante-mortem dextromethorphan

Discussion

The medical community generally considers dextromethorphan safe, as there have been very few reports of adverse effects caused by this drug [2]. Consequently, dextromethorphan is commonly used as a probe for CYP2D6 genetic polymorphism [12], [13].

Nevertheless, three case reports linking dextromethorphan to fatal outcomes have been published [15], [16]. The first case clearly involved a suicide attempt [15]. The circumstances in the other two deaths are not clear [15], [16]. In one case, a

Acknowledgements

We would like to acknowledge J. Steven Leeder PharmD PhD and Andrea Gaedigk from the Section of Pediatric Clinical Pharmacology and Experimental Therapeutics and the Pediatric Pharmacology Research Unit, The Children’s Mercy Hospital, Kansas City, Missouri, for performing the genotyping. Benoit Bailey was supported by a fellowship from the Canadian Society for Clinical Pharmacology.

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