Case reportDiscrepancy between CYP2D6 phenotype and genotype derived from post-mortem dextromethorphan blood level
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.
References (26)
- et al.
Massive dextromethorphan ingestion and abuse
Am. J. Emerg. Med.
(1995) - et al.
Inter-individual variation in the metabolism of dextromethorphan
Int. J. Pharm.
(1983) - et al.
Fatal intoxication by dextromethorphan: a report on two cases
Forensic Sci. Int.
(1988) - et al.
Post-mortem redistribution — a toxicological nightmare
Forensic Sci. Int.
(1990) - et al.
Cytochrome P450 2D6 (CYP 2D6) genotyping on postmortem blood as a supplementary tool for interpretation of forensic toxicological results
Forensic Sci. Int.
(1999) - et al.
Opioid analgesics and antagonists
- et al.
Dextromethorphan. An overview of safety issues
Drug Safety
(1992) - et al.
Dextromethorphan poisoning reversed by naloxone
Am. J. Emerg. Med.
(1991) - et al.
Toxicity with dextromethorphan-containing preparations: a literature review and report of two additional cases
Pediatr. Emerg. Care
(1991) - et al.
Dextromethorphan danger
New Engl. J. Med.
(1986)