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Pharmacokinetics and Pharmacodynamics of Dextromethorphan: Clinical and Forensic Aspects

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Pharmacokinetics and Pharmacodynamics of Dextromethorphan: Clinical and Forensic Aspects Drug Metabolism Reviews ISSN: 0360-2532 (Print) 1097-9883 (Online) Journal homepage: https://www.tandfonline.com/loi/idmr20 Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects Ana Rita Silva & Ricardo Jorge Dinis-Oliveira To cite this article: Ana Rita Silva & Ricardo Jorge Dinis-Oliveira (2020) Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects, Drug Metabolism Reviews, 52:2, 258-282, DOI: 10.1080/03602532.2020.1758712 To link to this article: https://doi.org/10.1080/03602532.2020.1758712 Published online: 12 May 2020. Submit your article to this journal Article views: 48 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=idmr20 DRUG METABOLISM REVIEWS 2020, VOL. 52, NO. 2, 258–282 https://doi.org/10.1080/03602532.2020.1758712 REVIEW ARTICLE Pharmacokinetics and pharmacodynamics of dextromethorphan: clinical and forensic aspects Ana Rita Silvaa and Ricardo Jorge Dinis-Oliveiraa,b,c aDepartment of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, Porto, Portugal; bDepartment of Sciences, IINFACTS – Institute of Research and Advanced Training in Health Sciences and Technologies, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal; cDepartment of Biological Sciences, Faculty of Pharmacy, Laboratory of Toxicology, UCIBIO, REQUIMTE, University of Porto, Porto, Portugal ABSTRACT ARTICLE HISTORY Dextromethorphan (DXM) is a safe and effective antitussive agent present in several over the Received 27 December 2019 counter cough and cold medications. At higher doses, it causes psychoactive effects, making it Accepted 7 April 2020 appealing for abuse. In this work, the pharmacokinetics and pharmacodynamics of DXM with KEYWORDS clinical and forensic relevance were extensively reviewed. DXM and related known metabolizing Dextromethorphan; metab- enzymes and metabolites were searched in books and in PubMed (U.S. National Library of olism; pharmacokinetics; Medicine) without a limiting period. Major metabolic pathways include sequential O-demethyla- clinical and forensic tion and N-demethylation of DXM, yielding dextrorphan (DXO), the major active metabolite, and aspects; abuse 3-hydroxymorphinan, the bi-demethylated product, respectively. The demethylation order described may reverse being the resultant mid product 3-methoxymorphinan. UDP-glucuronosyl- tranferase produces glucuronide conjugates. Genotypic variations in enzymes and interactions with other drugs can result in large inter-individual variability in the pharmacological and toxico- logical effects produced. Knowing the metabolism of DXM may help to better understand the inter-individual variability in the pharmacokinetics and pharmacodynamics and to avoid adverse effects. Introduction stimulation and N-methyl-D-aspartate (NMDA) antagon- ism (Brown et al. 2004). Moreover, especially in doses Dextromethorphan (DXM; d-methorphan) is a non-nar- higher than 100–200 mg, DXM has the potential to pro- cotic synthetic analog of codeine (Aumatell and Wells 1993), widely used as an antitussive agent in over-the- duce clinical signs and symptoms similar to those of counter (OTC) cough and cold medications (El-Naby phencyclidine (PCP) and ketamine, such as euphoria and Kamel 2015) and is considered safe and effective and dissociative hallucinations, effects that are probably when taken at therapeutic doses (Spangler et al. 2016). mediated by a rather nonselective action on serotonin r a b In 2015, in the USA, OTC medicines containing DXM reuptake inhibition and 1 opioid, 3 4 nicotinic, and comprised 85–90% of all medicines containing a cough NMDA receptors (Logan 2009; Logan et al. 2009, 2012). suppressant that were sold, in a total of 235 million Although structurally related to opioid agonists, DXM packages (Spangler et al. 2016). Codeine, levopropoxy- does not have relevant pharmacological activity at opi- phene, and noscapine are other opioids derivatives also oid receptors (Chen et al. 2005). DXM also is a seroto- used as antitussive agents (Dinis-Oliveira 2019). DXM nergic drug having a potential risk for serotonin may have several other medical uses, such as pain man- syndrome (Chyka et al. 2007; Dilich and Girgis 2017), agement, treatment of pseudobulbar affect, and psy- and enhances the analgesic action of morphine and chological applications (El-Naby and Kamel 2015). It is presumably other l-receptor agonists. purported to produce less constipation than codeine. Regarding metabolism, DXM is primarily metabolized DXM has a wide range of pharmacodynamic effects by cytochrome P450 (isoenzyme CYP2D6) producing its as consequence of its activity on numerous channels major active metabolite dextrorphan (DXO). and receptors. DXMs popular antitussive effects are Nevertheless, DXM is also a pharmacological active believed to result from its sigma-1 receptors (r1R) compound (Pechnick and Poland 2004). The expression CONTACT Ricardo Jorge Dinis-Oliveira [email protected], [email protected] Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, Alameda Prof. Hern^ani Monteiro, Porto 4200-319, Portugal ß 2020 Informa UK Limited, trading as Taylor & Francis Group DRUG METABOLISM REVIEWS 259 of CYP2D6 is genetically controlled and this enzyme This review aims to gather as much information as pos- polymorphism contributes to a variability in drug sible available in the literature concerning its chemical response and toxicity (Meyer et al. 1990; Burton et al. structure, pharmacokinetics, pharmacodynamics, 2006; Gaedigk 2013). This is even more relevant since pharmacogenomics and abuse potential, as well as clin- DXM is widely consumed and usually ingested licitly ical effects, toxicological analysis and treatment of when combined with other drugs, or illicitly as mixtures acute intoxications, with special focus on DXM metabol- of uncertain composition (Chyka et al. 2007; Banken ism and its implications in clinical and forensic and Foster 2008; Brown et al. 2018). interpretations. Even though DXM has been used as a nonprescrip- tion drug since 1958, only recently it has been consid- Methodology ered as a seriously emerging substance of abuse, with its recreational use becoming more frequent and wide- A narrative review was performed by searching articles spread since the 1990s (Banken and Foster 2008; in English, French, Spanish, and Portuguese in PubMed, Spangler et al. 2016). The availability of DXM, either in Scopus, Web of Science, and PsycINFO concerning legal, OTC formulations or as illicitly manufactured powder or laboratorial, clinical, ethical, forensic, and safety con- tablets containing DXM, alone or with other drugs, and cerns related to DXM and its known metabolizing the easy access through the internet may facilitate the enzymes and metabolites, without a limiting period. abuse and fatalities (Brown et al. 2018). The reports of Furthermore, electronic copies of the full papers were abuse involve most commonly teenagers, but also obtained from the retrieved journal articles and books young adults (Spangler et al. 2016). Data from related to this topic, which were further reviewed for pos- American Association of Poison Control Centers from sible additional publications related to pharmacokinetics 2000 to 2015 show a total number of 72,260 calls and pharmacodynamics aspects of DXM. Besides these reporting intentional abuse of a DXM cough and cold inclusion criteria, the World Health Organization (WHO) product, with a peak in 2006 (Karami et al. 2018). Since pre-review report on DXM was also reviewed to identify antitussive OTC medications that contain DXM are safe possible additional publications related to human and and effective, and acute bothersome coughing can non-human in vivo and in vitro studies. impair daily life, self-medication with these products, can contribute to make them about 85–90% of all med- Chemistry of dextromethorphan and analogs icines sold as cough suppressants and a total accounted of around 235 million of packages purchased in 2015 DXM (3-methoxy-N-methylmorphinan; Figure 1)isthe (Spangler et al. 2016). dextrorotatory [d-or(–)] enantiomer of levomethorphan Therefore, it is important to understand how DXM [l-or(þ)], which is the methyl ether of DXO (3-hydroxy-N- produces its pharmacological and toxicological effects. methylmorphinan) and levorphanol, respectively (Sromek Racemethorphan Dromoran® O HO O H N H N H H Dextromethorphan Dextrorphan O H (DXM; antitussive and (DXO; antitussive and hallucinogen) hallucinogen) N HO O HO Codeine H N H N H H Levomethorphan Levorphanol (analgesic) (Levo-Dromoran®; analgesic) Figure 1. Chemical structure of dextromethorphan and analogs. 260 A. R. SILVA AND R. J. DINIS-OLIVEIRA et al. 2014). Although former levorotatory compounds are DXM has been synthesized from a benzylisoquino- both opioid analgesics, only levorphanol was clinically line by a process known as Grewe’s cyclization to give developed (Gudin et al. 2016;LeRouzicetal.2019). the corresponding morphinan with a three-dimensional Moreover, levorphanol is the levorotatory isomer of structure. The isoquinoline is 1,2,3,4,5,6,7,8-octahydro-1- racemic 3-hydroxy-N-methylmorphinan (DromoranVR )and (4-methoxybenzyl) isoquinoline (there is just one V named as Levo-Dromoran R . DXM is named according to residual double bond at the fusion position
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