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Pharmacokinetic and Pharmacodynamic of Bupropion: Integrative Overview of Relevant Clinical and Forensic Aspects

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Pharmacokinetic and Pharmacodynamic of Bupropion: Integrative Overview of Relevant Clinical and Forensic Aspects Drug Metabolism Reviews ISSN: 0360-2532 (Print) 1097-9883 (Online) Journal homepage: https://www.tandfonline.com/loi/idmr20 Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects Rafaela Costa, Nuno G. Oliveira & Ricardo Jorge Dinis-Oliveira To cite this article: Rafaela Costa, Nuno G. Oliveira & Ricardo Jorge Dinis-Oliveira (2019): Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects, Drug Metabolism Reviews, DOI: 10.1080/03602532.2019.1620763 To link to this article: https://doi.org/10.1080/03602532.2019.1620763 Accepted author version posted online: 24 May 2019. Published online: 14 Jun 2019. Submit your article to this journal Article views: 35 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 https://doi.org/10.1080/03602532.2019.1620763 REVIEW ARTICLE Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects Rafaela Costaa, Nuno G. Oliveirab and Ricardo Jorge Dinis-Oliveiraa,c,d aDepartment of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, Porto, Portugal; bResearch Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal; cUCIBIO, REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal; dIINFACTS – Institute of Research and Advanced Training in Health Sciences and Technologies, Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, Gandra, Portugal ABSTRACT ARTICLE HISTORY Bupropion is an atypical antidepressant of the aminoketone group, structurally related to cathi- Received 15 February 2019 none, associated with a wide interindividual variability. An extensive pharmacokinetic and phar- Accepted 15 May 2019 macodynamic review of bupropion was performed, also focusing on chemical, pharmacological, KEYWORDS toxicological, clinical and forensic aspects of this drug without a limiting period. Bupropion is a Bupropion; pharmacokinet- chiral, basic, highly lipophilic drug, clinically used as racemate that undergoes extensive stereo- ics; metabolism; selective metabolism. Its major active metabolites, hydroxybupropion, threohydrobupropion, and pharmacodynamics; poly- erythrohydrobupropion reach higher plasma concentrations than bupropion. Bupropion exerts its morphisms; forensic and effects mainly by inhibiting dopamine and norepinephrine reuptake and by blocking several nic- clinical aspects otinic receptors. Recent reports highlight recreational use of bupropion via intranasal insufflation and intravenous use. Seizures, insomnia, agitation, headache, dry mouth, and nausea are some of the reported adverse effects. Neurologic effects are major signs of intoxication that should be carefully managed. Finally, the characterization of the polymorphic enzymes involved in the metabolism of bupropion is essential to understand factors that may influence the interindividual and intraindividual variability in bupropion metabolite exposure, including the evaluation of potential drug–drug interactions and pharmacogenetic implications. Introduction Bupropion (synonym: amfebutamone; (± or rac)- 2-(tert-butylamino)-3’chloropropiophenone; 1-(3-chlor- According to the World Health Organization, depressive ophenyl)-2-[(1,1-dimethylethyl)amino)]-propan-1-one; disorders are the single largest contributors to global tert disability, as shown by 7.5% of all Years Lived with 2-( -butylamino)-1-(3-chlorophenyl)propan-1-one) Disability (World Health Organization 2017). Depression was first described in 1969 (Mehta 1969) and then is also the major contributor to suicide. Antidepressants approved in 1985 by US Food and Drug Administration and/or psychotherapy are clinical approaches for the (FDA) as a major depressive disorder treatment, with a treatment of major depressive disorders. There are sev- maximum dose of 900 mg/d. Due to high incidence of eral classes of antidepressants: monoamine oxidase seizures in bulimic patients, bupropion was subse- inhibitors (MAOIs; e.g. phenelzine), tricyclic antidepres- quently withdrawn from the market (Horne et al. 1988). sants (e.g. desipramine), selective serotonin reuptake Further studies evidenced that the seizure risk was inhibitors (SSRIs; e.g. fluoxetine), serotonin and norepin- dose-dependent and bupropion was reintroduced in ephrine reuptake inhibitors (SNRIs; e.g. venlafaxine), the market with a maximum dose of 450 mg/d and con- and the atypical antidepressants (i.e. drugs that act by a traindicated for patients with increased risk of seizures mechanism of action other than the previously men- (Davidson 1989). Besides this immediate release (IR) for- tioned; e.g. bupropion). Even though the adverse mulation, delayed-release dosages by the administra- effects, safety and tolerability profile of antidepressants tion of sustained release (SR) and extended release (XL) vary widely between classes, the efficacy of different formulations are also available in order to maintain sta- classes of antidepressants is similar. ble plasmatic concentrations for a specific period of CONTACT Rafaela Costa [email protected]; Ricardo Jorge Dinis-Oliveira [email protected], [email protected] Department of Public Health and Forensic Sciences, and Medical Education, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal ß 2019 Informa UK Limited, trading as Taylor & Francis Group 2 R. COSTA ET AL. time with minimum side effects (Jefferson et al. 2005). Additional reports were obtained from the references Bupropion sustained release formulation was approved of the articles identified in the original search. alone or in combination with transdermal nicotine for VR the treatment of smoking cessation (Zyban ), whether Chemical structure and formulation or not a smoker was depressed (Hurt et al. 1997), and when combined with naltrexone for the treatment of The cathinone has a phenylalkylamine structure and is obesity (Yanovski and Yanovski 2015; Saunders et al. the main psychoactive naturally occurring alkaloid Catha edulis 2016). Bupropion extended release formulations were found in the leaves of the plant, commonly approved for the treatment of seasonal affective dis- known as khat (Marinetti and Antonides 2013; order (Niemegeers et al. 2013). Other off-label uses illus- Watterson and Olive 2014). Structural modifications trate the multifaceted therapeutic potential of of the cathinone core originate several compounds, bupropion for the treatment of the attention-deficit/ known as synthetic cathinones. In view of their chem- ical resemblance with amphetamines and due to the hyperactivity disorder (Wilens et al. 2005) and the psy- presence of the beta-ketone group at the b-position of choactive substance dependence, namely metham- the side chain, synthetic cathinones are often termed phetamine dependence (Charntikov et al. 2018). At the “bk-amphetamines” or “b-keto amphetamines” (Kelly pharmacodynamic level, bupropion is a noradrenaline 2011; Prosser and Nelson 2012; Miller et al. 2017; and dopamine reuptake inhibitor (NDRI) but also acts Valento and Lebin 2017). Synthetic cathinones are less as a non-competitive inhibitor of nicotine a b receptor 4 2 lipophilic than amphetamines due to the increased and by allosteric blockade of the 5-hydroxytryptamine polarity added by the b-keto moiety. Functional group (5-HT) receptors (Pandhare et al. 2017). 3A substitutions to the core structure of the parent cathi- In view of the relevance of bupropion in the clinical none compound (Figure 1) have yielded a large number and forensic context, an extensive knowledge on of synthetic cathinones, which can be separated into ’ bupropion s chemistry, pharmacokinetics, and pharma- four different chemical families based on the substitu- codynamics is crucial to maximize its clinical efficacy tions made (Valente et al. 2014; Miller et al. 2017; and predict its tolerability and safety profile when deal- Nobrega and Dinis-Oliveira 2018). Many synthetic cathi- ing with intoxications. This approach has also been par- nones (e.g. methcathinone and diethylpropion) were ticularly useful to explain clinical and forensic outcomes initially synthetized for medical purposes (e.g. anti- of different xenobiotics (Barbosa et al. 2016; Dinis- depressant and appetite suppressant, respectively). Oliveira 2016a, 2016b, 2017a, 2017b, 2017c). Further However, they were withdrawn from the market due to information on the genotoxicity and carcinogenicity its psychostimulant effects and abuse liability (Kelly data available for bupropion is also included herewith. 2011). Bupropion (Figure 1), a member of the N-alky- Overall, this work aims to provide a comprehensive lated cathinone group, is the only synthetic derivative review of the current data regarding the chemical, currently used in the clinical setting. Bupropion is a pharmacological, toxicological and forensic aspects monocyclic phenylaminoketone compound that of bupropion. besides the core structure of the parent drug has a tert- butyl moiety attached to the amine group and a chlor- ine group attached to the position 3’ of the aromatic Methodology ring. Both the phenyl ring substitution and the size and An exhaustive search was made in PubMed concerning branching of the N-alkyl group reduce the
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