2,282
Views
56
CrossRef citations to date
0
Altmetric
Review Articles

Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects

, &
Pages 293-313 | Received 15 Feb 2019, Accepted 15 May 2019, Published online: 14 Jun 2019

References

  • Amerio A, Gálvez JF, Odone A, Dalley SA, Ghaemi SN. 2015. Carcinogenicity of psychotropic drugs: a systematic review of US Food and Drug Administration–required preclinical in vivo studies. Aust NZ J Psychiatry. 49:686–696.
  • Arias HR, Santamaria A, Ali SF. 2009. Pharmacological and neurotoxicological actions mediated by bupropion and diethylpropion. Int Rev Neurobiol. 88:223–255.
  • Barbosa J, Faria J, Queiros O, Moreira R, Carvalho F, Dinis-Oliveira RJ. 2016. Comparative metabolism of tramadol and tapentadol: a toxicological perspective. Drug Metab Rev. 48:577–592.
  • Batra S, Bhushan R. 2016. Resolution of enantiomers of bupropion and its metabolites by liquid chromatography. Biomed Chromatogr. 30:670–682.
  • Benowitz NL, Zhu AZ, Tyndale RF, Dempsey D, Jacob P 3rd. 2013. Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state. Pharmacogenet Genomics. 23:135–141.
  • Bhattacharya SK, Nathawat LS, Damani P, Choksi AK, Banik A, Sinha K, Bhattacharya AS. 2013. Assessment of potential in vitro genotoxic and cytotoxic effects of bupropion hydrochloride (Wellbutrin) in human peripheral lymphocytes and human cortical neuron. Toxicol Int. 20:11–18.
  • Bhattacharya C, Kirby D, Van Stipdonk M, Stratford RE. 2019. Comparison of in vitro stereoselective metabolism of bupropion in human, monkey, rat, and mouse liver microsomes. Eur J Drug Metab Pharmacokinet. 4:261-274.
  • Bolen RD, Campbell Z, Bonilha L, Edwards JC. 2016. Alpha coma related to intentional bupropion overdose. J Neurol Sci. 365:48–49.
  • Bondarev ML, Bondareva TS, Young R, Glennon RA. 2003. Behavioral and biochemical investigations of bupropion metabolites. Eur J Pharmacol. 474:85–93.
  • Bowers GN Jr, Onoroski M. 1990. Hyperchloremia and the incidence of bromism in 1990. Clin Chem. 36:1399–1403.
  • Brambilla G, Martelli A. 2009. Update on genotoxicity and carcinogenicity testing of 472 marketed pharmaceuticals. Mutat Res. 681:209–229.
  • Brambilla G, Mattioli F, Martelli A. 2009. Genotoxic and carcinogenic effects of antipsychotics and antidepressants. Toxicology. 261:77–88.
  • Bredeloux P, Dubuc I, Costentin J. 2007. Comparisons between bupropion and dexamphetamine in a range of in vivo tests exploring dopaminergic transmission. Br J Pharmacol. 150:711–719.
  • Briggs GG, Samson JH, Ambrose PJ, Schroeder DH. 1993. Excretion of bupropion in breast milk. Ann Pharmacother. 27:431–433.
  • Brown KM, Crouch BI. 2017. Bupropion overdose: significant toxicity in pediatrics. Clin Pediatr Emerg Med. 18:212–217.
  • Bryant SG, Guernsey BG, Ingrim NB. 1983. Review of bupropion [Review]. Clin Pharm. 2:525–537.
  • Bucklin MH, Gorodetsky RM, Wiegand TJ. 2013. Prolonged lipemia and pancreatitis due to extended infusion of lipid emulsion in bupropion overdose. Clin Toxicol (Phila). 51:896–898.
  • Butz RF, Schroeder DH, Welch RM, Mehta NB, Phillips AP, Findlay JW. 1981. Radioimmunoassay and pharmacokinetic profile of bupropion in the dog. J Pharmacol Exp Ther. 217:602–610.
  • Caillier B, Pilote S, Castonguay A, Patoine D, Menard-Desrosiers V, Vigneault P, Hreiche R, Turgeon J, Daleau P, De Koninck Y. 2012. QRS widening and QT prolongation under bupropion: a unique cardiac electrophysiological profile. Fundam Clin Pharmacol. 26:599–608.
  • Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI. 2014. Bupropion and bupropion analogs as treatments for CNS disorders. Adv Pharmacol. 69:177–216.
  • Casey ER, Scott MG, Tang S, Mullins ME. 2011. Frequency of false positive amphetamine screens due to bupropion using the Syva EMIT II immunoassay. J Med Toxicol. 7:105–108.
  • Chao CT, Wu VC, Wang WJ. 2012. Charcoal hemoperfusion for bupropion overdose with ventricular tachycardia and status epilepticus. J Formos Med Assoc. 111:51–52.
  • Charntikov S, Pittenger ST, Pudiak CM, Bevins RA. 2018. The effect of N-acetylcysteine or bupropion on methamphetamine self-administration and methamphetamine-triggered reinstatement of female rats. Neuropharmacology. 135:487–495.
  • Chhabra N, DesLauriers C, Wahl M, Bryant SM. 2018. Management of severe bupropion poisoning with intravenous lipid emulsion. Clin Toxicol (Phila). 56:51–54.
  • Choi HD, Shin WG. 2015. Lack of association between DRD2 Taq1A gene polymorphism and smoking cessation therapy: a meta-analysis. Int J Clin Pharmacol Ther. 53:415–421.
  • Coles R, Kharasch ED. 2007. Stereoselective analysis of bupropion and hydroxybupropion in human plasma and urine by LC/MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 857:67–75.
  • Coles R, Kharasch ED. 2008. Stereoselective metabolism of bupropion by cytochrome P4502B6 (CYP2B6) and human liver microsomes. Pharm Res. 25:1405–1411.
  • Connarn JN, Flowers S, Kelly M, Luo R, Ward KM, Harrington G, Moncion I, Kamali M, McInnis M, Feng MR. 2017. Pharmacokinetics and pharmacogenomics of bupropion in three different formulations with different release kinetics in healthy human volunteers. Aaps J. 19:1513–1522.
  • Connarn JN, Zhang X, Babiskin A, Sun D. 2015. Metabolism of bupropion by carbonyl reductases in liver and intestine. Drug Metab Dispos. 43:1019–1027.
  • Cooper BR, Wang CM, Cox RF, Norton R, Shea V, Ferris RM. 1994. Evidence that the acute behavioral and electrophysiological effects of bupropion (Wellbutrin®) are mediated by a noradrenergic mechanism. Neuropsychopharmacology. 11:133.
  • Dagan Y, Yager J. 2018. Severe bupropion XR abuse in a patient with long-standing bulimia nervosa and complex PTSD. Int J Eat Disord. 51:1207–1209.
  • Damaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ, Martin BR. 2004. Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors. Mol Pharmacol. 66:675–682.
  • Damaj MI, Grabus SD, Navarro HA, Vann RE, Warner JA, King LS, Wiley JL, Blough BE, Lukas RJ, Carroll FI. 2010. Effects of hydroxymetabolites of bupropion on nicotine dependence behavior in mice. J Pharmacol Exp Ther. 334:1087–1095.
  • Davidson J. 1989. Seizures and bupropion: a review. J Clin Psychiatry. 50:256–261.
  • Denooz R, Mercerolle M, Lachatre G, Charlier C. 2010. Ultra-performance liquid chromatography- tandem mass spectrometry method for the determination of bupropion and its main metabolites in human whole blood. J Anal Toxicol. 34:280–286.
  • Dinis-Oliveira RJ. 2016a. Metabolomics of Delta9-tetrahydrocannabinol: implications in toxicity. Drug Metab Rev. 48:80–87.
  • Dinis-Oliveira RJ. 2016b. Metabolomics of methadone: clinical and forensic toxicological implications and variability of dose response. Drug Metab Rev. 48:568–576.
  • Dinis-Oliveira RJ. 2017. Metabolic profile of oxazepam and related benzodiazepines: clinical and forensic aspects. Drug Metab Rev. 49:451–463.
  • Dinis-Oliveira RJ. 2017a. Metabolism and metabolomics of ketamine: a toxicological approach. Forensic Sci Res. 2:2–10.
  • Dinis-Oliveira RJ. 2017b. Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. Drug Metab Rev. 49:84–91.
  • Dinis-Oliveira RJ. 2018. Metabolic profiles of propofol and fospropofol: clinical and forensic interpretative aspects. Biomed Res Int. 2018:6852857.
  • Donnelly K, Walkowiak HB, Donnelly C, Jenkinson E, Rizkalla J, Langford N. 2010. Bupropion toxicokinetic: a case report. Clin Toxicol (Phila). 48:385–387.
  • Druteika D, Zed PJ. 2002. Cardiotoxicity following bupropion overdose. Ann Pharmacother. 36:1791–1795.
  • Dunner DL, Zisook S, Billow AA, Batey SR, Johnston JA, Ascher JA. 1998. A prospective safety surveillance study for bupropion sustained-release in the treatment of depression. J Clin Psychiatry. 59:366–373.
  • Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT. 2006. Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent. CNS Drug Rev. 12:178–207.
  • Ekins S, Wrighton SA. 1999. The role of CYP2B6 in human xenobiotic metabolism. Drug Metab Rev. 31:719–754.
  • Fang QK, Han Z, Grover P, Kessler D, Senanayake CH, Wald SA. 2000. Rapid access to enantiopure bupropion and its major metabolite by stereospecific nucleophilic substitution on an α-ketotriflate. Tetrahedron: Asymmetry. 11:3659–3663.
  • Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM, Lindley CM. 2000. Validation of bupropion hydroxylation as a selective marker of human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos. 28:1222–1230.
  • Faucette SR, Hawke RL, Shord SS, Lecluyse EL, Lindley CM. 2001. Evaluation of the contribution of cytochrome P450 3A4 to human liver microsomal bupropion hydroxylation. Drug Metab Dispos. 29:1123–1129.
  • Fava M, Rush AJ, Thase ME, Clayton A, Stahl SM, Pradko JF, Johnston JA. 2005. 15 Years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry. 7:106–113.
  • Fiedorowicz JG, Swartz KL. 2004. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract. 10:239–248.
  • Findlay JW, Van Wyck Fleet J, Smith PG, Butz RF, Hinton ML, Blum MR, Schroeder DH. 1981. Pharmacokinetics of bupropion, a novel antidepressant agent, following oral administration to healthy subjects. Eur J Clin Pharmacol. 21:127–135.
  • Foley KF, Cozzi NV. 2003. Novel aminopropiophenones as potential antidepressants. Drug Dev Res. 60:252–260.
  • Foley KF, DeSanty KP, Kast RE. 2006. Bupropion: pharmacology and therapeutic applications. Expert Rev Neurother. 6:1249–1265.
  • Gheldiu AM, Popa A, Neag M, Muntean D, Bocsan C, Buzoianu A, Vlase L, Tomuta I, Briciu C. 2016. Assessment of a potential pharmacokinetic interaction between nebivolol and bupropion in healthy volunteers. Pharmacology. 98:190–198.
  • Grabus SD, Carroll FI, Damaj MI. 2012. Bupropion and its main metabolite reverse nicotine chronic tolerance in the mouse. Nicotine Tob Res. 14:1356–1361.
  • Gufford BT, Lu JB, Metzger IF, Jones DR, Desta Z. 2016. Stereoselective glucuronidation of bupropion metabolites in vitro and in vivo. Drug Metab Dispos. 44:544–553.
  • Gulec H, Babayigit M, Kurtay A, Sahap M, Ulus F, Tutal Z, Horasanli E. 2016. Seizure due to multiple drugs intoxication: a case report. Braz J Anesthesiol (English Edition). 66:651–653.
  • Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2017. 2016 annual report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila). 55:1072–1252.
  • Hassan EA, Aziz KBA, El-Awadi ME, Hanan MA. 2011. Anti-mutagenic effects of fennel plant (Foeniculum vulgare Mill) seeds and pure anethole: an in vitro test on mice. Nat Sci. 9:21–26.
  • Hayashi M, Kamata E, Hirose A, Takahashi M, Morita T, Ema M. 2005. In silico assessment of chemical mutagenesis in comparison with results of Salmonella microsome assay on 909 chemicals. Mutat Res/Genet Toxicol Environ Mutagen. 588:129–135.
  • Heise CW, Skolnik AB, Raschke RA, Owen-Reece H, Graeme KA. 2016. Two cases of refractory cardiogenic shock secondary to bupropion successfully treated with veno-arterial extracorporeal membrane oxygenation. J Med Toxicol. 12:301–304.
  • Henshall DC, Durmuller N, White HS, Williams R, Moser P, Dunleavy M, Silverstone PH. 2009. Electroencephalographic and behavioral convulsant effects of hydrobromide and hydrochloride salts of bupropion in conscious rodents. Neuropsychiatr Dis Treat. 5:189–206.
  • Hesse LM, Venkatakrishnan K, Court MH, von Moltke LL, Duan SX, Shader RI, Greenblatt DJ. 2000. CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants. Drug Metab Dispos. 28:1176–1183.
  • Hilliard WT, Barloon L, Farley P, Penn JV, Koranek A. 2013. Bupropion diversion and misuse in the correctional facility. J Correct Health Care. 19:211–217.
  • Hoiseth G, Haslemo T, Uthus LH, Molden E. 2015. Effect of CYP2B6*6 on steady-state serum concentrations of bupropion and hydroxybupropion in psychiatric patients: a study based on therapeutic drug monitoring data. Ther Drug Monit. 37:589–593.
  • Horne RL, Ferguson JM, Pope HG Jr, Hudson JI, Lineberry CG, Ascher J, Cato A. 1988. Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry. 49:262–266.
  • Hsyu PH, Singh A, Giargiari TD, Dunn JA, Ascher JA, Johnston JA. 1997. Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers. J Clin Pharmacol. 37:737–743.
  • Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, Khayrallah MA, Schroeder DR, Glover PN, Sullivan CR, et al. 1997. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med. 337:1195–1202.
  • ICH. 2017. Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk. In: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use I, editor. M7(R1).
  • Jain P, Paliwal N, Dubey N, Sharma S, Singh B. 2012. Liquid chromatography tandem mass spectrometry method for quantification of buproprion and hydroxy buproprion in human plasma and its application to bioequivalence study. Int J Drug Dev Res. 4:381–392.
  • Jefferson JW, Pradko JF, Muir KT. 2005. Bupropion for major depressive disorder: pharmacokinetic and formulation considerations. Clin Ther. 27:1685–1695.
  • Jepsen F, Matthews J, Andrews FJ. 2003. Sustained release bupropion overdose: an important cause of prolonged symptoms after an overdose. Emerg Med J. 20:560–561.
  • Johnston AJ, Ascher J, Leadbetter R, Schmith VD, Patel DK, Durcan M, Bentley B. 2002. Pharmacokinetic optimisation of sustained-release bupropion for smoking cessation. Drugs. 62:11–24.
  • Johnston JA, Fiedler-Kelly J, Glover ED, Sachs DP, Grasela TH, DeVeaugh-Geiss J. 2001. Relationship between drug exposure and the efficacy and safety of bupropion sustained release for smoking cessation. Nicotine Tob Res. 3:131–140.
  • Kalkhoran S, Benowitz NL, Rigotti NA. 2018. Reprint of: prevention and treatment of tobacco use: JACC *Health Promotion Series. J Am Coll Cardiol. 72:2964–2979.
  • Kelly JP. 2011. Cathinone derivatives: a review of their chemistry, pharmacology and toxicology. Drug Test Anal. 3:439–453.
  • Khan SR, Berendt RT, Ellison CD, Ciavarella AB, Asafu-Adjaye E, Khan MA, Faustino PJ. 2016. Bupropion hydrochloride. Profiles Drug Subst Excip Relat Methodol. 41:1–30.
  • Kharasch ED, Crafford A. 2019. Common polymorphisms of CYP2B6 influence stereoselective bupropion disposition. Clin Pharmacol Therapeut. 105:142-152.
  • Kharasch ED, Mitchell D, Coles R. 2008. Stereoselective bupropion hydroxylation as an in vivo phenotypic probe for cytochrome P4502B6 (CYP2B6) activity. J Clin Pharmacol. 48:464–474.
  • Kleemann A, Engel J, Kutscher B, Reichert D. 2009. Pharmaceutical substances: syntheses, patents and applications of the most relevant AIPs. 5th ed. New York (NY): Thieme Stuttgart.
  • Kriikku P, Ojanpera I. 2016. The relationship between bupropion and suicide in post-mortem investigations. Forensic Sci Int. 266:343–348.
  • Kunz SN, Þórðardóttir S, Rúnarsdóttir R. 2018. Restraint-related asphyxia on the basis of a drug-induced excited delirium. Forensic Sci Int. 288:e5–e9.
  • Laib AK, Brunen S, Pfeifer P, Vincent P, Hiemke C. 2014. Serum concentrations of hydroxybupropion for dose optimization of depressed patients treated with bupropion. Ther Drug Monit. 36:473–479.
  • Laizure SC, DeVane CL. 1985. Stability of bupropion and its major metabolites in human plasma. Ther Drug Monit. 7:447–450.
  • Lee AM, Jepson C, Hoffmann E, Epstein L, Hawk LW, Lerman C, Tyndale RF. 2007. CYP2B6 genotype alters abstinence rates in a bupropion smoking cessation trial. Biol Psychiatry. 62:635–641.
  • Livshits Z, Sampson BA, Howland MA, Hoffman RS, Nelson LS. 2015. Retained drugs in the gastrointestinal tracts of deceased victims of oral drug overdose. Clin Toxicol (Phila). 53:113–118.
  • Loboz KK, Gross AS, Ray J, McLachlan AJ. 2005. HPLC assay for bupropion and its major metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 823:115–121.
  • Louik C, Kerr S, Mitchell AA. 2014. First-trimester exposure to bupropion and risk of cardiac malformations. Pharmacoepidemiol Drug Saf. 23:1066–1075.
  • Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI. 2010. Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation. J Med Chem. 53:4731–4748.
  • Ma H, Zhang W, Yang X, Zhang Y, Wei S, Zhang H, Ma Y, Dang H. 2018. Effects of genetic polymorphisms of CYP2B6 on the pharmacokinetics of bupropion and hydroxybupropion in healthy Chinese subjects. Med Sci Monit. 24:2158–2163.
  • Marinetti LJ, Antonides HM. 2013. Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results. J Anal Toxicol. 37:135–146.
  • Martin P, Massol J, Colin JN, Lacomblez L, Puech AJ. 1990. Antidepressant profile of bupropion and three metabolites in mice. Pharmacopsychiatry. 23:187–194.
  • Masters AR, McCoy M, Jones DR, Desta Z. 2016a. Stereoselective method to quantify bupropion and its three major metabolites, hydroxybupropion, erythro-dihydrobupropion, and threo-dihydrobupropion using HPLC-MS/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 1015–1016:201–208.
  • Masters AR, Gufford BT, Lu JB, Metzger IF, Jones DR, Desta Z. 2016b. Chiral plasma pharmacokinetics and urinary excretion of bupropion and metabolites in healthy volunteers. J Pharmacol Exp Ther. 358:230–238.
  • Matsunaga T, Shintani S, Hara A. 2006. Multiplicity of mammalian reductases for xenobiotic carbonyl compounds. Drug Metab Pharmacokinet. 21:1–18.
  • McCormick J. 2002. Recreational bupropion abuse in a teenager. Br J Clin Pharmacol. 53:214–214.
  • Mehta NB, inventor; Burroughs Wellcome Co. http://www.freepatentsonline.com/3819706.html, assignee. 1969. Meta chloro substituted-alpha-butylamino-propiophenones. Great Britain.
  • Meng F, Yan J, Li Y, Fu PP, Fossom LH, Sood RK, Mans DJ, Chu P-I, Moore MM, Chen T. 2013. Genotoxicity of 2-bromo-3'-chloropropiophenone. Toxicol Appl Pharmacol. 270:158–163.
  • Mercerolle M, Denooz R, Lachatre G, Charlier C. 2008. A fatal case of bupropion (Zyban) overdose. J Anal Toxicol. 32:192–196.
  • Meyer A, Vuorinen A, Zielinska AE, Strajhar P, Lavery GG, Schuster D, Odermatt A. 2013. Formation of threohydrobupropion from bupropion is dependent on 11β-hydroxysteroid dehydrogenase 1. Drug Metab Dispos. 41:1671–1678.
  • Miller B, Kim J, Concheiro M. 2017. Stability of synthetic cathinones in oral fluid samples. Forensic Sci Int. 274:13–21.
  • Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2016. 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol (Phila). 54:924–1109.
  • Musso DL, Mehta NB, Soroko FE, Ferris RM, Hollingsworth EB, Kenney BT. 1993. Synthesis and evaluation of the antidepressant activity of the enantiomers of bupropion. Chirality. 5:495–500.
  • Niemegeers P, Dumont GJ, Patteet L, Neels H, Sabbe BG. 2013. Bupropion for the treatment of seasonal affective disorder. Expert Opin Drug Metab Toxicol. 9:1229–1240.
  • Nirogi R, Palacharla RC, Mohammed AR, Manoharan A, Ponnamaneni RK, Bhyrapuneni G. 2015. Evaluation of metabolism dependent inhibition of CYP2B6 mediated bupropion hydroxylation in human liver microsomes by monoamine oxidase inhibitors and prediction of potential as perpetrators of drug interaction. Chem Biol Interact. 230:9–20.
  • Nobrega L, Dinis-Oliveira RJ. 2018. The synthetic cathinone α-pyrrolidinovalerophenone (α-PVP): pharmacokinetic and pharmacodynamic clinical and forensic aspects. Drug Metab Rev. 50:125–139.
  • Noda AH, Schu U, Maier T, Knake S, Rosenow F. 2017. Epileptic seizures, coma and EEG burst-suppression from suicidal bupropion intoxication. Epileptic Disord. 19:109–113.
  • Oppek K, Koller G, Zwergal A, Pogarell O. 2014. Intravenous administration and abuse of bupropion: a case report and a review of the literature. J Addict Med. 8:290–293.
  • Pandhare A, Pappu AS, Wilms H, Blanton MP, Jansen M. 2017. The antidepressant bupropion is a negative allosteric modulator of serotonin type 3A receptors. Neuropharmacology. 113:89–99.
  • Paoloni R, Szekely I. 2002. Sustained-release bupropion overdose: a new entity for Australian emergency departments. Emerg Med (Fremantle). 14:109–112.
  • Patel K, Allen S, Haque MN, Angelescu I, Baumeister D, Tracy DK. 2016. Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Ther Adv Psychopharmacol. 6:99–144.
  • Petrides AK, Moskowitz J, Johnson-Davis KL, Jannetto PJ, Langman LJ, Clarke W, Marzinke MA. 2014. The development and validation of a turbulent flow-liquid chromatography-tandem mass spectrometric method for the simultaneous quantification of citalopram, sertraline, bupropion and hydroxybupropion in serum. Clin Biochem. 47:73–79.
  • Petsalo A, Turpeinen M, Tolonen A. 2007. Identification of bupropion urinary metabolites by liquid chromatography/mass spectrometry. Rapid Commun Mass Spectrom. 21:2547–2554.
  • Piper BJ, Suarez MJ, Piserchio JP, Shah DT, Simoyan OM, McCall KL, Desrosiers CE, Nichols SD. 2018. Illicit and prescription drug misuse as reported to the Maine Diversion Alert Program. Forensic Sci Int. 285:65–71.
  • Prosser JM, Nelson LS. 2012. The toxicology of bath salts: a review of synthetic cathinones. J Med Toxicol. 8:33–42.
  • Ramcharitar V, Levine BS, Goldberger BA, Caplan YH. 1992. Bupropion and alcohol fatal intoxication: case report. Forensic Sci Int. 56:151–156.
  • Ramirez Fernandez MD, Wille SM, Hill V, Samyn N. 2016. Determination of antidepressants in hair via UHPLC-MS/MS as a complementary informative tool for clinical and forensic toxicological assessments. Ther Drug Monit. 38:751–760.
  • Rau KS, Birdsall E, Hanson JE, Johnson-Davis KL, Carroll FI, Wilkins DG, Gibb JW, Hanson GR, Fleckenstein AE. 2005. Bupropion increases striatal vesicular monoamine transport. Neuropharmacology. 49:820–830.
  • Reese MJ, Wurm RM, Muir KT, Generaux GT, St John-Williams L, McConn DJ. 2008. An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction. Drug Metab Dispos. 36:1198–1201.
  • Reeves RR, Ladner ME. 2013. Additional evidence of the abuse potential of bupropion. J Clin Psychopharmacol. 33:584–585.
  • Reidy L, Walls HC, Steele BW. 2011. Crossreactivity of bupropion metabolite with enzyme-linked immunosorbent assays designed to detect amphetamine in urine. Ther Drug Monit. 33:366–368.
  • Rohrig TP, Ray NG. 1992. Tissue distribution of bupropion in a fatal overdose. J Anal Toxicol. 16:343–345.
  • Roshdy HM, Fyiad AA. 2010. Cytogenetic and biochemical effects of anti depression drug (wellbutrin) on male mice. New York Sci. 3:121–126.
  • Sager JE, Choiniere JR, Chang J, Stephenson-Famy A, Nelson WL, Isoherranen N. 2016a. Identification and structural characterization of three new metabolites of bupropion in humans. ACS Med Chem Lett. 7:791–796.
  • Sager JE, Price LS, Isoherranen N. 2016b. Stereoselective metabolism of bupropion to OH-bupropion, threohydrobupropion, erythrohydrobupropion, and 4'-OH-bupropion in vitro. Drug Metab Dispos. 44:1709–1719.
  • Sager JE, Tripathy S, Price LSL, Nath A, Chang J, Stephenson-Famy A, Isoherranen N. 2017. In vitro to in vivo extrapolation of the complex drug–drug interaction of bupropion and its metabolites with CYP2D6; simultaneous reversible inhibition and CYP2D6 downregulation. Biochem Pharmacol. 123:85–96.
  • Saunders KH, Igel LI, Aronne LJ. 2016. An update on naltrexone/bupropion extended-release in the treatment of obesity. Expert Opin Pharmacother. 17:2235–2242.
  • Schifano F, Chiappini S. 2018. Is there a potential of misuse for venlafaxine and bupropion?. Front Pharmacol. 9:239.
  • Schmit G, De Boosere E, Vanhaebost J, Capron A. 2017. Bupropion overdose resulted in a pharmacobezoar in a fatal bupropion (Wellbutrin((R))) sustained-release overdose: postmortem distribution of bupropion and its major metabolites. J Forensic Sci. 62:1674–1676.
  • Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A. 2012. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit Care. 16:R136.
  • Shader RI. 2009. Antidepressants as hydrobromide salts: are they a cause for concern? J Clin Psychopharmacol. 29:317–318.
  • Shah PA, Parekh JM, Shrivastav PS. 2017. Assessment of critical extraction and chromatographic parameters for the determination of bupropion and its three primary metabolites in human plasma by LC-MS/MS. Microchem J. 135:81–90.
  • Shalabi AR, Walther D, Baumann MH, Glennon RA. 2017. Deconstructed analogues of bupropion reveal structural requirements for transporter inhibition versus substrate-induced neurotransmitter release. ACS Chem Neurosci. 8:1397–1403.
  • Silverstone PH, Williams R, McMahon L, Fleming R, Fogarty S. 2008. Convulsive liability of bupropion hydrochloride metabolites in Swiss albino mice. Ann Gen Psychiatry. 7:19.
  • Snyder RD. 2009. An update on the genotoxicity and carcinogenicity of marketed pharmaceuticals with reference to in silico predictivity. Environ Mol Mutagen. 50:435–450.
  • Snyder RD, Green JW. 2001. A review of the genotoxicity of marketed pharmaceuticals. Mutat Res. 488:151–169.
  • Snyder RD, Pearl GS, Mandakas G, Choy WN, Goodsaid F, Rosenblum IY. 2004. Assessment of the sensitivity of the computational programs DEREK, TOPKAT, and MCASE in the prediction of the genotoxicity of pharmaceutical molecules. Environ Mol Mutagen. 43:143–158.
  • Spiller HA, Bottei E, Kalin L. 2008. Fatal bupropion overdose with post mortem blood concentrations. Forensic Sci Med Pathol. 4:47–50.
  • Spiller HA, Ramoska EA, Krenzelok EP, Sheen SR, Borys DJ, Villalobos D, Muir S, Jones-Easom L. 1994. Bupropion overdose: a 3-year multi-center retrospective analysis. Am J Emerg Med. 12:43–45.
  • Spina E, Trifiro G, Caraci F. 2012. Clinically significant drug interactions with newer antidepressants. CNS Drugs. 26:39–67.
  • Stall N, Godwin J, Juurlink D. 2014. Bupropion abuse and overdose. Can Med Assoc J = J L'Assoc Med Canad. 186:1015.
  • Stassinos GL, Klein-Schwartz W. 2016. Bupropion "Abuse" reported to US Poison Centers. J Addict Med. 10:357–362.
  • Stathis M, Scheffel U, Lever SZ, Boja JW, Carroll FI, Kuhar MJ. 1995. Rate of binding of various inhibitors at the dopamine transporter in vivo. Psychopharmacology (Berl.). 119:376–384.
  • Suckow RF, Smith TM, Perumal AS, Cooper TB. 1986. Pharmacokinetics of bupropion and metabolites in plasma and brain of rats, mice, and guinea pigs. Drug Metab Dispos. 14:692–697.
  • Suckow RF, Zhang MF, Cooper TB. 1997. Enantiomeric determination of the phenylmorpholinol metabolite of bupropion in human plasma using coupled achiral–chiral liquid chromatography. Biomed Chromatogr. 11:174–179.
  • Suma R, Kosanam H, Sai Prakash PK. 2006. Stability study of bupropion and olanzapine in formaldehyde solutions. Rapid Commun Mass Spectrom. 20:1390–1394.
  • Swan GE, Jack LM, Valdes AM, Ring HZ, Ton CC, Curry SJ, McAfee T. 2007. Joint effect of dopaminergic genes on likelihood of smoking following treatment with bupropion SR. Health Psychol. 26:361–368.
  • Swan GE, Valdes AM, Ring HZ, Khroyan TV, Jack LM, Ton CC, Curry SJ, McAfee T. 2005. Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR. Pharmacogenomics J. 5:21–29.
  • Teitelbaum AM, Flaker AM, Kharasch ED. 2016a. Development and validation of a high-throughput stereoselective LC-MS/MS assay for bupropion, hydroxybupropion, erythrohydrobupropion, and threohydrobupropion in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 1017–1018:101–113.
  • Teitelbaum AM, Flaker AM, Kharasch ED. 2016b. Development, validation and application of a comprehensive stereoselective LC/MS-MS assay for bupropion and oxidative, reductive, and glucuronide metabolites in human urine. J Chromatogr B Analyt Technol Biomed Life Sci. 1027:239–253.
  • Thase ME, Haight BR, Johnson MC, Hunt T, Krishen A, Fleck RJ, Modell JG. 2008. A randomized, double-blind, placebo-controlled study of the effect of sustained-release bupropion on blood pressure in individuals with mild untreated hypertension. J Clin Psychopharmacol. 28:302–307.
  • Todor I, Popa A, Neag M, Muntean D, Bocsan C, Buzoianu A, Vlase L, Gheldiu AM, Briciu C. 2016. Evaluation of a potential metabolism-mediated drug-drug interaction between atomoxetine and bupropion in healthy volunteers. J Pharm Pharm Sci. 19:198–207.
  • Tucker WE Jr. 1983. Preclinical toxicology of bupropion: an overview. J Clin Psychiatry. 44:60–62.
  • Turpeinen M, Koivuviita N, Tolonen A, Reponen P, Lundgren S, Miettunen J, Metsärinne K, Rane A, Pelkonen O, Laine K. 2007. Effect of renal impairment on the pharmacokinetics of bupropion and its metabolites. Br J Clin Pharmacol. 64:165–173.
  • Turpeinen M, Raunio H, Pelkonen O. 2006. The functional role of CYP2B6 in human drug metabolism: substrates and inhibitors in vitro, in vivo and in silico. Curr Drug Metab. 7:705–714.
  • Valente MJ, Guedes de Pinho P, de Lourdes Bastos M, Carvalho F, Carvalho M. 2014. Khat and synthetic cathinones: a review. Arch Toxicol. 88:15–45.
  • Valento M, Lebin J. 2017. Emerging drugs of abuse: synthetic cannabinoids, phenylethylamines (2C Drugs), and synthetic cathinones. Clin Pediatr Emerg Med. 18:203–211.
  • Vazquez-Gomez E, Arias HR, Feuerbach D, Miranda-Morales M, Mihailescu S, Targowska-Duda KM, Jozwiak K, Garcia-Colunga J. 2014. Bupropion-induced inhibition of α7 nicotinic acetylcholine receptors expressed in heterologous cells and neurons from dorsal raphe nucleus and hippocampus. Eur J Pharmacol. 740:103–111.
  • Walsky RL, Astuccio AV, Obach RS. 2006. Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6. J Clin Pharmacol. 46:1426–1438.
  • Wang TS, Shiah IS, Yeh CB, Chang CC. 2005. Acute psychosis following sustained release bupropion overdose. Prog Neuropsychopharmacol Biol Psychiatry. 29:149–151.
  • Wang X, Vernikovskaya DI, Abdelrahman DR, Hankins GD, Ahmed MS, Nanovskaya TN. 2012. Simultaneous quantitative determination of bupropion and its three major metabolites in human umbilical cord plasma and placental tissue using high-performance liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal. 70:320–329.
  • Watkins SS, Koob GF, Markou A. 2000. Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nicotine Tob Res. 2:19–37.
  • Watterson LR, Olive MF. 2014. Synthetic cathinones and their rewarding and reinforcing effects in rodents. Adv Neurosci (Hindawi). 2014:209875.
  • Weintraub D, Linder MW. 2000. Amphetamine positive toxicology screen secondary to bupropion. Depress Anxiety. 12:53–54.
  • Welch RM, Lai AA, Schroeder DH. 1987. Pharmacological significance of the species differences in bupropion metabolism. Xenobiotica. 17:287–298.
  • Wilens TE, Haight BR, Horrigan JP, Hudziak JJ, Rosenthal NE, Connor DF, Hampton KD, Richard NE, Modell JG. 2005. Bupropion XL in adults with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled study. Biol Psychiatry. 57:793–801.
  • World Health Organization. 2017. Depression and other common mental disorders: global health estimates. Geneva: World Health Organization.
  • Worrall SP, Almond MK, Dhillon S. 2004. Pharmacokinetics of bupropion and its metabolites in haemodialysis patients who smoke. A single dose study. Nephron Clin Pract. 97:c83–c89.
  • Xu H, Loboz KK, Gross AS, McLachlan AJ. 2007. Stereoselective analysis of hydroxybupropion and application to drug interaction studies. Chirality. 19:163–170.
  • Yanovski SZ, Yanovski JA. 2015. Naltrexone extended-release plus bupropion extended-release for treatment of obesity. Jama. 313:1213–1214.
  • Yeniceli D, Şener E, Korkmaz OT, Doğrukol-Ak D, Tuncel N. 2011. A simple and sensitive LC-ESI-MS (ion trap) method for the determination of bupropion and its major metabolite, hydroxybupropion in rat plasma and brain microdialysates. Talanta. 84:19–26.
  • Yoon G, Westermeyer J. 2013. Intranasal bupropion abuse: case report. Am J Addict. 22:180.
  • Zanger UM, Klein K. 2013. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance. Front Genet. 4:24.
  • Zanger UM, Klein K, Saussele T, Blievernicht J, Hofmann MH, Schwab M. 2007. Polymorphic CYP2B6: molecular mechanisms and emerging clinical significance. Pharmacogenomics. 8:743–759.
  • Zhu AZ, Cox LS, Nollen N, Faseru B, Okuyemi KS, Ahluwalia JS, Benowitz NL, Tyndale RF. 2012. CYP2B6 and bupropion's smoking-cessation pharmacology: the role of hydroxybupropion. Clin Pharmacol Ther. 92:771–777.
  • Zhu Y, Kolawole T, Jimenez XF. 2016. Atypical findings in massive bupropion overdose: a case report and discussion of psychopharmacologic issues. J Psychiatr Pract. 22:405–409.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.