Metabolic bioactivation of antidepressants: advance and underlying hepatotoxicity

References

• 2012a. Milnacipran, in: liverTox: clinical and research information on drug-induced liver injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases.
   Google Scholar
• 2012b. Protriptyline, in: liverTox: clinical and research information on drug-induced liver injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases.
   Google Scholar
• 2012c. Tranylcypromine, in: liverTox: clinical and research information on drug-induced liver injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases.
   Google Scholar
• 2013. Serotonin antagonist reuptake inhibitors (SARIs). In: Gebhart GF, Schmidt RF, editors. Encyclopedia of pain. Berlin, Heidelberg: Springer; p. 3471.
   Google Scholar
• 2016. Tranylcypromine. In: Aronson JK, editor. Meyler’s side effects of drugs. Sixteenth edition. Oxford: Elsevier; p. 111–113.
   Google Scholar
• Bonkovsky HL, Blanchette PL, Schned AR. 1986. Severe liver injury due to phenelzine with unique hepatic deposition of extracellular material. Am J Med. 80(4):689–692. doi: 10.1016/0002-9343(86)90826-0.
   PubMed Web of Science ®Google Scholar
• Abbas S Marwaha R. 2022. Amoxapine. Treasure Island (FL): StatPearls Publishing LLC.
   Google Scholar
• Allison R, Guraka A, Shawa IT, Tripathi G, Moritz W, Kermanizadeh A. 2023. Drug induced liver injury – a 2023 update. J Toxicol Environ Health B Crit Rev. 26(8):442–467. doi: 10.1080/10937404.2023.2261848.
   PubMed Web of Science ®Google Scholar
• Anderson BN, Henrikson IR. 1978. Jaundice and eosinophilia associated with amitriptyline. J Clin Psychiatry. 39(9):730–731.
   PubMed Web of Science ®Google Scholar
• Andrade RJ, Lucena MI, Kaplowitz N, García-Muņoz B, Borraz Y, Pachkoria K, García-Cortés M, Fernández MC, Pelaez G, Rodrigo L, et al. 2006. Outcome of acute idiosyncratic drug-induced liver injury: long-term follow-up in a hepatotoxicity registry. Hepatology. 44(6):1581–1588. doi: 10.1002/hep.21424.
   PubMed Web of Science ®Google Scholar
• Aranda-Michel J, Koehler A, Bejarano PA, Poulos JE, Luxon BA, Khan CM, Ee LC, Balistreri WF, Weber FL.Jr. 1999. Nefazodone-induced liver failure: report of three cases. Ann Intern Med. 130(4 Pt 1):285–288. doi: 10.7326/0003-4819-130-4-199902160-00013.
   PubMed Web of Science ®Google Scholar
• Argikar UA, Mangold JB, Harriman SP. 2011. Strategies and chemical design approaches to reduce the potential for formation of reactive metabolic species. Curr Top Med Chem. 11(4):419–449. doi: 10.2174/156802611794480891.
   PubMed Web of Science ®Google Scholar
• Argoti D, Liang L, Conteh A, Chen L, Bershas D, Yu CP, Vouros P, Yang E. 2005. Cyanide trapping of iminium ion reactive intermediates followed by detection and structure identification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Chem Res Toxicol. 18(10):1537–1544. doi: 10.1021/tx0501637.
   PubMed Web of Science ®Google Scholar
• Atkinson RM, Ditman KS. 1965. Tranylcypromine: a review. Clin Pharmacol Ther. 6(5):631–655. doi: 10.1002/cpt196565631.
   PubMed Web of Science ®Google Scholar
• Attia SM. 2010. Deleterious effects of reactive metabolites. Oxid Med Cell Longev. 3(4):238–253. doi: 10.4161/oxim.3.4.13246.
   PubMed Web of Science ®Google Scholar
• Baillie TA, Rettie AE. 2011. Role of biotransformation in drug-induced toxicity: influence of intra- and inter-species differences in drug metabolism. Drug Metab Pharmacokinet. 26(1):15–29. doi: 10.2133/dmpk.dmpk-10-rv-089.
   PubMed Web of Science ®Google Scholar
• Ban TA, Wilson WH, McEvoy JP. 1980. Amoxapine: a review of literature. Int Pharmacopsychiatry. 15(3):166–170. doi: 10.1159/000468433.
   PubMedGoogle Scholar
• Bandt C, Hoffbauer FW. 1964. Liver injury associated with tranylcypromine therapy. JAMA. 188(8):752–753. doi: 10.1001/jama.1964.03060340050015.
   PubMed Web of Science ®Google Scholar
• Bauman JN, Frederick KS, Sawant A, Walsky RL, Cox LM, Obach RS, Kalgutkar AS. 2008. Comparison of the bioactivation potential of the antidepressant and hepatotoxin nefazodone with aripiprazole, a structural analog and marketed drug. Drug Metab Dispos. 36(6):1016–1029. doi: 10.1124/dmd.108.020545.
   PubMed Web of Science ®Google Scholar
• Benbow SJ, Gill G. 1997. Paroxetine and hepatotoxicity. BMJ. 314(7091):1387–1387. doi: 10.1136/bmj.314.7091.1387a.
   PubMedGoogle Scholar
• Bermingham DP, Blakely RD. 2016. Kinase-dependent regulation of monoamine neurotransmitter transporters. Pharmacol Rev. 68(4):888–953. doi: 10.1124/pr.115.012260.
   PubMed Web of Science ®Google Scholar
• Bissig KD, Han W, Barzi M, Kovalchuk N, Ding L, Fan X, Pankowicz FP, Zhang QY, Ding X. 2018. P450-humanized and human liver chimeric mouse models for studying xenobiotic metabolism and toxicity. Drug Metab Dispos. 46(11):1734–1744. doi: 10.1124/dmd.118.083303.
   PubMed Web of Science ®Google Scholar
• Bolton JL, Trush MA, Penning TM, Dryhurst G, Monks TJ. 2000. Role of quinones in toxicology. Chem Res Toxicol. 13(3):135–160. doi: 10.1021/tx9902082.
   PubMed Web of Science ®Google Scholar
• Breyer-Pfaff U. 2004. The metabolic fate of amitriptyline, nortriptyline and amitriptylinoxide in man. Drug Metab Rev. 36(3–4):723–746. doi: 10.1081/dmr-200033482.
   PubMed Web of Science ®Google Scholar
• Brink A, Pähler A, Funk C, Schuler F, Schadt S. 2017. Minimizing the risk of chemically reactive metabolite formation of new drug candidates: implications for preclinical drug design. Drug Discov Today. 22(5):751–756. doi: 10.1016/j.drudis.2016.11.018.
   PubMed Web of Science ®Google Scholar
• Casini AF, Pompella A, Comporti M. 1985. Liver glutathione depletion induced by bromobenzene, iodobenzene, and diethylmaleate poisoning and its relation to lipid peroxidation and necrosis. Am J Pathol. 118(2):225–237.
   PubMed Web of Science ®Google Scholar
• Chan CY, New LS, Ho HK, Chan EC. 2011. Reversible time-dependent inhibition of cytochrome P450 enzymes by duloxetine and inertness of its thiophene ring towards bioactivation. Toxicol Lett. 206(3):314–324. doi: 10.1016/j.toxlet.2011.07.019.
   PubMed Web of Science ®Google Scholar
• Chaurasiya ND, Leon F. 2022. Natural products inhibitors of monoamine oxidases-potential new drug leads for neuroprotection, neurological disorders, and neuroblastoma. Molecules. 27 (13):4297.
   Google Scholar
• Chen F, Jiang H, Xu J, Wang S, Meng D, Geng P, Dai D, Zhou Q, Zhou Y. 2020. In vitro and in vivo rat model assessments of the effects of vonoprazan on the pharmacokinetics of venlafaxine. Drug Des Devel Ther. 14:4815–4824. doi: 10.2147/DDDT.S276704.
   PubMed Web of Science ®Google Scholar
• Choudhury Y, Toh YC, Xing J, Qu Y, Poh J, Li H, Tan HS, Kanesvaran R, Yu H, Tan MH. 2017. Patient-specific hepatocyte-like cells derived from induced pluripotent stem cells model pazopanib-mediated hepatotoxicity. Sci Rep. 7(1):41238. doi: 10.1038/srep41238.
   PubMedGoogle Scholar
• Chu AG, Gunsolly BL, Summers RW, Alexander B, McChesney C, Tanna VL. 1983. Trazodone and liver toxicity. Ann Intern Med. 99(1):128–129. doi: 10.7326/0003-4819-99-1-128_3.
   PubMed Web of Science ®Google Scholar
• Chu A, Wadhwa R. 2022. Selective serotonin reuptake inhibitors. Treasure Island (FL): StatPearls Publishing LLC.
   Google Scholar
• Cosme A, Barrio J, Lobo C, Gil I, Castiella A, Arenas JI. 1996. Acute cholestasis by fluoxetine. Am J Gastroenterol. 91(11):2449–2450.
   PubMed Web of Science ®Google Scholar
• Danan G, Bernuau J, Moullot X, Degott C, Pessayre D. 1984. Amitriptyline-induced fulminant hepatitis. Digestion. 30(3):179–184. doi: 10.1159/000199103.
   PubMed Web of Science ®Google Scholar
• De Craemer D, Kerckaert I, Roels F. 1991. Hepatocellular peroxisomes in human alcoholic and drug-induced hepatitis: a quantitative study. Hepatology. 14(5):811–817. doi: 10.1002/hep.1840140512.
   PubMed Web of Science ®Google Scholar
• de Man RA. 1997. Severe hepatitis attributed to paroxetine (Seroxat). Ned Tijdschr Geneeskd. 141(11):540–542.
   PubMedGoogle Scholar
• Deodhar M, Rihani SBA, Darakjian L, Turgeon J, Michaud V. 2021. Assessing the mechanism of fluoxetine-mediated CYP2D6 inhibition. Pharmaceutics. 13(2):148.
   Google Scholar
• DeSanty KP, Amabile CM. 2007. Antidepressant-induced liver injury. Ann Pharmacother. 41(7):1201–1211. doi: 10.1345/aph.1K114.
   PubMed Web of Science ®Google Scholar
• DeVane CL, Liston HL, Markowitz JS. 2002. Clinical pharmacokinetics of sertraline. Clin Pharmacokinet. 41(15):1247–1266. doi: 10.2165/00003088-200241150-00002.
   PubMed Web of Science ®Google Scholar
• Dykens JA, Jamieson JD, Marroquin LD, Nadanaciva S, Xu JJ, Dunn MC, Smith AR, Will Y. 2008. In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci. 103(2):335–345. doi: 10.1093/toxsci/kfn056.
   PubMed Web of Science ®Google Scholar
• Erdogan A, Ozcay F, Piskin E, Karaman MG, Bilezikci B, Calik M, Tekin I, Haberal M. 2011. Idiosyncratic liver failure probably associated with atomoxetine: a case report. J Child Adolesc Psychopharmacol. 21(3):295–297. doi: 10.1089/cap.2010.0101.
   PubMed Web of Science ®Google Scholar
• Fang L, Wang S, Cao L, Yao K. 2021. Early intervention of acute liver injury related to venlafaxine: a case report. Medicine. 100(49):e28140. doi: 10.1097/MD.0000000000028140.
   PubMed Web of Science ®Google Scholar
• Favreau LV, Palamanda JR, Lin CC, Nomeir AA. 1999. Improved reliability of the rapid microtiter plate assay using recombinant enzyme in predicting CYP2D6 inhibition in human liver microsomes. Drug Metab Dispos. 27(4):436–439.
   PubMed Web of Science ®Google Scholar
• Ferguson JM. 2001. SSRI antidepressant medications: adverse effects and tolerability. Prim Care Companion J Clin Psychiatry. 3(1):22–27. doi: 10.4088/pcc.v03n0105.
   PubMedGoogle Scholar
• Fowler JS, Logan J, Volkow ND, Shumay E, McCall-Perez F, Jayne M, Wang GJ, Alexoff DL, Apelskog-Torres K, Hubbard B, et al. 2015. Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain. Neuropsychopharmacology. 40(3):650–657. doi: 10.1038/npp.2014.214.
   PubMed Web of Science ®Google Scholar
• Freiesleben SD, Furczyk K. 2015. A systematic review of agomelatine-induced liver injury. J Mol Psychiatry. 3(1):4. doi: 10.1186/s40303-015-0011-7.
   PubMedGoogle Scholar
• Friedman RA, Leon AC. 2007. Expanding the black box - depression, antidepressants, and the risk of suicide. N Engl J Med. 356(23):2343–2346. doi: 10.1056/NEJMp078015.
   PubMed Web of Science ®Google Scholar
• Friedrich ME, Akimova E, Huf W, Konstantinidis A, Papageorgiou K, Winkler D, Toto S, Greil W, Grohmann R, Kasper S. 2016. Drug-induced liver injury during antidepressant treatment: results of AMSP, a drug surveillance program. Int J Neuropsychopharmacol. 19(4): pyv126. doi: 10.1093/ijnp/pyv126.
   Google Scholar
• Fromenty B, Pessayre D. 1995. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol Ther. 67(1):101–154. doi: 10.1016/0163-7258(95)00012-6.
   PubMed Web of Science ®Google Scholar
• Gahr M, Freudenmann RW, Connemann BJ, Hiemke C, Schönfeldt-Lecuona C. 2013. Agomelatine and hepatotoxicity: implications of cumulated data derived from spontaneous reports of adverse drug reactions. Pharmacopsychiatry. 46(6):214–220. doi: 10.1055/s-0033-1353156.
   PubMed Web of Science ®Google Scholar
• Ganesan A, Arimondo PB, Rots MG, Jeronimo C, Berdasco M. 2019. The timeline of epigenetic drug discovery: from reality to dreams. Clin Epigenetics. 11(1):174. doi: 10.1186/s13148-019-0776-0.
   Google Scholar
• Geneve J, Larrey D, Letteron P, Descatoire V, Tinel M, Amouyal G, Pessayre D. 1987. Metabolic activation of the tricyclic antidepressant amineptine–I. Cytochrome P-450-mediated in vitro covalent binding. Biochem Pharmacol. 36(3):323–329. doi: 10.1016/0006-2952(87)90289-9.
   PubMed Web of Science ®Google Scholar
• Gillman PK. 2007. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. Br J Pharmacol. 151(6):737–748. doi: 10.1038/sj.bjp.0707253.
   PubMed Web of Science ®Google Scholar
• Gómez-Gil E, Salmerón JM, Mas A. 1996. Phenelzine-induced fulminant hepatic failure. Ann Intern Med. 124(7):692–693. doi: 10.7326/0003-4819-124-7-199604010-00014.
   PubMed Web of Science ®Google Scholar
• Grislain L, Gelé P, Bromet N, Luijten W, Volland JP, Mocaer E, Kamoun A. 1990. Metabolism of amineptine in rat, dog and man. Eur J Drug Metab Pharmacokinet. 15(4):339–345. doi: 10.1007/BF03190224.
   PubMed Web of Science ®Google Scholar
• Gronewold A, Dettling A, Haffner HT, Skopp G. 2009. Doxepin and nordoxepin concentrations in body fluids and tissues in doxepin associated deaths. Forensic Sci Int. 190(1–3):74–79. doi: 10.1016/j.forsciint.2009.05.015.
   PubMed Web of Science ®Google Scholar
• Hara Y, Nakajima M, Miyamoto KI, Yokoi T. 2005. Inhibitory effects of psychotropic drugs on mexiletine metabolism in human liver microsomes: prediction of in vivo drug interactions. Xenobiotica. 35(6):549–560. doi: 10.1080/00498250500158134.
   PubMed Web of Science ®Google Scholar
• Hautekeete ML, Colle I, van Vlierberghe H, Elewaut A. 1998. Symptomatic liver injury probably related to sertraline. Gastroenterol Clin Biol. 22(3):364–365.
   PubMedGoogle Scholar
• Heijne WH, Slitt AL, van Bladeren PJ, Groten JP, Klaassen CD, Stierum RH, van Ommen B. 2004. Bromobenzene-induced hepatotoxicity at the transcriptome level. Toxicol Sci. 79(2):411–422. doi: 10.1093/toxsci/kfh128.
   PubMed Web of Science ®Google Scholar
• Hetrick SE, McKenzie JE, Bailey AP, Sharma V, Moller CI, Badcock PB, Cox GR, Merry SN, Meader N. 2021. New generation antidepressants for depression in children and adolescents: a network meta-analysis. Cochrane Database Syst Rev. 5(5):Cd013674. doi: 10.1002/14651858.CD013674.pub2.
   PubMedGoogle Scholar
• Hidalgo FJ, Zamora R. 2019. Formation of phenylacetic acid and benzaldehyde by degradation of phenylalanine in the presence of lipid hydroperoxides: new routes in the amino acid degradation pathways initiated by lipid oxidation products. Food Chem X. 2:100037. doi: 10.1016/j.fochx.2019.100037.
   PubMedGoogle Scholar
• Hillhouse TM, Porter JH. 2015. A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 23(1):1–21. doi: 10.1037/a0038550.
   PubMed Web of Science ®Google Scholar
• Horst DA, Grace ND, LeCompte PM. 1980. Prolonged cholestasis and progressive hepatic fibrosis following imipramine therapy. Gastroenterology. 79(3):550–554. doi: 10.1016/0016-5085(80)90383-2.
   PubMed Web of Science ®Google Scholar
• Hosack T, Damry D, Biswas S. 2023. Drug-induced liver injury: a comprehensive review. Therap Adv Gastroenterol. 16:17562848231163410. doi: 10.1177/17562848231163410.
   Web of Science ®Google Scholar
• Hosokawa M, Satoh T. 1988. Effects of hypophysectomy and pituitary hormones on hepatic microsomal carboxylesterase isozymes in male rats. Res Commun Chem Pathol Pharmacol. 62(2):279–288.
   PubMedGoogle Scholar
• Hucker HB, Balletto AJ, Demetriades J, Arison BH, Zacchei AG. 1975. Epoxide metabolites of protriptyline in rat urine. Drug Metab Dispos. 3(2):80–84.
   PubMed Web of Science ®Google Scholar
• Hussaini SH, Farrington EA. 2007. Idiosyncratic drug-induced liver injury: an overview. Expert Opin Drug Saf. 6(6):673–684. doi: 10.1517/14740338.6.6.673.
   PubMed Web of Science ®Google Scholar
• Hussaini SH, Farrington EA. 2014. Idiosyncratic drug-induced liver injury: an update on the 2007 overview. Expert Opin Drug Saf. 13(1):67–81. doi: 10.1517/14740338.2013.828032.
   PubMed Web of Science ®Google Scholar
• Hyttel J, Bøgesø KP, Perregaard J, Sánchez C. 1992. The pharmacological effect of citalopram residues in the (S)-(+)-enantiomer. J Neural Transm Gen Sect. 88(2):157–160. doi: 10.1007/BF01244820.
   PubMed Web of Science ®Google Scholar
• Isobe T, Hichiya H, Hanioka N, Yamamoto S, Shinoda S, Funae Y, Satoh T, Yamano S, Narimatsu S. 2005. Different effects of desipramine on bufuralol 1’’-hydroxylation by rat and human CYP2D enzymes. Biol Pharm Bull. 28(4):634–640. doi: 10.1248/bpb.28.634.
   PubMed Web of Science ®Google Scholar
• Iverson S, Zahid N, Uetrecht JP. 2002. Predicting drug-induced agranulocytosis: characterizing neutrophil-generated metabolites of a model compound, DMP 406, and assessing the relevance of an in vitro apoptosis assay for identifying drugs that may cause agranulocytosis. Chem Biol Interact. 142(1-2):175–199. doi: 10.1016/s0009-2797(02)00061-3.
   PubMed Web of Science ®Google Scholar
• Jauch R, Kopitar Z, Prox A, Zimmer A. 1976. Pharmacokinetics and metabolism of trazodone in man (author’s transl). Arzneimittelforschung. 26(11):2084–2089.
   PubMed Web of Science ®Google Scholar
• Johnston DE, Wheeler DE. 1997. Chronic hepatitis related to use of fluoxetine. Am J Gastroenterol. 92(7):1225–1226.
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS. 2017. Liabilities associated with the formation of "hard" electrophiles in reactive metabolite trapping screens. Chem Res Toxicol. 30(1):220–238. doi: 10.1021/acs.chemrestox.6b00332.
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS, Dalvie D. 2015. Predicting toxicities of reactive metabolite-positive drug candidates. Annu Rev Pharmacol Toxicol. 55(1):35–54. doi: 10.1146/annurev-pharmtox-010814-124720.
   PubMedGoogle Scholar
• Kalgutkar AS, Dalvie DK, O’Donnell JP, Taylor TJ, Sahakian DC. 2002. On the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics. Curr Drug Metab. 3(4):379–424. doi: 10.2174/1389200023337360.
   PubMedGoogle Scholar
• Kalgutkar AS, Gardner I, Obach RS, Shaffer CL, Callegari E, Henne KR, Mutlib AE, Dalvie DK, Lee JS, Nakai Y, et al. 2005. A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab. 6(3):161–225. doi: 10.2174/1389200054021799.
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS, Vaz AD, Lame ME, Henne KR, Soglia J, Zhao SX, Abramov YA, Lombardo F, Collin C, Hendsch ZS, et al. 2005. Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab Dispos. 33(2):243–253. doi: 10.1124/dmd.104.001735.
   PubMed Web of Science ®Google Scholar
• Karp JF, Skidmore E, Lotz M, Lenze E, Dew MA, Reynolds CF. 2009. Use of the late-life function and disability instrument to assess disability in major depression. J Am Geriatr Soc. 57(9):1612–1619. doi: 10.1111/j.1532-5415.2009.02398.x.
   PubMed Web of Science ®Google Scholar
• Katarey D, Verma S. 2016. Drug-induced liver injury. Clin Med. 16(Suppl 6):s104–s109. doi: 10.7861/clinmedicine.16-6-s104.
   PubMedGoogle Scholar
• Keegan AD. 1993. Doxepin-induced recurrent acute hepatitis. Aust N Z J Med. 23(5):523–523. doi: 10.1111/j.1445-5994.1993.tb01843.x.
   PubMedGoogle Scholar
• Kirchheiner J, Meineke I, Müller G, Roots I, Brockmöller J. 2002. Contributions of CYP2D6, CYP2C9 and CYP2C19 to the biotransformation of E- and Z-doxepin in healthy volunteers. Pharmacogenetics. 12(7):571–580. doi: 10.1097/00008571-200210000-00010.
   PubMedGoogle Scholar
• Kitteringham NR, Lambert C, Maggs JL, Colbert J, Park BK. 1988. A comparative study of the formation of chemically reactive drug metabolites by human liver microsomes. Br J Clin Pharmacol. 26(1):13–21. doi: 10.1111/j.1365-2125.1988.tb03358.x.
   PubMed Web of Science ®Google Scholar
• Klerman GL, Cole JO. 1965. Clinical pharmacology of imipramine and related antidepressant compounds. Pharmacol Rev. 17:101–141.
   PubMed Web of Science ®Google Scholar
• Klopčič I, Dolenc MS. 2019. Chemicals and drugs forming reactive quinone and quinone imine metabolites. Chem Res Toxicol. 32(1):1–34. doi: 10.1021/acs.chemrestox.8b00213.
   PubMed Web of Science ®Google Scholar
• Koff RS. 1995. Drug-induced liver disease. Hepatology. 21(4):1200–1201. doi: 10.1002/hep.1840210447.
   Google Scholar
• Korobkova EA, Nemeth J, Cadougan M, Venkatratnam A, Bassit M, Azar N. 2012. Reactive metabolites of desipramine and clomipramine: the kinetics of formation and reactivity with DNA. Bioorg Med Chem. 20(1):340–345. doi: 10.1016/j.bmc.2011.10.075.
   PubMed Web of Science ®Google Scholar
• Koyama E, Chiba K, Tani M, Ishizaki T. 1996. Identification of human cytochrome P450 isoforms involved in the stereoselective metabolism of mianserin enantiomers. J Pharmacol Exp Ther. 278(1):21–30.
   PubMed Web of Science ®Google Scholar
• Lapierre YD. 1989. A review of trimipramine. 30 years of clinical use. Drugs. 38(Suppl 1):17–24. doi: 10.2165/00003495-198900381-00006.
   PubMedGoogle Scholar
• Larrey D, Tinel M, Lettéron P, Maurel P, Loeper J, Belghiti J, Pessayre D. 1990. Metabolic activation of the new tricyclic antidepressant tianeptine by human liver cytochrome P450. Biochem Pharmacol. 40(3):545–550. doi: 10.1016/0006-2952(90)90554-x.
   PubMed Web of Science ®Google Scholar
• Larsen JK, Krogh-Nielsen L, Brøsen K. 2015. The use of the monoamine oxidase inhibitor isocarboxazide in treatment-resistant depression. Ugeskr Laeger. 177(52):V06150499.
   PubMedGoogle Scholar
• Lazaros GA, Stavrinos C, Papatheodoridis GV, Delladetsima JK, Toliopoulos A, Tassopoulos NC. 1996. Amineptine induced liver injury. Report of two cases and brief review of the literature. Hepatogastroenterology. 43(10):1015–1019.
   PubMedGoogle Scholar
• Lee KC, Chen JJ. 2007. Transdermal selegiline for the treatment of major depressive disorder. Neuropsychiatr Dis Treat. 3:527–537.
   PubMedGoogle Scholar
• Lee YC, Chen PP. 2010. A review of SSRIs and SNRIs in neuropathic pain. Expert Opin Pharmacother. 11(17):2813–2825. doi: 10.1517/14656566.2010.507192.
   PubMed Web of Science ®Google Scholar
• Lee CW, Suh JM, Jang HW. 2019. Chemical sensors based on two-dimensional (2D) materials for selective detection of ions and molecules in liquid. Front Chem. 7:708. doi: 10.3389/fchem.2019.00708.
   PubMed Web of Science ®Google Scholar
• Lewis JH. 2000. Drug-induced liver disease. Med Clin North Am. 84(5):1275–1311, x. doi: 10.1016/s0025-7125(05)70287-x.
   PubMed Web of Science ®Google Scholar
• Li Y, Wang Y, Zhang N, Zhou S, Peng Y, Zheng J. 2021. Glutathione conjugation and protein modification resulting from metabolic activation of venlafaxine in vitro and in vivo. Xenobiotica. 51(11):1303–1317. doi: 10.1080/00498254.2021.1946204.
   PubMed Web of Science ®Google Scholar
• Lieberman III J. 2003. History of the use of antidepressants in primary care. J Clin Psychiatry. 2003, 5.
   Google Scholar
• Limban C, Nuţă DC, Chiriţă C, Negreș S, Arsene AL, Goumenou M, Karakitsios SP, Tsatsakis AM, Sarigiannis DA. 2018. The use of structural alerts to avoid the toxicity of pharmaceuticals. Toxicol Rep. 5:943–953. doi: 10.1016/j.toxrep.2018.08.017.
   PubMed Web of Science ®Google Scholar
• Liu X, Lu YF, Guan X, Zhao M, Wang J, Li F. 2016. Characterizing novel metabolic pathways of melatonin receptor agonist agomelatine using metabolomic approaches. Biochem Pharmacol. 109:70–82. doi: 10.1016/j.bcp.2016.03.020.
   PubMed Web of Science ®Google Scholar
• López-Torres E, Lucena MI, Seoane J, Verge C, Andrade RJ. 2004. Hepatotoxicity related to citalopram. Am J Psychiatry. 161(5):923–924.
   PubMed Web of Science ®Google Scholar
• Lucena MI, Carvajal A, Andrade RJ, Velasco A. 2003. Antidepressant-induced hepatotoxicity. Expert Opin Drug Saf. 2(3):249–262. doi: 10.1517/14740338.2.3.249.
   PubMedGoogle Scholar
• Ly JQ, Messick K, Qin A, Takahashi RH, Choo EF. 2017. Utility of CYP3A4 and PXR-CAR-CYP3A4/3A7 transgenic mouse models to assess the magnitude of CYP3A4 mediated drug-drug interactions. Mol Pharm. 14(5):1754–1759. doi: 10.1021/acs.molpharmaceut.7b00006.
   PubMedGoogle Scholar
• MacKenzie KR, Zhao M, Barzi M, Wang J, Bissig KD, Maletic-Savatic M, Jung SY, Li F. 2020. Metabolic profiling of norepinephrine reuptake inhibitor atomoxetine. Eur J Pharm Sci. 153:105488. doi: 10.1016/j.ejps.2020.105488.
   PubMed Web of Science ®Google Scholar
• Madrigal-Bujaidar E, Cárdenas García Y, Alvarez-González I. 2010. Chromosomal aberrations induced by imipramine and desipramine in mouse. Hum Exp Toxicol. 29(4):297–302. doi: 10.1177/0960327110361751.
   PubMed Web of Science ®Google Scholar
• Manapany M, Marchetti B, Bertrand-Lepensec D, Lacroix G, Legré M. 1993. Acute cytolytic hepatitis caused by amoxapine. Gastroenterol Clin Biol. 17(5):405–406.
   PubMedGoogle Scholar
• Masubuchi Y, Igarashi S, Suzuki T, Horie T, Narimatsu S. 1996. Imipramine-induced inactivation of a cytochrome P450 2D enzyme in rat liver microsomes: in relation to covalent binding of its reactive intermediate. J Pharmacol Exp Ther. 279(2):724–731.
   PubMed Web of Science ®Google Scholar
• Masubuchi Y, Kawaguchi Y. 2013. Time-dependent inhibition of CYP3A4 by sertraline, a selective serotonin reuptake inhibitor. Biopharm Drug Dispos. 34(8):423–430. doi: 10.1002/bdd.1857.
   PubMed Web of Science ®Google Scholar
• McIntyre RS, Panjwani ZD, Nguyen HT, Woldeyohannes HO, Alsuwaidan M, Soczynska JK, Lourenco MT, Konarski JZ, Kennedy SH. 2008. The hepatic safety profile of duloxetine: a review. Expert Opin Drug Metab Toxicol. 4(3):281–285. doi: 10.1517/17425255.4.3.281.
   PubMed Web of Science ®Google Scholar
• Miura M, Ohkubo T. 2007. Identification of human cytochrome P450 enzymes involved in the major metabolic pathway of fluvoxamine. Xenobiotica. 37(2):169–179. doi: 10.1080/00498250600718464.
   PubMed Web of Science ®Google Scholar
• Morgan DH. 1969. Jaundice associated with amitriptyline. Br J Psychiatry. 115(518):105–106. doi: 10.1192/bjp.115.518.105.
   PubMed Web of Science ®Google Scholar
• Nelson SD, Mitchell JR, Snodgrass WR, Timbrell JA. 1978. Hepatotoxicity and metabolism of iproniazid and isopropylhydrazine. J Pharmacol Exp Ther. 206(3):574–585.
   PubMed Web of Science ®Google Scholar
• Nelson SD, Mitchell JR, Timbrell JA, Snodgrass WR, Corcoran GB.3rd 1976. Isoniazid and iproniazid: activation of metabolites to toxic intermediates in man and rat. Science. 193(4256):901–903. doi: 10.1126/science.7838.
   PubMed Web of Science ®Google Scholar
• Norman BH. 2020. Drug induced liver injury (DILI). Mechanisms and medicinal chemistry avoidance/mitigation strategies. J Med Chem. 63(20):11397–11419. doi: 10.1021/acs.jmedchem.0c00524.
   PubMed Web of Science ®Google Scholar
• Obach RS, Cox LM, Tremaine LM. 2005. Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study. Drug Metab Dispos. 33(2):262–270. doi: 10.1124/dmd.104.002428.
   PubMed Web of Science ®Google Scholar
• Obach RS, Dalvie DK. 2006. Metabolism of nomifensine to a dihydroisoquinolinium ion metabolite by human myeloperoxidase, hemoglobin, monoamine oxidase A, and cytochrome P450 enzymes. Drug Metab Dispos. 34(8):1310–1316. doi: 10.1124/dmd.106.010173.
   PubMed Web of Science ®Google Scholar
• Olianas MC, Dedoni S, Onali P. 2012. The atypical antidepressant mianserin exhibits agonist activity at κ-opioid receptors. Br J Pharmacol. 167(6):1329–1341. doi: 10.1111/j.1476-5381.2012.02078.x.
   PubMed Web of Science ®Google Scholar
• Orr ST, Ripp SL, Ballard TE, Henderson JL, Scott DO, Obach RS, Sun H, Kalgutkar AS. 2012. Mechanism-based inactivation (MBI) of cytochrome P450 enzymes: structure-activity relationships and discovery strategies to mitigate drug-drug interaction risks. J Med Chem. 55(11):4896–4933. doi: 10.1021/jm300065h.
   PubMed Web of Science ®Google Scholar
• Owen JR, Nemeroff CB. 1998. New antidepressants and the cytochrome P450 system: focus on venlafaxine, nefazodone, and mirtazapine. Depress Anxiety. 7(Suppl 1):24–32. doi: 10.1002/(SICI)1520-6394(1998)7:1+<24::AID-DA7>3.0.CO;2-F.
   PubMedGoogle Scholar
• Paech C, Salach JI, Singer TP. 1980. Suicide inactivation of monoamine oxidase by trans-phenylcyclopropylamine. J Biol Chem. 255(7):2700–2704.
   PubMed Web of Science ®Google Scholar
• Paludetto M-N, Stigliani J-L, Robert A, Bernardes-Génisson V, Chatelut E, Puisset F, Arellano C. 2020. Involvement of pazopanib and sunitinib aldehyde reactive metabolites in toxicity and drug–drug interactions in vitro and in patient samples. Chem Res Toxicol. 33(1):181–190. doi: 10.1021/acs.chemrestox.9b00205.
   PubMed Web of Science ®Google Scholar
• Paris BL, Ogilvie BW, Scheinkoenig JA, Ndikum-Moffor F, Gibson R, Parkinson A. 2009. In vitro inhibition and induction of human liver cytochrome p450 enzymes by milnacipran. Drug Metab Dispos. 37(10):2045–2054. doi: 10.1124/dmd.109.028274.
   PubMed Web of Science ®Google Scholar
• Park SH, Ishino R. 2013. Liver injury associated with antidepressants. Curr Drug Saf. 8(3):207–223. doi: 10.2174/1574886311308030011.
   PubMedGoogle Scholar
• Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP. 2005. The role of metabolic activation in drug-induced hepatotoxicity. Annu Rev Pharmacol Toxicol. 45(1):177–202. doi: 10.1146/annurev.pharmtox.45.120403.100058.
   PubMedGoogle Scholar
• Park BK, Laverty H, Srivastava A, Antoine DJ, Naisbitt D, Williams DP. 2011. Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity. Chem Biol Interact. 192(1–2):30–36. doi: 10.1016/j.cbi.2010.09.011.
   PubMed Web of Science ®Google Scholar
• Patterson JF. 1987. Amoxapine associated with hepatotoxicity. J Clin Psychopharmacol. 7:50–51.
   PubMed Web of Science ®Google Scholar
• Pechulis AD, Beck JP, Curry MA, Wolf MA, Harms AE, Xi N, Opalka C, Sweet MP, Yang Z, Vellekoop AS, et al. 2012. 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors. Bioorg Med Chem Lett. 22(23):7219–7222. doi: 10.1016/j.bmcl.2012.09.050.
   PubMed Web of Science ®Google Scholar
• Pedersen AM, Enevoldsen HK. 1996. Nortriptyline-induced hepatic failure. Ther Drug Monit. 18(1):100–102. doi: 10.1097/00007691-199602000-00017.
   PubMed Web of Science ®Google Scholar
• Perucca E, Gatti G, Spina E. 1994. Clinical pharmacokinetics of fluvoxamine. Clin Pharmacokinet. 27(3):175–190. doi: 10.2165/00003088-199427030-00002.
   PubMed Web of Science ®Google Scholar
• Phillips C. 2017. Brain-derived neurotrophic factor, depression, and physical activity: making the neuroplastic connection. Neural Plast. 2017:7260130–7260117. doi: 10.1155/2017/7260130.
   PubMed Web of Science ®Google Scholar
• Polasek TM, Miners JO. 2008. Time-dependent inhibition of human drug metabolizing cytochromes P450 by tricyclic antidepressants. Br J Clin Pharmacol. 65(1):87–97. doi: 10.1111/j.1365-2125.2007.02964.x.
   PubMed Web of Science ®Google Scholar
• Powell WJ, Jr., Koch-Weser J, Williams RA. 1968. Lethal hepatic necrosis after therapy with imipramine and desipramine. Jama. 206(3):642–645.
   PubMed Web of Science ®Google Scholar
• Price LH, Nelson JC, Waltrip RW. 1983. Desipramine-associated hepatitis. J Clin Psychopharmacol. 3(4):243–246.
   PubMed Web of Science ®Google Scholar
• Prox A, Breyer-Pfaff U. 1987. Amitriptyline metabolites in human urine. Identification of phenols, dihydrodiols, glycols, and ketones. Drug Metab Dispos. 15(6):890–896.
   PubMed Web of Science ®Google Scholar
• Qin X, Hakenjos JM, MacKenzie KR, Barzi M, Chavan H, Nyshadham P, Wang J, Jung SY, Guner JZ, Chen S, et al. 2022. Metabolism of a selective serotonin and norepinephrine reuptake inhibitor duloxetine in liver microsomes and mice. Drug Metab Dispos. 50(2):128–139. doi: 10.1124/dmd.121.000633.
   PubMed Web of Science ®Google Scholar
• Qin X, Xie C, Hakenjos JM, Mackenzie KM, Barzi M, Nyshadham P, Khalil SM, Bissig K-D, Gonzalez FJ, Matzuk MM, et al. 2022. Cyp1a2-knockout increases the systemic exposure of a serotonin and norepinephrine reuptake inhibitor duloxetine in mice. The FASEB J. 36(S1) doi: 10.1096/fasebj.2022.36.S1.L7654.
   Google Scholar
• Remy AJ, Larrey D, Pageaux GP, Ribstein J, Ramos J, Michel H. 1995. Cross hepatotoxicity between tricyclic antidepressants and phenothiazines. Eur J Gastroenterol Hepatol. 7(4):373–376.
   PubMed Web of Science ®Google Scholar
• Rettman KS, McClintock C. 2001. Hepatotoxicity after short-term trazodone therapy. Ann Pharmacother. 35(12):1559–1561. doi: 10.1345/aph.10406.
   PubMed Web of Science ®Google Scholar
• Ricca Rosellini S, Grilli F, Gaudio M, Saragoni A, Miglio F. 1990. Hepatic injury associated with amineptine therapy. Ital J Gastroenterol. 22(1):40–43.
   PubMedGoogle Scholar
• Riley RJ, Maggs JL, Lambert C, Kitteringham NR, Park BK. 1988. An in vitro study of the microsomal metabolism and cellular toxicity of phenytoin, sorbinil and mianserin. Br J Clin Pharmacol. 26(5):577–588. doi: 10.1111/j.1365-2125.1988.tb05298.x.
   PubMed Web of Science ®Google Scholar
• Riley RJ, Roberts P, Kitteringham NR, Park BK. 1990. Formation of cytotoxic metabolites from phenytoin, imipramine, desipramine, amitriptyline and mianserin by mouse and human hepatic microsomes. Biochem Pharmacol. 39(12):1951–1958. doi: 10.1016/0006-2952(90)90614-q.
   PubMed Web of Science ®Google Scholar
• Roberts P, Kitteringham NR, Park BK. 1993. Elucidation of the structural requirements for the bioactivation of mianserin in-vitro. J Pharm Pharmacol. 45(7):663–665. doi: 10.1111/j.2042-7158.1993.tb05674.x.
   PubMed Web of Science ®Google Scholar
• Rochat B, Kosel M, Boss G, Testa B, Gillet M, Baumann P. 1998. Stereoselective biotransformation of the selective serotonin reuptake inhibitor citalopram and its demethylated metabolites by monoamine oxidases in human liver. Biochem Pharmacol. 56(1):15–23. doi: 10.1016/s0006-2952(98)00008-2.
   PubMed Web of Science ®Google Scholar
• Romero E, Gómez Castellanos JR, Gadda G, Fraaije MW, Mattevi A. 2018. Same substrate, many reactions: oxygen activation in flavoenzymes. Chem Rev. 118(4):1742–1769. doi: 10.1021/acs.chemrev.7b00650.
   PubMed Web of Science ®Google Scholar
• Rosenblum LE, Korn RJ, Zimmerman HJ. 1960. Hepatocellular jaundice as a complication of iproniazid therapy. Arch Intern Med. 105(4):583–593. doi: 10.1001/archinte.1960.00270160081010.
   PubMedGoogle Scholar
• Saef MA, Yilanli M, and Saadabadi A. 2022. Protriptyline. Treasure Island (FL): StatPearls Publishing LLC.
   Google Scholar
• Salama A, Mueller-Eckhardt C. 1985. The role of metabolite-specific antibodies in nomifensine-dependent immune hemolytic anemia. N Engl J Med. 313(8):469–474. doi: 10.1056/NEJM198508223130803.
   PubMed Web of Science ®Google Scholar
• Sánchez C, Bøgesø KP, Ebert B, Reines EH, Braestrup C. 2004. Escitalopram versus citalopram: the surprising role of the R-enantiomer. Psychopharmacology. 174(2):163–176. doi: 10.1007/s00213-004-1865-z.
   PubMed Web of Science ®Google Scholar
• Schönfeld P, Wojtczak L. 2016. Short- and medium-chain fatty acids in energy metabolism: the cellular perspective. J Lipid Res. 57(6):943–954. doi: 10.1194/jlr.R067629.
   PubMed Web of Science ®Google Scholar
• Shaefer MS, Edmunds AL, Markin RS, Wood RP, Pillen TJ, Shaw BW.Jr. 1990. Hepatic failure associated with imipramine therapy. Pharmacotherapy. 10(1):66–69. doi: 10.1002/j.1875-9114.1990.tb02551.x.
   PubMed Web of Science ®Google Scholar
• Shin HS. 1997. Metabolism of selegiline in humans. Identification, excretion, and stereochemistry of urine metabolites. Drug Metab Dispos. 25(6):657–662.
   PubMed Web of Science ®Google Scholar
• Shin JG, Park JY, Kim MJ, Shon JH, Yoon YR, Cha IJ, Lee SS, Oh SW, Kim SW, Flockhart DA. 2002. Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro: mechanism of drug interaction between TCAs and phenytoin. Drug Metab Dispos. 30(10):1102–1107. doi: 10.1124/dmd.30.10.1102.
   PubMed Web of Science ®Google Scholar
• Sidhu G, Marwaha R. 2023. Phenelzine. Treasure Island (FL): StatPearls Publishing LLC.
   Google Scholar
• Solomons K, Gooch S, Wong A. 2005. Toxicity with selective serotonin reuptake inhibitors. Am J Psychiatry. 162(6):1225–1225. doi: 10.1176/appi.ajp.162.6.1225.
   PubMed Web of Science ®Google Scholar
• Spigset O, Axelsson S, Norström A, Hägg S, Dahlqvist R. 2001. The major fluvoxamine metabolite in urine is formed by CYP2D6. Eur J Clin Pharmacol. 57(9):653–658. doi: 10.1007/s002280100373.
   PubMed Web of Science ®Google Scholar
• Sridar C, Kenaan C, Hollenberg PF. 2012. Inhibition of bupropion metabolism by selegiline: mechanism-based inactivation of human CYP2B6 and characterization of glutathione and peptide adducts. Drug Metab Dispos. 40(12):2256–2266. doi: 10.1124/dmd.112.046979.
   PubMed Web of Science ®Google Scholar
• Stepan AF, Walker DP, Bauman J, Price DA, Baillie TA, Kalgutkar AS, Aleo MD. 2011. Structural alert/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: a perspective based on the critical examination of trends in the top 200 drugs marketed in the United States. Chem Res Toxicol. 24(9):1345–1410. doi: 10.1021/tx200168d.
   PubMed Web of Science ®Google Scholar
• Szewczuk-Bogusławska M, Kiejna A, Beszłej JA, Orzechowska-Juzwenko K, Milejski P. 2004. Doxepin inhibits CYP2D6 activity in vivo. Pol J Pharmacol. 56(4):491–494.
   PubMedGoogle Scholar
• Tanum L, Strand LP, Refsum H. 2010. Serum concentrations of citalopram–dose-dependent variation in R- and S-enantiomer ratios. Pharmacopsychiatry. 43(5):190–193. doi: 10.1055/s-0030-1254106.
   PubMed Web of Science ®Google Scholar
• Taziki S, Sattari MR, Eghbal MA. 2013. Mechanisms of trazodone-induced cytotoxicity and the protective effects of melatonin and/or taurine toward freshly isolated rat hepatocytes. J Biochem Mol Toxicol. 27(10):457–462. doi: 10.1002/jbt.21509.
   PubMed Web of Science ®Google Scholar
• Teo YL, Ho HK, Chan A. 2015. Formation of reactive metabolites and management of tyrosine kinase inhibitor-induced hepatotoxicity: a literature review. Expert Opin Drug Metab Toxicol. 11(2):231–242. doi: 10.1517/17425255.2015.983075.
   PubMed Web of Science ®Google Scholar
• Thompson RA, Isin EM, Li Y, Weaver R, Weidolf L, Wilson I, Claesson A, Page K, Dolgos H, Kenna JG. 2011. Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development. Chem Biol Interact. 192(1–2):65–71. doi: 10.1016/j.cbi.2010.11.002.
   PubMed Web of Science ®Google Scholar
• Thompson RA, Isin EM, Ogese MO, Mettetal JT, Williams DP. 2016. Reactive metabolites: current and emerging risk and hazard assessments. Chem Res Toxicol. 29(4):505–533. doi: 10.1021/acs.chemrestox.5b00410.
   PubMed Web of Science ®Google Scholar
• Todorović Vukotić N, Đorđević J, Pejić S, Đorđević N, Pajović SB. 2021. Antidepressants- and antipsychotics-induced hepatotoxicity. Arch Toxicol. 95(3):767–789. doi: 10.1007/s00204-020-02963-4.
   PubMed Web of Science ®Google Scholar
• Trenton AJ, Currier GW. 2001. Treatment of comorbid tuberculosis and depression. Prim Care Companion J Clin Psychiatry. 3(6):236–243. doi: 10.4088/pcc.v03n0610.
   PubMedGoogle Scholar
• Usui T, Mise M, Hashizume T, Yabuki M, Komuro S. 2009. Evaluation of the potential for drug-induced liver injury based on in vitro covalent binding to human liver proteins. Drug Metab Dispos. 37(12):2383–2392. doi: 10.1124/dmd.109.028860.
   PubMed Web of Science ®Google Scholar
• Venkatakrishnan K, Schmider J, Harmatz JS, Ehrenberg BL, von Moltke LL, Graf JA, Mertzanis P, Corbett KE, Rodriguez MC, Shader RI, et al. 2001. Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies. J Clin Pharmacol. 41(10):1043–1054. doi: 10.1177/00912700122012634.
   PubMed Web of Science ®Google Scholar
• Voican CS, Corruble E, Naveau S, Perlemuter G. 2014. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 171(4):404–415. doi: 10.1176/appi.ajp.2013.13050709.
   PubMed Web of Science ®Google Scholar
• Volz HP, Gleiter CH. 1998. Monoamine oxidase inhibitors. A perspective on their use in the elderly. Drugs Aging. 13(5):341–355. doi: 10.2165/00002512-199813050-00002.
   PubMed Web of Science ®Google Scholar
• von Moltke LL, Greenblatt DJ, Duan SX, Schmider J, Kudchadker L, Fogelman SM, Harmatz JS, Shader RI. 1996. Phenacetin O-deethylation by human liver microsomes in vitro: inhibition by chemical probes, SSRI antidepressants, nefazodone and venlafaxine. Psychopharmacology. 128(4):398–407. doi: 10.1007/s002130050149.
   PubMed Web of Science ®Google Scholar
• Weber J, Siddiqui MA, Wagstaff AJ, McCormack PL. 2010. Low-dose doxepin: in the treatment of insomnia. CNS Drugs. 24(8):713–720. doi: 10.2165/11200810-000000000-00000.
   PubMed Web of Science ®Google Scholar
• Wen B, Fitch WL. 2009. Screening and characterization of reactive metabolites using glutathione ethyl ester in combination with Q-trap mass spectrometry. J Mass Spectrom. 44(1):90–100. doi: 10.1002/jms.1475.
   PubMed Web of Science ®Google Scholar
• Wen B, Ma L, Rodrigues AD, Zhu M. 2008. Detection of novel reactive metabolites of trazodone: evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. Drug Metab Dispos. 36(5):841–850. doi: 10.1124/dmd.107.019471.
   PubMed Web of Science ®Google Scholar
• Wen B, Ma L, Zhu M. 2008. Bioactivation of the tricyclic antidepressant amitriptyline and its metabolite nortriptyline to arene oxide intermediates in human liver microsomes and recombinant P450s. Chem Biol Interact. 173(1):59–67. doi: 10.1016/j.cbi.2008.02.001.
   PubMed Web of Science ®Google Scholar
• Wong YC, Wo SK, Zuo Z. 2012. Investigation of the disposition of loxapine, amoxapine and their hydroxylated metabolites in different brain regions, CSF and plasma of rat by LC-MS/MS. J Pharm Biomed Anal. 58:83–93. doi: 10.1016/j.jpba.2011.09.020.
   PubMed Web of Science ®Google Scholar
• Wu G, Vashishtha SC, Erve JC. 2010. Characterization of glutathione conjugates of duloxetine by mass spectrometry and evaluation of in silico approaches to rationalize the site of conjugation for thiophene containing drugs. Chem Res Toxicol. 23(8):1393–1404. doi: 10.1021/tx100141d.
   PubMed Web of Science ®Google Scholar
• Yang M, Du K, Hou Y, Xie S, Dong Y, Li D, Du Y. 2019. Synergistic antifungal effect of amphotericin B-loaded poly (lactic-co-glycolic acid) nanoparticles and ultrasound against Candida albicans biofilms. Antimicrob Agents Chemother. 63(4):e02022-18. doi: 10.1128/AAC.02022-18.
   Google Scholar
• Yon J, Anuras S. 1975. Hepatitis caused by amitriptyline therapy. JAMA. 232(8):833–834.
   PubMed Web of Science ®Google Scholar
• You Y, Wang X, Ma K, Li J, Peng Y, Zheng J. 2021. Metabolic activation of atomoxetine mediated by cytochrome P450 2D6. Chem Res Toxicol. 34(9):2135–2144. doi: 10.1021/acs.chemrestox.1c00216.
   PubMed Web of Science ®Google Scholar
• Yuan Q, Hou J, Liao Y, Zheng L, Lu F, Wang K, Wu G. 2020. Lymph node metastasis in suprasternal space and intra-infrahyoid strap muscle space from papillary thyroid carcinoma. J Otolaryngol Head Neck Surg. 49(1):64. doi: 10.1186/s40463-020-00461-2.
   Google Scholar
• Yu J, Brown DG, Burdette D. 2010. In vitro metabolism studies of nomifensine monooxygenation pathways: metabolite identification, reaction phenotyping, and bioactivation mechanism. Drug Metab Dispos. 38(10):1767–1778. doi: 10.1124/dmd.110.033910.
   PubMed Web of Science ®Google Scholar
• Yu J, Mathisen DE, Burdette D, Brown DG, Becker C, Aharony D. 2010. Identification of multiple glutathione conjugates of 8-amino- 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (nomifensine) in liver microsomes and hepatocyte preparations: evidence of the bioactivation of nomifensine. Drug Metab Dispos. 38(1):46–60. doi: 10.1124/dmd.109.028803.
   PubMed Web of Science ®Google Scholar
• Zhang Z, Tang W. 2018. Drug metabolism in drug discovery and development. Acta Pharm Sin B. 8(5):721–732. doi: 10.1016/j.apsb.2018.04.003.
   PubMed Web of Science ®Google Scholar
• Zhao SX, Dalvie DK, Kelly JM, Soglia JR, Frederick KS, Smith EB, Obach RS, Kalgutkar AS. 2007. NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine. Chem Res Toxicol. 20(11):1649–1657. doi: 10.1021/tx700132x.
   PubMed Web of Science ®Google Scholar
• Zheng J, Ma L, Xin B, Olah T, Humphreys WG, Zhu M. 2007. Screening and identification of GSH-trapped reactive metabolites using hybrid triple quadruple linear ion trap mass spectrometry. Chem Res Toxicol. 20(5):757–766. doi: 10.1021/tx600277y.
   PubMed Web of Science ®Google Scholar
• Ziegler VE, Biggs JT, Wylie LT, Rosen SH, Hawf DJ, Coryell WH. 1978. Doxepin kinetics. Clin Pharmacol Ther. 23(5):573–579. doi: 10.1002/cpt1978235573.
   PubMed Web of Science ®Google Scholar
• Zimmerman HJ, Rosenblum L, Korn RJ, Feldman PE. 1959. Some preliminary clinical and biochemical aspects of liver function in patients receiving iproniazid. Ann N Y Acad Sci. 80(3):915–927. doi: 10.1111/j.1749-6632.1959.tb49267.x.
   PubMed Web of Science ®Google Scholar