Evaluation of in vitro hepatotoxicity of perampanel in comparison with carbamazepine: old versus new

Year 2023, Volume: 2 Issue: 2, 59 - 70, 28.08.2023

Gülnar Farmanlı , Sinem Ilgın , Bülent Ergun , Merve Baysal , Abdullah Burak Karaduman , Özlem Atlı Eklioğlu

https://doi.org/10.55971/EJLS.1324501

Abstract

Since the liver metabolizes many drugs, including antiepileptics, this organ is the main target of drug-induced damage. There is very little data on hepatotoxicity due to carbamazepine and perampanel metabolized in the liver. The available data are based solely on published case reports. For this reason, this study aims to evaluate the hepatotoxicity of carbamazepine and perampanel, which are frequently used in treating epilepsy and which do not have a detailed investigation, although they are suspected of hepatotoxicity. Hepatotoxicity in the HepG2 cell line, IC50 values were calculated by MTT cytotoxicity test, followed by determination of apoptosis/necrosis, various biochemical analyzes (ALT, AST, urea), which is currently a biomarker for liver injury, and hepatotoxicity by ROS and GSH determination. Both drugs increased liver biomarkers, oxidative stress, and cytotoxicity in HepG2 cells. The investigation found that the drugs triggered liver apoptosis, not necrosis. In conclusion, Perampanel may have hepatotoxicity similar to carbamazepine.

Keywords

Antiepileptic drugs, epilepsy, hepatotoxicity, HepG2, liver

Supporting Institution

Anadolu University

Project Number

1905S075

References

• Akdağ G, Algın Dİ, Erdinç OO. Epilepsi. Osmangazi Tıp Dergisi. (2016); 38(1):35-41. https://doi.org/10.20515/otd.88853
• Meyer A, Dua T, Ma J, Saxena S, Birbeck G. Global disparities in the epilepsy treatment gap: a systematic review. Bull World Health Organ. (2010); 88:260–266. https://doi.org/10.2471/BLT.09.064147
• Stafstrom CE, Carmant L. Seizures and Epilepsy: An Overview for Neuroscientists. Cold Spring Harb Perspect Med. (2015); 5(6):1-19. https://doi.org/10.1101/cshperspect.a022426
• Liu P, Zhang Y, Xu X, Zhou M, Fei Y, Zhang L. Mining and analysis of adverse drug reactions associated with perampanel based on FAERS database. Epilepsy & Behavior. (2023); 145. https://doi.org/10.1016/j.yebeh.2023.109283
• Toklu Z. Epilepside Tedavi Stratejileri. Kocatepe Medical Journal. (2015); 16:147-150. https://doi.org/10.18229/ktd.55178
• Vickery PB, Tillery EE, DeFalco AP. Intravenous Carbamazepine for Adults With Seizures. Annals of Pharmacotherapy. (2017); 1 –5. https://doi.org/10.1177/106002801773678
• Osuntokun OS, Babatunde AA, Olayiwola G, Atere TG, Oladokun OO, Adedokun, KI. Assessment of the biomarkers of hepatotoxicity following carbamazepine, levetiracetam, and carbamazepine-levetiracetam adjunctive treatment in male Wistar rats. Toxicology Reports. (2021); 8:592-598 https://doi.org/10.1016/j.toxrep.2021.03.008
• Lim SN, Wu T, Tseng WEJ. Efficacy and safety of perampanel in refractory and super-refractory status epilepticus: cohort study of 81 patients and literature review. J Neurol (2021); 268:3744–3757 https://doi.org/10.1007/s00415-021-10506-9
• Kamitaki BK, Minacapelli CD, Zhang P, Wachuku C, Gupta K, Catalano C, Rustgi V. Drug-induced liver injury associated with antiseizure medications from the FDA Adverse Event Reporting System (FAERS). Epilepsy & Behavior. (2021); 117 https://doi.org/10.1016/j.yebeh.2021.107832
• Faulkner MA. Perampanel: A new agent for adjunctive treatment of partial seizures. Am J Health-Syst Pharm. (2014); 71, 191-198. https://doi.org/10.2146/ajhp130203
• Pandit A, Sachdeva T, Bafna P. Drug-Induced Hepatotoxicity: A Review. Journal of Applied Pharmaceutical Science. (2012); 2 (5):233-243. https://doi.org/10.7324/JAPS.2012.2541
• Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scand. (2008); 118:281–290. https://doi.org/10.1111/j.1600-0404.2008.01009.x
• Antoine DJ, Mercer AE, Williams DP, Park BK. Mechanism-based bioanalysis and biomarkers for hepatic chemical stress. Xenobiotica. (2009); 39 (8):565–577. https://doi.org/10.1080/00498250903046993
• Al-Sayed E, Esmat A. Hepatoprotective and antioxidant effect of ellagitannins and galloyl esters isolated from Melaleuca styphelioides on carbon tetrachloride-induced hepatotoxicity in HepG2 cells. Pharmaceutical Biology. 82016); 54(9):1727-1735. https://doi.org/10.3109/13880209.2015.1125933
• Mosmann T. Rapid Colorimetric Assay for Cellular Growth and Survival: Application to Proliferation and Cytotoxicity Assays. Journal oflmmunological Methods. (1983); 65: 55-63. https://doi.org/10.1016/0022-1759(83)90303-4
• Shehu AI, Ma X, Venkataramanan R. Mechanisms of Drug İnduced Hepatotoxicity. Clin Liver Dis. (2017); 21: 35–54. https://doi.org/10.1016/j.cld.2016.08.002
• Güleş Ö, Eren Ü. Apoptozun Belirlenmesinde Kullanılan Yöntemler. Yüzüncü Yıl Üniversitesi Veteriner Fakültesi Dergisi. (2008); 19(2): 73-78.
• Banfalvi G. Methods to detect apoptotic cell death. Apoptosis. (2017); 22(2):306-323. https://doi.org/10.1007/s10495-016-1333-3
• Morales-Diaz MMD, Pinilla-Roa E, Ruiz I. Suspected Carbamazepine-Induced Hepatotoxicity. Pharmacotherapy. (1999); 19(2): 252–255. https://doi.org/10.1592/phco.19.3.252.30918
• Majid O, Laurenza A, Ferry J. Hussein Z. Impact of perampanel on pharmacokinetics of concomitant antiepileptics in patients with partial‐onset seizures: pooled analysis of clinical trials. Br J Clin Pharmacol. (2016); 82(2):422–430. https://doi.org/10.1111/bcp.12951
• Vidaurre J, Gedela S, Yarosz S. Antiepileptic Drugs and Liver Disease. Pediatr Neurol. (2017); 77: 23–36. https://doi.org/10.1016/j.pediatrneurol.2017.09.013
• Van den Hof WFPM, Coonen MLJ, Herwijnen M, Brauers K, Wodzig WKWH, Delft JHM, Kleinjans JCS. Classification of Hepatotoxicants Using HepG2 Cells: A Proof of Principle Study. Chem. Res. Toxicol. (2014); 27:433−442. https://doi.org/10.1021/tx4004165
• Summeren AV, Renes J, Bouwman FG, Noben J, Delft JHM, Kleinjans JCS, Mariman ECM. Proteomics Investigations of Drug-Induced Hepatotoxicity in HepG2 Cells. Toxicological Sciences. (2011); 120(1):109–122. https://doi.org/10.1093/toxsci/kfq380
• O’Brier PJ, Irwin W, Diaz D, Howard-Cofield E, Krejsa CM, Slaughter R, Gao B, Kaludercic N, Angeline A, Bernardi P, Brain P, Hougham C. High concordance of drug-induced human hepatotoxicity with in vitro cytotoxicity measured in a novel cell-based model using high content screening. Arch Toxicol. (2006); 80: 580–604. https://doi.org/10.1007/s00204-006-0091-3
• Fotakis G, Timbrell JA. In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. Toxicology Letters. (2005); 160:171-177. https://doi.org/10.1016/j.toxlet.2005.07.001
• Jain AK, Singh D, Dubey K, Maurya R, Mittal S, Pandey AK. Models and Methods for In Vitro Toxicity. In Vitro Toxicology. (2018); 45-65.
• Riss TL, Moravec RA, Niles AL, Duellman S, Benink HA, Worzella TJ, Minor L. Cell Viability Assays. Sittampalam GS, Coussens NP. Assay Guidance Manual. (2016); 357-387.
• Lange F, Weßlau W, Porath K, Hörnschemeyer J, Bergner C, Krause BJ, Mullins CS, Linnebacher M, Köhling R, Kirschstein T. AMPA receptor antagonist perampanel affects glioblastoma cell growth and glutamate release in vitro. PLoS ONE. (2019); 14(2):1-17. https://doi.org/10.1371/journal.pone.0211644
• Beutler AS, Li S, Nicol R, Walsh MJ. Carbamazepine is an inhibitor of histone deacetylases. Life Sciences. (2005) ; 76(26):3107-3115. https://doi.org/10.1016/j.lfs.2005.01.003
• Zhang J, Zhong Q. Histone deacetylase inhibitors and cell death. Cell Mol Life Sci. (2014); 71(20): 3885–3901. https://doi.org/10.1007/s00018-014-1656-6
• Babu GN, Gupta M. Therapeutics in Neurodegenerative Disorders: Emerging Compounds of Interest. Emerging Trends in Chemical Sciences. (2017); 37–56. https://doi.org/10.1007/978-3-319-60408-4_4
• Hasan FAM, Owyed S. Interpretation of liver chemistry tests. Bull Kuwait Inst Med Spec. (2003); 2:27-31.
• Teranishi H, Kagamiyama H, Teranishi K, Wada H, Yamano T. Cytosolic and Mitochondrial Isoenzymes of Glutamic-Oxalacetic Transaminase from Human Heart. The ournal of Biolocigal chemistry. (1978); 253(24):8842-8847. https://doi.org/10.1016/0006-8993(87)91068-7
• Kim W, Flamm SL, Di Bisceglie AM, Bodenheimer HC. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology. (2008); 47(4):1363-1370 https://doi.org/10.1002/hep.22109
• Wang H, Ran J, Jiang T. Urea. Urea Transporters. (2014); 7–29. https://doi.org/10.1007/978-94-017-9343-8_2
• Waring WS, Stephen AFL, Robinson ODG, Dow MA, Pettie JM. Serum urea concentration and the risk of hepatotoxicity after paracetamol overdose. Q J Med. (2008); 101(5):359–363. https://doi.org/10.1093/qjmed/hcn023
• Holmes GL. Carbamazepine adverse effects. Levy RH, Mattson RH, Meldrum BS, Perucca E. Antiepileptic drugs 5nd ed. (2002); 285-294.
• Hussein RRS, Soliman RH, Abdelhaleem A AM, Tawfeik MH, Abdelrahim MEA. Effects of Antiepileptic Drugs on liver enzymes. Beni-Suef University Journal of Basic and Applied Sciences. (2013);2(1): 14-19. https://doi.org/10.1016/j.bjbas.2013.09.002
• Hadzagic-Catibusic F, Hasanbegovic E, Melunovic M, Zubcevic S, Uzicanin S. Effects of Carbamazepine and Valproate on Serum Aspartate Aminotransferase, Alanine Aminotransferase and Gamma - Glutamyltransferase in Children. Med Arch. (2017); 71(4):239-242. https://doi.org/10.5455/medarh.2017.71.239-242
• Novy J, Rothuizen LE, Buclin T, Rossetti AO. Perampanel: A Significant Liver Enzyme Inducer in Some Patients? European Neurology. (2014); 72:213–216. https://doi.org/10.1159/000362446
• Yoshikawa T, Naito Y. What Is Oxidative Stress? JMAJ. (2002); 45(7):271–276. https://doi.org/10.1016/S0026-0495(00)80077-3
• Köken T, Kahraman A, Serteser M, Gökçe Ç. Hemodiyaliz ve Oksidatif Stres. Kocatepe Tıp Dergisi. (2004); 5:9-13.
• Jambunathan N. Determination and detection of reactive oxygen species (ROS), lipid peroxidation, and electrolyte leakage in plants. Methods in Molecular Biology. (2010); 639:292-298. https://doi.org/10.1007/978-1-60761-702-0_18
• Sanchez-Valle V, Chavez-Tapia NC, Uribe M, Mendez-Sanchez N. Role of oxidative stress and molecular changes in liver fibrosis: A review. Curr. Med. Chem. (2012); 19: 4850–4860. https://doi.org/10.2174/092986712803341520
• Iida A, Sasaki E, Yano A, Tsuneyama K, Fukami T, Nakajima M, Yokoi T. Carbamazepine-Induced Liver Injury Requires CYP3A-Med iated Metabolism and Glutathione Depletion in Rats. Drug Metab Dispos. (2015); 43:958–968. https://doi.org/10.1124/dmd.115.063370
• Panayiotopoulos CP. Carbamazepine. The Epilepsies: Seizures, Syndromes and Management ; (2005) ISBN-10: 1-904218-34-2
• Sasaki E, Iida A, Oda S, Tsuneyama K, Fukamia T, Nakajimaa M, Yokoiac T. Pathogenetic analyses of carbamazepine-induced liver injury in F344 rats focused on immune- and inflammation-related factors. Experimental and Toxicologic Pathology. (2016); 68(1):27-38. https://doi.org/10.1016/j.etp.2015.09.004
• Eghbal MA, Taziki S, Sattari MR. Role of Melatonin and Taurine Against Carbamazepine-induced Toxicity in Freshly Isolated Rat Hepatocytes. Int. J. Morphol. (2013); 31(3):1081-1089. http://dx.doi.org/10.4067/S0717-95022013000300049
• Besag FMC, Patsalos PN. Clinical efficacy of perampanel for partial-onset and primary generalized tonic–clonic seizures. Neuropsychiatric Disease and Treatment. (2016); 12:1215–1220. https://doi.org/10.2147/NDT.S83842
• Patsalos PN. The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist. Epilepsia. (2015); 56(1):12–27. https://doi.org/10.1111/epi.12865
• Faulkner MA, Burke RA. Safety profile of two novel antiepileptic agents approved for the treatment of refractory partial seizures: ezogabine (retigabine) and perampanel. Expert Opin. Drug. Saf. (2013); 12(6):847-855 https://doi.org/10.1517/14740338.2013.823399
• Plosker GL. Perampanel: As Adjunctive Therapy in Patients with Partial-Onset Seizures. CNS Drugs. (2012); 26:1085–1096. https://doi.org/10.1007/s40263-012-0021-2