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Review

Recent advances in understanding the hepatotoxicity associated with protein kinase inhibitors

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Pages 217-226 | Received 19 Nov 2019, Accepted 06 Feb 2020, Published online: 12 Feb 2020

References

  • Pertea M, Shumate A, Pertea G, et al. CHESS: a new human gene catalog curated from thousands of large-scale RNA sequencing experiments reveals extensive transcriptional noise. Genome Biol. 2018 Nov 28;19(1):208.
  • Wilson LJ, Linley A, Hammond DE, et al. New perspectives, opportunities, and challenges in exploring the human protein kinome. Cancer Res. 2018 Jan 1;78(1):15–29.
  • Bhullar KS, Lagaron NO, McGowan EM, et al. Kinase-targeted cancer therapies: progress, challenges and future directions. Mol Cancer. 2018 Feb 19;17(1):48.
  • New drugs at FDA: CDER’s new molecular entities and new therapeutic biological products. Silver Spring (MD): U.S. Food and Drug Administration [cited 2019 Oct 30]. Available from: https://www.fda.gov/drugs/development-approval-process-drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products
  • Feng B, Xu JJ, Bi YA, et al. Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714. Toxicol Sci. 2009 Apr;108(2):492–500.
  • Regev A, Seeff LB, Merz M, et al. Causality assessment for suspected DILI during clinical phases of drug development. Drug Saf. 2014 Nov;37(Suppl 1):S47–56.
  • Danan G, Teschke R. Drug-induced liver injury: why is the roussel uclaf causality assessment method (RUCAM) still used 25 years after its launch? Drug Saf. 2018 Aug;41(8):735–743.
  • Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul;109(7):950–966. quiz 967.
  • European Association for the Study of the Liver. Electronic address eee, Clinical Practice Guideline Panel C, Panel m, et al. EASL clinical practice guidelines: drug-induced liver injury. J Hepatol. 2019 Jun;70(6):1222–1261.
  • Yu YC, Mao YM, Chen CW, et al. CSH guidelines for the diagnosis and treatment of drug-induced liver injury. Hepatol Int. 2017 May;11(3):221–241.
  • Teschke R. Top-ranking drugs out of 3312 drug-induced liver injury cases evaluated by the roussel uclaf causality assessment method. Expert Opin Drug Metab Toxicol. 2018 Nov;14(11):1169–1187.
  • Ricart AD. Drug-induced liver injury in oncology. Ann Oncol. 2017 Aug 1;28(8):2013–2020.
  • Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in Mainland China. Gastroenterology. 2019 Jun;156(8):2230–2241 e11.
  • Bjornsson ES, Bergmann OM, Bjornsson HK, et al. Incidence, presentation, and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013 Jun;144(7):1419–1425. 1425 e1-3; quiz e19-20.
  • Chalasani N, Bonkovsky HL, Fontana R, et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015 Jun;148(7):1340–52 e7.
  • Bjornsson ES. Hepatotoxicity by drugs: the most common implicated agents. Int J Mol Sci. 2016 Feb 6;17(2):224.
  • Bjornsson ES. Drug-induced liver injury: an overview over the most critical compounds. Arch Toxicol. 2015 Mar;89(3):327–334.
  • The DailyMed. Washington (DC): National Institutes of Health, U.S. National Library of Medicine, Health & Human Services [cited 2019 Oct 30]. Available from: https://dailymed.nlm.nih.gov/dailymed/
  • The LiverTox: clinical and research information on drug-induced liver injury. Bethesda (MD): National Center for Biotechnology Information, U.S. National Library of Medicine [cited 2019 Oct 30]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548196/
  • Zhang J, Salminen A, Yang X, et al. Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria. Arch Toxicol. 2017 Aug;91(8):2921–2938.
  • Zhang J, Ren L, Yang X, et al. Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 2018 Jul;291:138–148.
  • Schoning V, Krahenbuhl S, Drewe J. The hepatotoxic potential of protein kinase inhibitors predicted with random forest and artificial neural networks. Toxicol Lett. 2018 Dec;15(299):145–148.
  • Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf. 2013 Jul;36(7):491–503.
  • Chen M, Vijay V, Shi Q, et al. FDA-approved drug labeling for the study of drug-induced liver injury. Drug Discov Today. 2011 Aug;16(15–16):697–703.
  • Hoofnagle JH, Serrano J, Knoben JE, et al. LiverTox: a website on drug-induced liver injury. Hepatology. 2013 Mar;57(3):873–874.
  • Qosa H, Avaritt BR, Hartman NR, et al. In vitro UGT1A1 inhibition by tyrosine kinase inhibitors and association with drug-induced hyperbilirubinemia. Cancer Chemother Pharmacol. 2018 Nov;82(5):795–802.
  • Paludetto MN, Puisset F, Chatelut E, et al. Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: implications for drug-drug interactions and hepatotoxicity. Med Res Rev. 2019 May 20;39:2105–2152.
  • Korprasertthaworn P, Chau N, Nair PC, et al. Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202. Biochem Pharmacol. 2019 Aug 22;169:113616.
  • Filppula AM, Neuvonen PJ, Backman JT. In vitro assessment of time-dependent inhibitory effects on CYP2C8 and CYP3A activity by fourteen protein kinase inhibitors. Drug Metab Dispos. 2014 Jul;42(7):1202–1209.
  • Kadi AA, Darwish HW, Abuelizz HA, et al. Identification of reactive intermediate formation and bioactivation pathways in Abemaciclib metabolism by LC-MS/MS: in vitro metabolic investigation. R Soc Open Sci. 2019 Jan;6(1):181714.
  • Thakkar D, Kate AS. Update on metabolism of abemaciclib: in silico, in vitro, and in vivo metabolite identification and characterization using high resolution mass spectrometry. Drug Test Anal. 2019 Nov 7:1-12. Available from: https://doi.org/10.1002/dta.2725
  • Fava C, Rege-Cambrin G, Saglio G. The choice of first-line chronic myelogenous leukemia treatment. Ann Hematol. 2015 Apr;94(Suppl 2):S123–31.
  • Han JM, Yee J, Cho YS, et al. Factors influencing imatinib-induced hepatotoxicity. Cancer Res Treat. 2019 Jun 26;52(1):181-188.
  • Ridruejo E, Cacchione R, Villamil AG, et al. Imatinib-induced fatal acute liver failure. World J Gastroenterol. 2007 Dec 28;13(48):6608–6611.
  • Thia TJ, Tan HH, Chuah TH, et al. Imatinib mesylate-related fatal acute hepatic failure in a patient with chronic myeloid leukaemia and chronic hepatitis B infection. Singapore Med J. 2008 Mar;49(3):e86–9.
  • Paech F, Bouitbir J, Krahenbuhl S. Hepatocellular toxicity associated with tyrosine kinase inhibitors: mitochondrial damage and inhibition of glycolysis. Front Pharmacol. 2017;8:367.
  • Bilgi N, Bell K, Ananthakrishnan AN, et al. Imatinib and Panax ginseng: a potential interaction resulting in liver toxicity. Ann Pharmacother. 2010 May;44(5):926–928.
  • Au A, Aziz Baba A, Goh AS, et al. Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients. Biomed Pharmacother. 2014 Apr;68(3):343–349.
  • Takimoto T, Kijima T, Otani Y, et al. Polymorphisms of CYP2D6 gene and gefitinib-induced hepatotoxicity. Clin Lung Cancer. 2013 Sep;14(5):502–507.
  • Chen J, Gu R, Wang Q, et al. Gefitinib-induced hepatotoxicity in patients treated for non-small cell lung cancer. Onkologie. 2012;35(9):509–513.
  • McGraw J, Waller D. Cytochrome P450 variations in different ethnic populations. Expert Opin Drug Metab Toxicol. 2012 Mar;8(3):371–382.
  • Yamaori S, Yamazaki H, Iwano S, et al. Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5 and CYP3A7: lack of co-regulation of the expression of CYP3A in Japanese livers. Xenobiotica. 2005 Jan;35(1):69–83.
  • Park YH, Cho S, Yee J, et al. Factors affecting time to reach and recover from gefitinib-induced hepatotoxicity. Anticancer Drugs. 2018 Jun;29(5):471–476.
  • Kobayashi H, Sato K, Niioka T, et al. Relationship among Gefitinib exposure, polymorphisms of its metabolizing enzymes and transporters, and side effects in Japanese patients with non-small-cell lung cancer. Clin Lung Cancer. 2015 Jul;16(4):274–281.
  • Sugiyama E, Umemura S, Nomura S, et al. Impact of single nucleotide polymorphisms on severe hepatotoxicity induced by EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer harboring EGFR mutations. Lung Cancer. 2015 Nov;90(2):307–313.
  • Li X, Kamenecka TM, Cameron MD. Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities. Chem Res Toxicol. 2009 Oct;22(10):1736–1742.
  • Liu X, Lu Y, Guan X, et al. Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism. Biochem Pharmacol. 2015 Sep 1;97(1):111–121.
  • Takeda M, Nakagawa K. Toxicity profile of epidermal growth factor receptor tyrosine kinase inhibitors in patients with epidermal growth factor receptor gene mutation-positive lung cancer. Mol Clin Oncol. 2017 Jan;6(1):3–6.
  • Chen X, Yang S, Pan Y, et al. Mitochondrial pathway-mediated apoptosis is associated with erlotinib-induced cytotoxicity in hepatic cells. Oncol Lett. 2018 Jan;15(1):783–788.
  • Kim MK, Yee J, Cho YS, et al. Risk factors for erlotinib-induced hepatotoxicity: a retrospective follow-up study. BMC Cancer. 2018 Oct 16;18(1):988.
  • Li X, Kamenecka TM, Cameron MD. Cytochrome P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile. Drug Metab Dispos. 2010 Jul;38(7):1238–1245.
  • Castellino S, O’Mara M, Koch K, et al. Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity. Drug Metab Dispos. 2012 Jan;40(1):139–150.
  • Eno MR, El-Gendy Bel D, Cameron MD. P450 3A-catalyzed O-dealkylation of lapatinib induces mitochondrial stress and activates Nrf2. Chem Res Toxicol. 2016 May 16;29(5):784–796.
  • Hardy KD, Wahlin MD, Papageorgiou I, et al. Studies on the role of metabolic activation in tyrosine kinase inhibitor-dependent hepatotoxicity: induction of CYP3A4 enhances the cytotoxicity of lapatinib in HepaRG cells. Drug Metab Dispos. 2014 Jan;42(1):162–171.
  • Moon JY, Han JM, Seo I, et al. Risk factors associated with the incidence and time to onset of lapatinib-induced hepatotoxicity. Breast Cancer Res Treat. 2019 Aug 1;178:239–244.
  • Teo YL, Saetaew M, Chanthawong S, et al. Effect of CYP3A4 inducer dexamethasone on hepatotoxicity of lapatinib: clinical and in vitro evidence. Breast Cancer Res Treat. 2012 Jun;133(2):703–711.
  • Spraggs CF, Budde LR, Briley LP, et al. HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. J Clin Oncol. 2011 Feb 20;29(6):667–673.
  • Schaid DJ, Spraggs CF, McDonnell SK, et al. Prospective validation of HLA-DRB1*07:01 allele carriage as a predictive risk factor for lapatinib-induced liver injury. J Clin Oncol. 2014 Aug 1;32(22):2296–2303.
  • Tangamornsuksan W, Kongkaew C, Scholfield CN, et al. HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity: a systematic review and meta-analysis. Pharmacogenomics J. 2019 Aug 6;20(1):47–56.
  • Spraggs CF, Xu CF, Hunt CM. Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics. 2013 Apr;14(5):541–554.
  • Mingard C, Paech F, Bouitbir J, et al. Mechanisms of toxicity associated with six tyrosine kinase inhibitors in human hepatocyte cell lines. J Appl Toxicol. 2018 Mar;38(3):418–431.
  • Choudhury Y, Toh YC, Xing J, et al. Patient-specific hepatocyte-like cells derived from induced pluripotent stem cells model pazopanib-mediated hepatotoxicity. Sci Rep. 2017 Jan 25;7:41238.
  • Wang YK, Yang XN, Liang WQ, et al. A metabolomic perspective of pazopanib-induced acute hepatotoxicity in mice. Xenobiotica. 2019 Jun;49(6):655–670.
  • Paludetto MN, Stigliani JL, Robert A, et al. Involvement of pazopanib and sunitinib aldehyde reactive metabolites in toxicity and drug-drug interactions in vitro and in patient samples. Chem Res Toxicol. 2019 Sep 26;33(1):181-190.
  • Paludetto MN, Bijani C, Puisset F, et al. Metalloporphyrin-catalyzed oxidation of sunitinib and pazopanib, two anticancer tyrosine kinase inhibitors: evidence for new potentially toxic metabolites. J Med Chem. 2018 Sep 13;61(17):7849–7860.
  • Xu CF, Johnson T, Wang X, et al. HLA-B*57:01 confers susceptibility to pazopanib-associated liver injury in patients with cancer. Clin Cancer Res. 2016 Mar 15;22(6):1371–1377.
  • Paech F, Abegg VF, Duthaler U, et al. Sunitinib induces hepatocyte mitochondrial damage and apoptosis in mice. Toxicology. 2018 Nov 1;409:13–23.
  • Zhao Q, Zhang T, Xiao XR, et al. Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity. Br J Pharmacol. 2019 Jul;176(13):2162–2178.
  • Amaya GM, Durandis R, Bourgeois DS, et al. Cytochromes P450 1A2 and 3A4 catalyze the metabolic activation of sunitinib. Chem Res Toxicol. 2018 Jul 16;31(7):570–584.
  • Rimassa L, Pressiani T, Personeni N, et al. Regorafenib for the treatment of unresectable hepatocellular carcinoma. Expert Rev Anticancer Ther. 2017 Jul;17(7):567–576.
  • Weng Z, Luo Y, Yang X, et al. Regorafenib impairs mitochondrial functions, activates AMP-activated protein kinase, induces autophagy, and causes rat hepatocyte necrosis. Toxicology. 2015 Jan 2;327:10–21.
  • Paech F, Mingard C, Grunig D, et al. Mechanisms of mitochondrial toxicity of the kinase inhibitors ponatinib, regorafenib and sorafenib in human hepatic HepG2 cells. Toxicology. 2018 Feb 15;395:34–44.
  • Wang YK, Xiao XR, Xu KP, et al. Metabolic profiling of the anti-tumor drug regorafenib in mice. J Pharm Biomed Anal. 2018 Sep 10;159:524–535.
  • Jung D, Han JM, Yee J, et al. Factors affecting crizotinib-induced hepatotoxicity in non-small cell lung cancer patients. Med Oncol. 2018 Oct 26;35(12):154.
  • Zhu J, Wang P, Shehu AI, et al. Identification of novel pathways in idelalisib metabolism and bioactivation. Chem Res Toxicol. 2018 Jul 16;31(7):548–555.
  • Chen CM, Wu WB, Chen JF, et al. Characterization of the in vitro metabolites of idelalisib in liver microsomes and interspecies comparison. J Pharm Biomed Anal. 2019 Jan 5;162:249–256.
  • Mosedale M, Cai Y, Eaddy JS, et al. Identification of candidate risk factor genes for human idelalisib toxicity using a collaborative cross approach. Toxicol Sci. 2019 Sep 10;172:265–278.
  • Lin KR, Huang JT, Henderson CJ, et al. Novel pathways of ponatinib disposition catalyzed by CYP1A1 involving generation of potentially toxic metabolites. J Pharmacol Exp Ther. 2017 Oct;363(1):12–19.
  • Xue T, Luo P, Zhu H, et al. Oxidative stress is involved in dasatinib-induced apoptosis in rat primary hepatocytes. Toxicol Appl Pharmacol. 2012 Jun 15;261(3):280–291.
  • Lasser KE, Allen PD, Woolhandler SJ, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA. 2002 May 1;287(17):2215–2220.

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