Metabolic activation of tyrosine kinase inhibitors: recent advance and further clinical practice

References

• Abdelhameed AS, Attwa MW, Kadi AA. 2019. Liquid chromatography–tandem mass spectrometry metabolic profiling of nazartinib reveals the formation of unexpected reactive metabolites. R Soc Open Sci. 6(8):190852.
   PubMed Web of Science ®Google Scholar
• Abdelhameed AS, Attwa MW, Kadi AA. 2020a. Characterization of stable and reactive metabolites of the anticancer drug, ensartinib, in human liver microsomes using LC–MS/MS: an in silico and practical bioactivation approach. Drug Des Devel Ther. 14:5259–5273.
   PubMed Web of Science ®Google Scholar
• Abdelhameed AS, Attwa MW, Kadi AA. 2020b. Identification of iminium intermediates generation in the metabolism of tepotinib using LC–MS/MS: in silico and practical approaches to bioactivation pathway elucidation. Molecules. 25(21):5004.
   PubMed Web of Science ®Google Scholar
• AlAsmari AF, Ali N, AlAsmari F, AlAnazi WA, AlShammari MA, Al-Harbi NO, Alhoshani A, As Sobeai HM, AlSwayyed M, AlAnazi MM, et al. 2020. Liraglutide attenuates gefitinib-induced cardiotoxicity and promotes cardioprotection through the regulation of MAPK/NF-κB signaling pathways. Saudi Pharm J. 28(4):509–518.
   PubMed Web of Science ®Google Scholar
• Alhoshani A, Alanazi FE, Alotaibi MR, Attwa MW, Kadi AA, Aldhfyan A, Akhtar S, Hourani S, Agouni A, Zeidan A, et al. 2020. EGFR inhibitor gefitinib induces cardiotoxicity through the modulation of cardiac PTEN/Akt/FoxO3a pathway and reactive metabolites formation: in vivo and in vitro rat studies. Chem Res Toxicol. 33(7):1719–1728.
   PubMed Web of Science ®Google Scholar
• Al-Shakliah NS, Attwa MW, AlRabiah H, Kadi AA. 2021. Identification and characterization of in vitro, in vivo, and reactive metabolites of tandutinib using liquid chromatography ion trap mass spectrometry. Anal Methods. 13(3):399–410.
   PubMed Web of Science ®Google Scholar
• Amaya GM, Durandis R, Bourgeois DS, Perkins JA, Abouda AA, Wines KJ, Mohamud M, Starks SA, Daniels RN, Jackson KD. 2018. Cytochromes P450 1A2 and 3A4 catalyze the metabolic activation of sunitinib. Chem Res Toxicol. 31(7):570–584.
   PubMed Web of Science ®Google Scholar
• Amer SM, Kadi AA, Darwish HW, Attwa MW. 2017. Identification and characterization of in vitro phase I and reactive metabolites of masitinib using a LC–MS/MS method: bioactivation pathway elucidation. RSC Adv. 7(8):4479–4491.
   Web of Science ®Google Scholar
• Andreu I, Lence E, González-Bello C, Mayorga C, Cuquerella MC, Vayá I, Miranda MA. 2020. Protein binding of lapatinib and its N- and O-dealkylated metabolites interrogated by fluorescence, ultrafast spectroscopy and molecular dynamics simulations. Front Pharmacol. 11:576495.
   PubMed Web of Science ®Google Scholar
• Attwa MW, Kadi AA. 2019. Sapitinib: reactive intermediates and bioactivation pathways characterized by LC–MS/MS. RSC Adv. 9(57):32995–33006.
   PubMed Web of Science ®Google Scholar
• Attwa MW, Kadi AA, Abdelhameed AS. 2018. Characterization of reactive intermediates formation in dacomitinib metabolism and bioactivation pathways elucidation by LC–MS/MS: in vitro phase I metabolic investigation. RSC Adv. 8(68):38733–38744.
   PubMed Web of Science ®Google Scholar
• Attwa MW, Kadi AA, Alrabiah H, Darwish HW. 2018. LC–MS/MS reveals the formation of iminium and quinone methide reactive intermediates in entrectinib metabolism: in vivo and in vitro metabolic investigation. J Pharm Biomed Anal. 160:19–30.
   PubMed Web of Science ®Google Scholar
• Attwa MW, Kadi AA, Abdelhameed AS. 2019a. Detection and characterization of olmutinib reactive metabolites by LC–MS/MS: elucidation of bioactivation pathways. J Sep Sci. 43(4):201900818.
   Web of Science ®Google Scholar
• Attwa MW, Kadi AA, Abdelhameed AS. 2019b. Reactive intermediates and bioactivation pathways characterization of avitinib by LC–MS/MS: in vitro metabolic investigation. J Pharm Biomed Anal. 164:659–667.
   PubMed Web of Science ®Google Scholar
• Attwa MW, Kadi AA, AlRabiah H, Darwish HW. 2019. Reactive intermediates in naquotinib metabolism identified by liquid chromatography–tandem mass spectrometry: phase I metabolic profiling. RSC Adv. 9(18):10211–10225.
   PubMed Web of Science ®Google Scholar
• Attwa MW, Kadi AA, Darwish HW. 2019. Belizatinib: novel reactive intermediates and bioactivation pathways characterized by LC–MS/MS. J Pharm Biomed Anal. 171:132–147.
   PubMed Web of Science ®Google Scholar
• Attwa MW, Kadi AA, Darwish HW, Alrabiah H. 2018. LC–MS/MS reveals the formation of reactive ortho-quinone and iminium intermediates in saracatinib metabolism: phase I metabolic profiling. Clin Chim Acta. 482:84–94.
   PubMed Web of Science ®Google Scholar
• Attwa MW, Kadi AA, Darwish HW, Amer SM, Al-Shakliah NS. 2018. Identification and characterization of in vivo, in vitro and reactive metabolites of vandetanib using LC–ESI–MS/MS. Chem Cent J. 12(1):1–16.
   PubMedGoogle Scholar
• Bart AG, Scott EE. 2018. Structures of human cytochrome P450 1A1 with bergamottin and erlotinib reveal active-site modifications for binding of diverse ligands. J Biol Chem. 293(50):19201–19210.
   PubMed Web of Science ®Google Scholar
• Bissada JE, Truong V, Abouda AA, Wines KJ, Crouch RD, Jackson KD. 2019. Interindividual variation in CYP3A activity influences lapatinib bioactivation. Drug Metab Dispos. 47(11):1257–1269.
   PubMed Web of Science ®Google Scholar
• Bouitbir J, Alshaikhali A, Panajatovic M, Abegg V, Paech F, Krähenbühl S. 2020. Mechanisms of cardiotoxicity associated with tyrosine kinase inhibitors in H9c2 cells and mice. Eur Cardiol. 15:e33.
   PubMedGoogle Scholar
• Burnham EA, Abouda AA, Bissada JE, Nardone-White DT, Beers JL, Lee J, Vergne MJ, Jackson KD. 2022. Interindividual variability in cytochrome P450 3A and 1A activity influences sunitinib metabolism and bioactivation. Chem Res Toxicol. 35(5):792–806.
   PubMed Web of Science ®Google Scholar
• Castellino S, O'Mara M, Koch K, Borts DJ, Bowers GD. 2012. Human metabolism of lapatinib, a dual kinase inhibitor: implications for hepatotoxicity[J]. Drug Metab Dispos, 40(1): 139 –150.
   Google Scholar
• Chan EC, New LS, Chua TB, Yap CW, Ho HK, Nelson SD. 2012. Interaction of lapatinib with cytochrome P450 3A5. Drug Metab Dispos. 40(7):1414–1422.
   Google Scholar
• Cho T, Uetrecht J. 2017. How reactive metabolites induce an immune response that sometimes leads to an idiosyncratic drug reaction. Chem Res Toxicol. 30(1):295–314.
   PubMed Web of Science ®Google Scholar
• Dong J, Li S, Liu G. 2021. Binimetinib is a potent reversible and time-dependent inhibitor of cytochrome P450 1A2. Chem Res Toxicol. 34(4):1169–1174.
   PubMed Web of Science ®Google Scholar
• García-Lainez G, Vayá I, Marín MP, Miranda MA, Andreu I. 2021. In vitro assessment of the photo(geno)toxicity associated with lapatinib, a tyrosine kinase inhibitor. Arch Toxicol. 95(1):169–178.
   PubMed Web of Science ®Google Scholar
• Ghasoub R, Albattah A, Elazzazy S, Alokka R, Nemir A, Alhijji I, Taha R. 2020. Ibrutinib-associated sever skin toxicity: a case of multiple inflamed skin lesions and cellulitis in a 68-year-old male patient with relapsed chronic lymphocytic leukemia – case report and literature review. J Oncol Pharm Pract. 26(2):487–491.
   PubMed Web of Science ®Google Scholar
• Ghassabian S, Gillani TB, Rawling T, Crettol S, Nair PC, Murray M. 2019. Sorafenib N-oxide is an inhibitor of human hepatic CYP3A4. AAPS J. 21(2):15.
   PubMed Web of Science ®Google Scholar
• Guan S, Chen X, Chen Y, Wan G, Su Q, Liang H, Yang Y, Fang W, Huang Y, Zhao H, et al. 2022. FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy. Acta Pharm Sin B. 12(9):3639–3649.
   PubMed Web of Science ®Google Scholar
• Guo X, Li W, Li Q, Chen Y, Zhao G, Peng Y, Zheng J. 2019. Tofacitinib is a mechanism-based inactivator of cytochrome P450 3A4. Chem Res Toxicol. 32(9):1791–1800.
   PubMed Web of Science ®Google Scholar
• Guo X, Jia Y, Han L, Zhao Y, Li W, Zhang Z, Peng Y, Zheng J. 2019. Metabolic activation of tofacitinib mediated by myeloperoxidase in vitro. Chem Res Toxicol. 32(12):2459–2465.
   PubMed Web of Science ®Google Scholar
• He C, Wan H. 2018. Drug metabolism and metabolite safety assessment in drug discovery and development. Expert Opin Drug Metab Toxicol. 14(10):1071–1085.
   PubMed Web of Science ®Google Scholar
• Ho HK, Chan JC, Hardy KD, Chan EC. 2015. Mechanism-based inactivation of CYP450 enzymes: a case study of lapatinib. Drug Metab Rev. 47(1):21–28.
   PubMed Web of Science ®Google Scholar
• Imano H, Kato R, Ijiri Y, Hayashi T. 2021. Activation of inflammasomes by tyrosine kinase inhibitors of vascular endothelial growth factor receptor: implications for VEGFR TKIs-induced immune related adverse events. Toxicol In Vitro. 71:105063.
   PubMed Web of Science ®Google Scholar
• Jackson KD, Amaya GM, Durandis R, Wines KJ, Abouda AA, Starks SA, Daniels RN. 2018. Metabolic activation of sunitinib: implications for sunitinib-induced toxicities. Cancer Res. 78(13_Suppl.):4911.
   Web of Science ®Google Scholar
• Jiang H, Jin Y, Yan H, Xu Z, Yang B, He Q, Luo P. 2021. Hepatotoxicity of FDA-approved small molecule kinase inhibitors. Expert Opin Drug Saf. 20(3):335–348.
   PubMed Web of Science ®Google Scholar
• Kadi AA, Amer SM, Darwish HW, Attwa MW. 2017. LC–MS/MS reveals the formation of aldehydes and iminium reactive intermediates in foretinib metabolism: phase I metabolic profiling. RSC Adv. 7(58):36279–36287.
   Web of Science ®Google Scholar
• Kadi AA, Darwish HW, Abuelizz HA, Alsubi TA, Attwa MW. 2019. Identification of reactive intermediate formation and bioactivation pathways in abemaciclib metabolism by LC–MS/MS: in vitro metabolic investigation. R Soc Open Sci. 6(1):181714.
   PubMed Web of Science ®Google Scholar
• Kadi AA, Darwish HW, Attwa MW, Amer SM. 2016. Detection and characterization of ponatinib reactive metabolites by liquid chromatography tandem mass spectrometry and elucidation of bioactivation pathways. RSC Adv. 6(76):72575–72585.
   Web of Science ®Google Scholar
• Kato R, Ijiri Y. 2022. Regorafenib and reactive metabolite of sunitinib activate inflammasomes: implications for multi tyrosine kinase inhibitor-induced immune related adverse events. Pharmazie. 77(2):54–58.
   PubMed Web of Science ®Google Scholar
• Kato R, Ijiri Y, Hayashi T, Uetrecht J. 2020. Reactive metabolite of gefitinib activates inflammasomes: implications for gefitinib-induced idiosyncratic reaction. J Toxicol Sci. 45(11):673–680.
   PubMed Web of Science ®Google Scholar
• Keller KL, Franquiz MJ, Duffy AP, Trovato JA. 2018. Drug–drug interactions in patients receiving tyrosine kinase inhibitors. J Oncol Pharm Pract. 24(2):110–115.
   PubMed Web of Science ®Google Scholar
• Kim L, Fowler B, Campbell CM, Slivnick J, Nawaz H, Kaka Y, Ruz P, Vallakati A, Baliga R, Vasu S, et al. 2021. Acute cardiotoxicity after initiation of the novel tyrosine kinase inhibitor gilteritinib for acute myeloid leukemia. Cardio-Oncology. 7(1):1–6.
   Google Scholar
• Korashy HM, Attafi IM, Ansari MA, Assiri MA, Belali OM, Ahmad SF, Al-Alallah IA, Anazi FEA, Alhaider AA. 2016. Molecular mechanisms of cardiotoxicity of gefitinib in vivo and in vitro rat cardiomyocyte: role of apoptosis and oxidative stress. Toxicol Lett. 252:50–61.
   PubMed Web of Science ®Google Scholar
• Li X, Kamenecka TM, Cameron MD. 2009. Bioactivation of the epidermal growth factor receptor inhibitor gefitinib: implications for pulmonary and hepatic toxicities. Chem Res Toxicol. 22(10):1736–1742.
   PubMed Web of Science ®Google Scholar
• Li X, Kamenecka TM, Cameron MD. 2010. Cytochrome P450-mediated bioactivation of the epidermal growth factor receptor inhibitor erlotinib to a reactive electrophile. Drug Metab Dispos. 38(7):1238–1245.
   PubMed Web of Science ®Google Scholar
• Li F, Lu J, Ma X. 2011. Profiling the reactive metabolites of xenobiotics using metabolomic technologies. Chem Res Toxicol. 24(5):744–751.
   PubMed Web of Science ®Google Scholar
• Lin D, Kostov R, Huang JT, Henderson CJ, Wolf CR. 2017. Novel pathways of ponatinib disposition catalyzed by CYP1A1 involving generation of potentially toxic metabolites. J Pharmacol Exp Ther. 363(1):12–19.
   PubMed Web of Science ®Google Scholar
• Liu X, Lu Y, Guan X, Dong B, Chavan H, Wang J, Zhang Y, Krishnamurthy P, Li F. 2015. Metabolomics reveals the formation of aldehydes and iminium in gefitinib metabolism. Biochem Pharmacol. 97(1):111–121.
   PubMed Web of Science ®Google Scholar
• Ma C, Wu Z, Wang X, Huang M, Wei X, Wang W, Qu H, Qiaolongbatu X, Lou Y, Jing L, et al. 2022. A systematic comparison of anti-angiogenesis efficacy and cardiotoxicity of receptor tyrosine kinase inhibitors in zebrafish model. Toxicol Appl Pharmacol. 450:116162.
   PubMed Web of Science ®Google Scholar
• Murray M, Gillani TB, Rawling T, Nair PC. 2019. Inhibition of hepatic CYP2D6 by the active N-oxide metabolite of sorafenib. AAPS J. 21(6):107.
   PubMed Web of Science ®Google Scholar
• Nair PC, Gillani TB, Rawling T, Murray M. 2021. Differential inhibition of human CYP2C8 and molecular docking interactions elicited by sorafenib and its major N-oxide metabolite. Chem Biol Interact. 338:109401.
   PubMed Web of Science ®Google Scholar
• Nardone-White DT, Bissada JE, Abouda AA, Jackson KD. 2021. Detoxication versus bioactivation pathways of lapatinib in vitro: UGT1A1 catalyzes the hepatic glucuronidation of debenzylated lapatinib. Drug Metab Dispos. 49(3):233–244.
   PubMed Web of Science ®Google Scholar
• Oda S, Miyazaki N, Tsuneyama K, Yokoi T. 2020. Exacerbation of gefitinib-induced liver injury by glutathione reduction in mice. J Toxicol Sci. 45(8):493–502.
   PubMed Web of Science ®Google Scholar
• Paech F, Bouitbir J, Krähenbühl S. 2017. Hepatocellular toxicity associated with tyrosine kinase inhibitors: mitochondrial damage and inhibition of glycolysis. Front Pharmacol. 8:367.
   PubMed Web of Science ®Google Scholar
• Paludetto MN, Bijani C, Puisset F, Bernardes-Génisson V, Arellano C, Robert A. 2018. Metalloporphyrin-catalyzed oxidation of sunitinib and pazopanib, two anticancer tyrosine kinase inhibitors: evidence for new potentially toxic metabolites. J Med Chem. 61(17):7849–7860.
   PubMed Web of Science ®Google Scholar
• Paludetto MN, Puisset F, Chatelut E, Arellano C. 2019. Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: implications for drug–drug interactions and hepatotoxicity. Med Res Rev. 39(6):2105–2152.
   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.
   PubMed Web of Science ®Google Scholar
• Rood JJM, Dormans PJA, van Haren MJ, Schellens JHM, Beijnen JH, Sparidans RW. 2018. Bioanalysis of ibrutinib, and its dihydrodiol- and glutathione cycle metabolites by liquid chromatography–tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 1090:14–21.
   PubMed Web of Science ®Google Scholar
• Rood JJ, Jamalpoor A, van Hoppe S, van Haren MJ, Wasmann RE, Janssen MJ, Schinkel AH, Masereeuw R, Beijnen JH, Sparidans RW. 2021. Extrahepatic metabolism of ibrutinib. Invest New Drugs. 39(1):1–14.
   PubMed Web of Science ®Google Scholar
• Rood JJM, van Haren MJ, Beijnen JH, Sparidans RW. 2020. Bioanalysis of EGFRm inhibitor osimertinib, and its glutathione cycle- and desmethyl metabolites by liquid chromatography–tandem mass spectrometry. J Pharm Biomed Anal. 177:112871.
   PubMed Web of Science ®Google Scholar
• Schadt S, Bister B, Chowdhury SK, Funk C, Hop CECA, Humphreys WG, Igarashi F, James AD, Kagan M, Khojasteh SC, et al. 2018. A decade in the MIST: learnings from investigations of drug metabolites in drug development under the “metabolites in safety testing” regulatory guidance. Drug Metab Dispos. 46(6):865–878.
   PubMed Web of Science ®Google Scholar
• Sestier M, Hillis C, Fraser G, Leong D. 2021. Bruton’s tyrosine kinase inhibitors and cardiotoxicity: more than just atrial fibrillation. Curr Oncol Rep. 23(10):1–12.
   Web of Science ®Google Scholar
• Shi Q, Yang X, Ren L, Mattes WB. 2020. Recent advances in understanding the hepatotoxicity associated with protein kinase inhibitors. Expert Opin Drug Metab Toxicol. 16(3):217–226.
   PubMed Web of Science ®Google Scholar
• Sibaud V, Beylot-Barry M, Protin C, Vigarios E, Recher C, Ysebaert L. 2020. Dermatological toxicities of Bruton’s tyrosine kinase inhibitors. Am J Clin Dermatol. 21(6):799–812.
   PubMed Web of Science ®Google Scholar
• Singh AP, Umbarkar P, Tousif S, Lal H. 2020. Cardiotoxicity of the BCR-ABL1 tyrosine kinase inhibitors: emphasis on ponatinib. Int J Cardiol. 316:214–221.
   PubMed Web of Science ®Google Scholar
• Sun C, Zhao H, Li W, Jia Y, Yang Y, Peng Y, Zheng J. 2021. Icotinib induces mechanism-based inactivation of recombinant human CYP3A4/5 possibly via heme destruction by ketene intermediate. Drug Metab Dispos. 49(10):892–901.
   PubMed Web of Science ®Google Scholar
• Tang LWT, Teng JW, Koh SK, Zhou L, Go ML, Chan ECY. 2021. Mechanism-based inactivation of cytochrome P450 3A4 and 3A5 by the fibroblast growth factor receptor inhibitor erdafitinib. Chem Res Toxicol. 34(7):1800–1813.
   PubMed Web of Science ®Google Scholar
• Tang LWT, Teng JW, Verma RK, Koh SK, Zhou L, Go ML, Fan H, Chan ECY. 2021. Infigratinib is a reversible inhibitor and mechanism-based inactivator of cytochrome P450 3A4. Drug Metab Dispos. 49(9):856–868.
   PubMedGoogle Scholar
• Tangamornsuksan W, Kongkaew C, Scholfield CN, Subongkot S, Lohitnavy M. 2020. HLA-DRB1*07:01 and lapatinib-induced hepatotoxicity: a systematic review and meta-analysis. Pharmacogenomics J. 20(1):47–56.
   PubMed Web of Science ®Google Scholar
• Tao G, Dagher F, Ghose R. 2022. Neratinib causes non-recoverable gut injury and reduces intestinal cytochrome P450 3A enzyme in mice. Toxicol Res. 11(1):184–194.
   Web of Science ®Google Scholar
• Tateishi Y, Shibazaki C, Takahashi K, Nakamura S, Kazuki Y, Mashino T, Ohe T. 2022. Synthesis and evaluation of tofacitinib analogs designed to mitigate metabolic activation. Drug Metab Pharmacokinet. 43:100439.
   PubMed Web of Science ®Google Scholar
• Teng WC, Oh JW, New LS, Wahlin MD, Nelson SD, Ho HK, Chan EC. 2010. Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol Pharmacol. 78(4):693–703.
   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.
   PubMed Web of Science ®Google Scholar
• Towles JK, Clark RN, Wahlin MD, Uttamsingh V, Rettie AE, Jackson KD. 2016. Cytochrome P450 3A4 and CYP3A5-catalyzed bioactivation of lapatinib. Drug Metab Dispos. 44(10):1584–1597.
   PubMed Web of Science ®Google Scholar
• van Leeuwen RW, van Gelder T, Mathijssen RH, Jansman FG. 2014. Drug–drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol. 15(8):e315–e326.
   PubMed Web of Science ®Google Scholar
• Wang L, Guo L, Wang Y, Guo R, Xu Z, Gao Z, Xie L, Chen J, Chen Y, Liu Y, et al. 2021. Metabolic disposition of [14C]-abivertinib, an epidermal growth factor receptor tyrosine kinase inhibitor: role of glutathione conjugation. Br J Clin Pharmacol. 87(3):1475–1485.
   PubMed Web of Science ®Google Scholar
• Wang H, Sheehan RP, Palmer AC, Everley RA, Boswell SA, Ron-Harel N, Ringel AE, Holton KM, Jacobson CA, Erickson AR, et al. 2019. Adaptation of human iPSC-derived cardiomyocytes to tyrosine kinase inhibitors reduces acute cardiotoxicity via metabolic reprogramming. Cell Syst. 8(5):412–426.e7.
   PubMed Web of Science ®Google Scholar
• Wang Z, Wang X, Wang Z, Feng Y, Jia Y, Jiang L, Xia Y, Cao J, Liu Y. 2021. Comparison of hepatotoxicity associated with new BCR-ABL tyrosine kinase inhibitors vs imatinib among patients with chronic myeloid leukemia: a systematic review and meta-analysis. JAMA Netw Open. 4(7):e2120165.
   PubMed Web of Science ®Google Scholar
• Wu Q, Bai B, Tian C, Li D, Yu H, Song B, Li B, Chu X. 2022. The molecular mechanisms of cardiotoxicity induced by HER2, VEGF, and tyrosine kinase inhibitors: an updated review. Cardiovasc Drugs Ther. 36(3):511–524.
   PubMed Web of Science ®Google Scholar
• Xie C, Zhou J, Guo Z, Diao X, Gao Z, Zhong D, Jiang H, Zhang L, Chen X. 2013. Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol. 168(7):1687–1706.
   PubMed Web of Science ®Google Scholar
• Yan H, Du J, Chen X, Yang B, He Q, Yang X, Luo P. 2019. ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway. Toxicol Appl Pharmacol. 383:114768.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Cai Y, Zhang S-R, Li C-Y, Jiang L-L, Wei P, He M-F. 2021. Mechanism of hepatotoxicity of first-line tyrosine kinase inhibitors: gefitinib and afatinib. Toxicol Lett. 343:1–10.
   PubMed Web of Science ®Google Scholar
• Zhang J, Ren L, Yang X, White M, Greenhaw J, Harris T, Wu Q, Bryant M, Papoian T, Mattes W, et al. 2018. Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes. Toxicol Lett. 291:138–148.
   PubMed Web of Science ®Google Scholar
• Zhang J, Salminen A, Yang X, Luo Y, Wu Q, White M, Greenhaw J, Ren L, Bryant M, Salminen W, et al. 2017. Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria. Arch Toxicol. 91(8):2921–2938.
   PubMed Web of Science ®Google Scholar
• Zhao H, Li S, Yang Z, Peng Y, Chen X, Zheng J. 2018. Identification of ketene-reactive intermediate of erlotinib possibly responsible for inactivation of P450 enzymes. Drug Metab Dispos. 46(4):442–450.
   PubMed Web of Science ®Google Scholar
• Zhao Q, Zhang T, Xiao XR, Huang JF, Wang Y, Gonzalez FJ, Li F. 2019. Impaired clearance of sunitinib leads to metabolic disorders and hepatotoxicity. Br J Pharmacol. 176(13):2162.
   PubMed Web of Science ®Google Scholar