Quantitative analysis and pharmacokinetic study of a novel diarylurea EGFR inhibitor (ZCJ14) in rat plasma using a validated LC-MS/MS method

Zuo, Sai-Jie; Cheng, Xiao-Liang; Liu, Dong-Zheng; Feng, Wei-Yi; Cao, Yong-Xiao; Zhang, San-Qi

doi:10.2478/acph-2021-0024

Abstract

1-(4-(Pyrrolidin-1-yl-methyl)phenyl)-3-(4-((3-(trifluoromethyl) phenyl)amino)quinazolin-6-yl)urea (ZCJ14), a novel epidermal growth factor receptor (EGFR) inhibitor, with diarylurea moiety, displays anticancer effect. In the present study, an LCMS/MS method was established to determine the concentration of ZCJ14 in rat plasma. Furthermore, the method was applied to investigate the pharmacokinetic characteristics of ZCJ14. Chromatographic separation of ZCJ14 and internal standard (IS) [1-phenyl-3-(4-((3-(trifluoromethyl)phenyl)amino) quinazolin-6-yl)urea] was accomplished by gradient elution using the Kromasil C₁₈ column. The selected reaction monitoring transitions were performed at m/z 507.24→436.18 and 424.13→330.96 for ZCJ14 and IS, resp. The established method was linear over the concentration range of 10–1000 ng mL⁻¹. The intra- and inter-day precisions were < 11.0 % (except for LLOQ which was up to 14.3 %) and the respective accuracies were within the range of 87.5–99.0 %. The extraction recovery and matrix effect were within the range of 88.4–104.5 % and 87.3–109.9 %, resp. ZCJ14 was stable under all storage conditions. The validated method was successfully applied to the pharmacokinetic study of ZCJ14 in rats, and the pharmacokinetic parameters have been determined. The oral bioavailability of ZCJ14 was found to be 46.1 %. Overall, this accurate and reliable quantification method might be useful for other diarylurea moiety-containing drugs.

References

1. N. Marcoux, S. N. Gettinger, G. O. Kane, K. C. Arbour, F. A. Shepherd, Z. Piotrowska and L. V. Sequist, EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes, J. Clin. Oncol.37 (2019) 278–285; https://doi.org/10.1200/JCO.18.0158510.1200/JCO.18.01585700177630550363
Search in Google Scholar Back to article
2. M. M. Moasser, Targeting the function of the HER2 oncogene in human cancer therapeutics, Oncogene26 (2007) 6577–6592; https://doi.org/10.1038/sj.onc.121047810.1038/sj.onc.1210478307158017486079
Search in Google Scholar Back to article
3. C. Yewale, D. Baradia, I. Vhora, S. Patil and A. Misra, Epidermal growth factor receptor targeting in cancer: a review of trends and strategies, Biomaterials34 (2013) 8690–8707; https://doi.org/10.1016/j.biomaterials.2013.07.10010.1016/j.biomaterials.2013.07.10023953842
Search in Google Scholar Back to article
4. T. Ishikawa, M. Seto, H. Banno, Y. Kawakita, M. Oorui, A. Nakayama, H. Miki, H. Kamiguchi, T. Tanaka, N. Habuka, S. Sogabe, J. Yano, K. Aertgeerts and K. Kamiyama, Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo[3,2-d]pyrimidine scaffold, J. Med. Chem.54 (2011) 8030–8050; https://doi.org/10.1021/jm200863410.1021/jm200863422003817
Search in Google Scholar Back to article
5. S. Kamath and J. K. Buolamwini, Targeting EGFR and HER-2 receptor tyrosine kinases for cancer drug discovery and development, Med. Res. Rev. 26 (2006) 569–594; https://doi.org/10.1002/med.2007010.1002/med.2007016788977
Search in Google Scholar Back to article
6. E. Avizienyte, R. A. Ward and A. P. Garner, Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations, Biochem. J. 415 (2008) 197–206; https://doi.org/10.1042/BJ2008072810.1042/BJ2008072818588508
Search in Google Scholar Back to article
7. Y. B. Li, Z. Q. Wang, X. Yan, M. W. Chen, J. L. Bao, G. S. Wu, Z. M. Ge, D. M. Zhou, Y. T. Wang and R. T. Li, IC-4, a new irreversible EGFR inhibitor, exhibits prominent anti-tumor and anti-angiogenesis activities, Cancer Lett.340 (2013) 88–96; https://doi.org/10.1016/j.canlet.2013.07.00510.1016/j.canlet.2013.07.00523856030
Search in Google Scholar Back to article
8. L. V. Sequsit, J. C. Soria, J. W. Goldman, H. A. Wakelee, S. M. Gadgeel, A. Varga, V. Papadimitrakopoulou, B. J. Solomon, G. R. Oxnard, R. Dziadziuszko, D. L. Aisner, R. C. Doebele, C. Galasso, E. B. Garon, R. S. Heist, J. Logan, J. W. Neal, M. A. Mendenhall, S. Nichols, Z. Piotrowska, A. J. Wozniak, M. Raponi, C. A. Karlovich, S. Jaw-Tsai, J. Isaacson, D. Despain, S. L. Matheny, L. Rolfe, A. R. Allen and D. R. Camidge, Rociletinib in EGFR-mutated non-small-cell lung cancer, New Engl. J. Med.372 (2015) 1700–1709; https://doi.org/10.1056/NEJMoa141365410.1056/NEJMoa141365425923550
Search in Google Scholar Back to article
9. S. L. Greig, Osimertinib: First global approval, Drugs76 (2016) 263–273; https://doi.org/10.1007/s40265-015-0533-410.1007/s40265-015-0533-426729184
Search in Google Scholar Back to article
10. K. S. Thress, C. P. Paweletz, E. Felip, B. C. Cho, D. Stetson, B. Dougherty, Z. W. Lai, A. Markovets, A. Vivancos, Y. N. Kuang, D. Ercan, S. E. Matthews, M. Cantarini, J. C. Barrett, P. A. Jänne and G. R. Oxnard, Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M, Nat. Med.21 (2015) 560–562; https://doi.org/10.1038/nm.385410.1038/nm.3854477118225939061
Search in Google Scholar Back to article
11. X. Zhang, F. Xu, L. Tong, T. Zhang, H. Xie, X. Lu, X. Ren and K. Ding, Design and synthesis of selective degraders of EGFRL858R/T790M mutant, Eur. J. Med. Chem.192 (2020) Article ID 112199; https://doi.org/10.1016/j.ejmech.2020.11219910.1016/j.ejmech.2020.11219932171162
Search in Google Scholar Back to article
12. Y. Y. Xu, Y. Cao, H. Ma, H. Q. Li and G. Z. Ao, Design, synthesis and molecular docking of a, b-unsaturated cyclohexanone analogous of curcumin as potent EGFR inhibitors with antiproliferative activity, Bioorg. Med. Chem.21 (2013) 388–394; https://doi.org/10.1016/j.bmc.2012.11.03110.1016/j.bmc.2012.11.03123245570
Search in Google Scholar Back to article
13. V. Nelson, J. Ziehr, M. Agulnik and M. Johnson, Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC, Onco Target. Ther.6 (2013) 135–143; https://doi.org/10.2147/OTT.S2316510.2147/OTT.S23165359403723493883
Search in Google Scholar Back to article
14. B. R. Kang, A. L. Shan, Y. P. Li, J. Xu, S. M. Lu and S. Q. Zhang, Discovery of 2-aryl-8-hydroxy (or methoxy)-isoquinolin-1(2H)-ones as novel EGFR inhibitor by scaffold hopping, Bioorg. Med. Chem.21 (2013) 6956–6964; https://doi.org/10.1016/j.bmc.2013.09.02710.1016/j.bmc.2013.09.02724094432
Search in Google Scholar Back to article
15. M. R. V. Finlay, M. Anderton, S. Ashton, P. Ballard, P. A. Bethel, M. R. Box, R. H. Bradbury, S. J. Brown, S. Butterworth, A. Campbell, C. Chorley, N. D. Colclough, A. E. Cross, G. S. Currie, M. Grist, L. Hassall, G. B. Hill, D. James, P. Kemmitt, T. Klinowska, G. Lamont, S. G. Lamont, N. Martin, H. L. McFarland, M. J. Mellor, J. P. Orme, D. Perkins, P. Perkins, G. Richmond, P. Smith, R. A. Ward, W. J. Waring, D. Whittaker, S. Wells and G. L. Wrigley, Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor, J. Med. Chem.57 (2014) 8249–8267; https://doi.org/10.1021/jm500973a10.1021/jm500973a25271963
Search in Google Scholar Back to article
16. Y. M. Zhang, M. D. Tortorella, J. X. Liao, X. C. Qin, T. T. Chen, J. F. Luo, J. T. Guan, J. J. Talley and Z. C. Tu, Synthesis and evaluation of novel Erlotinib–NSAID conjugates as more comprehensive anticancer agents, ACS Med. Chem. Lett.6 (2015) 1086–1090; https://doi.org/10.1021/acsmedchemlett.5b0028610.1021/acsmedchemlett.5b00286460106126487917
Search in Google Scholar Back to article
17. K. M. Amin, F. F. Barsoum, F. M. Awadallah and N. E. Mohamed, Identification of new potent phthalazine derivatives with VEGFR-2 and EGFR kinase inhibitory activity, Eur. J. Med. Chem.123 (2016) 191–201; https://doi.org/10.1016/j.ejmech.2016.07.04910.1016/j.ejmech.2016.07.04927484508
Search in Google Scholar Back to article
18. H. Zhang, J. Wang, Y. Shen, H. Y. Wang, W. M. Duan, H. Y. Zhao, Y. Y. Hei, M. H. Xin, Y. X. Cao and S. Q. Zhang, Discovery of 2,4,6-trisubstituted pyrido[3,4-d]pyrimidine derivatives as new EGFRTKIs, Eur. J. Med. Chem.148 (2018) 221–237; https://doi.org/10.1016/j.ejmech.2018.02.05110.1016/j.ejmech.2018.02.05129466773
Search in Google Scholar Back to article
19. S. J. Zuo, S. Zhang, S. Mao, X. X. Xie, X. Xiao, M. H. Xin, W. Xuan, Y. Y. He, Y. X. Cao and S. Q. Zhang, Combination of 4-anilinoquinazoline, arylurea and tertiary amine moiety to discover novel anticancer agents, Bioorg. Med. Chem.24 (2016) 179–190; https://doi.org/10.1016/j.bmc.2015.12.00110.1016/j.bmc.2015.12.00126706113
Search in Google Scholar Back to article
20. E. R. Lepper, S. M. Swain, A. R. Tan, W. D. Figg and A. Sparreboom, Liquid chromatographic determination of Erlotinib (OSI-774), an epidermal growth factor receptor tyrosine kinase inhibitor, J. Chromatogr. B796 (2003) 181–188; https://doi.org/10.1016/j.jchromb.2003.08.01510.1016/j.jchromb.2003.08.01514552829
Search in Google Scholar Back to article
21. A. R. Masters, C. J. Sweeney and D. R. Jones, The quantification of Erlotinib (OSI-774) and OSI-420 in human plasma by liquid chromatography-tandem mass spectrometry, J. Chromatogr. B848 (2007) 379–383; https://doi.org/10.1016/j.jchromb.2006.10.04610.1016/j.jchromb.2006.10.04617101305
Search in Google Scholar Back to article
22. L. Z. Wang, M. Y. Lim, T. M. Chin, W. L. Thuya, P. L. Nye, A. Wong, S. Y. Chan, B. C. Goh and P. C. Ho, Rapid determination of gefitinib and its main metabolite, O-desmethyl gefitinib in human plasma using liquid chromatography–tandem mass spectrometry, J. Chromatogr. B879 (2011) 2155–2161; https://doi.org/10.1016/j.jchromb.2011.05.05610.1016/j.jchromb.2011.05.05621703945
Search in Google Scholar Back to article
23. M. Zhao, C. Hartke, A. Jimeno, J. Li, P. He, Y. Zabelina, M. Hidalgo and S. D. Baker, Specific method for determination of gefitinib in human plasma, mouse plasma and tissues using high performance liquid chromatography coupled to tandem mass spectrometry, J. Chromatogr. B819 (2005) 73–80; https://doi.org/10.1016/j.jchromb.2005.01.02710.1016/j.jchromb.2005.01.02715797523
Search in Google Scholar Back to article
24. U.S. Food and Drug Administration, Bioanalytical Method Validation Guidance for Industry, US Department of Health and Human Services, FDA, Center for Drug Evaluation and Research (CDER), Silver Spring (MD) USA, 2018; https://www.fda.gov/media/70858/download; last access date June 1, 2020.
Search in Google Scholar Back to article
25. Y. Zhang, M. R. Huo, J. P. Zhou, S. F. Xie and P. K. Solver, An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel, Comput. Meth. Prog. Bio.99 (2010) 306–314; https://doi.org/10.1016/j.cmpb.2010.01.00710.1016/j.cmpb.2010.01.00720176408
Search in Google Scholar Back to article
26. B. Ma, Q. Zhang, G. J. Wang, Z. M. Wu, J. P. Shaw, Y. Y. Hu, Y. B. Wang, Y. T. Zheng, Z. D. Yang and H. J. Ying, Synthesis and pharmacokinetics of strontium fructose 1,6-diphosphate (Sr-FDP) as a potential antiosteoporosis agent in intact and ovariectomized rats, J. Inorg. Biochem.105 (2011) 563–568; https://doi.org/10.1016/j.jinorgbio.2011.01.00110.1016/j.jinorgbio.2011.01.00121345324
Search in Google Scholar Back to article
27. W. Jiang, J. J. Yang, L. Cao, X. Xiao, X. L. Shi and Y. X. Cao, Modifications of the method for calculating absolute drug bioavailability, J. Pharm. Pharm. Sci.19 (2016) 181–187; https://doi.org/10.18433/J3RG7810.18433/J3RG7827518168
Search in Google Scholar Back to article
28. N. R. Srinivas, Double or multiple/secondary peaks in pharmacokinetics: considerations and challenges from a bio-analytical perspective, Biomed. Chromatogr.26 (2012) 407–408; https://doi.org/10.1002/bmc.268010.1002/bmc.268022213389
Search in Google Scholar Back to article
29. J. B. Johnston, S. Navaratnam, M. W. Pitz, J. M. Maniate, E. Wiechec, H. Baust, J. Gingerich, G. P. Skliris, L. C. Murphy and M. Los, Targeting the EGFR pathway for cancer therapy, Curr. Med. Chem.13 (2006) 3483–3492; https://doi.org/10.2174/09298670677902617410.2174/09298670677902617417168718
Search in Google Scholar Back to article
30. D. Mckillop, E. A. Partridge, M. Hutchison, S. A. Rhead, A. C. Parry, J. Bardsley, H. M. Woodman and H. C. Swaisland, Pharmacokinetics of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat and dog, Xenobiotica34 (2004) 901–915; https://doi.org/10.1080/0049825040000918910.1080/0049825040000918915764410
Search in Google Scholar Back to article

Quantitative analysis and pharmacokinetic study of a novel diarylurea EGFR inhibitor (ZCJ14) in rat plasma using a validated LC-MS/MS method

Abstract

Paradigm

My account