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Determination of A Novel Selective B-RafV600E Inhibitor (LXK4) in Dog Plasma by HPLC–MS/MS and its Application in a Pharmacokinetic Study

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Abstract

A rapid and sensitive HPLC–MS/MS assay was established and validated to quantify LXK4, a novel potent B-RafV600E inhibitor in dog plasma. The samples prepared by liquid–liquid extraction using ethyl acetate were separated on a Phenomenex C8 column with mobile phase of water–methanol. LXK4 and IS were all detected by monitoring the precursor → product ion transition of m/z 413.4 → 345.4 and 401.3 → 333.3, respectively, using multiple reaction monitoring (MRM) scan mode with positive ionization mode. The liner calibration curves for LXK4 in dog plasma ranged from 0.5 to 1000 ng mL−1 with the lower limit of quantification of 0.5 ng mL−1. The intra- and inter-day precisions were lower than 12.0%, and the accuracy ranged from −4.6 to 9.5%. The validated assay was successfully used as a new approach to study the pharmacokinetics of LXK4 in beagle dogs and the oral bioavailability of LXK4 was determined to be 30.5%.

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References

  1. Heath E, Kaufman K, Christopherson R (2011) Int J Biochem Cell Biol 43:29–32

    Article  CAS  Google Scholar 

  2. Dhillon AS, Hagan S, Rath O, Kolch W (2007) Oncogene 26:3279–3290

    Article  CAS  Google Scholar 

  3. Marais R, Marshall CJ (1996) Cancer Surv 27:101–125

    CAS  Google Scholar 

  4. Peyssonnaux C, Eychène A (2001) Biol Cell 93:53–62

    Article  CAS  Google Scholar 

  5. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee M-K, Attar N, Sazegar H (2010) Nature 468:973–977

    Article  CAS  Google Scholar 

  6. Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, Stephens P, Edkins S, Tsui WW, Chan AS (2002) Cancer Res 62:6451–6455

    CAS  Google Scholar 

  7. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) Cancer Res 63:1454–1457

    CAS  Google Scholar 

  8. Dhomen N, Marais R (2007) Curr Opin Genet Dev 17:31–39

    Article  CAS  Google Scholar 

  9. Karasarides M, Chiloeches A, Hayward R, Niculescu-Duvaz D, Scanlon I, Friedlos F, Ogilvie L, Hedley D, Martin J, Marshall CJ (2004) Oncogene 23:6292–6298

    Article  CAS  Google Scholar 

  10. Holderfield M, Deuker MM, McCormick F, McMahon M (2014) Nat Rev Cancer 14:455–467

    Article  CAS  Google Scholar 

  11. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W (2002) Nature 417:949–954

    Article  CAS  Google Scholar 

  12. Fiskus W, Mitsiades N (2016) Annu Rev Med 67:29–43

    Article  CAS  Google Scholar 

  13. Wang X, Kim J (2012) J Med Chem 55:7332–7341

    Article  CAS  Google Scholar 

  14. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M (2004) Cancer Res 64:7099–7109

    Article  CAS  Google Scholar 

  15. Eisen T, Ahmad T, Flaherty K, Gore M, Kaye S, Marais R, Gibbens I, Hackett S, James M, Schuchter L (2006) Br J Cancer 95:581–586

    Article  CAS  Google Scholar 

  16. Yang H, Higgins B, Kolinsky K, Packman K, Go Z, Iyer R, Kolis S, Zhao S, Lee R, Grippo JF (2010) Cancer Res 70:5518–5527

    Article  CAS  Google Scholar 

  17. Falchook G, Long G, Kurzrock R, Kim K, Arkenau H, Brown M, Hamid O, Infante J, Millward M, Pavlick A (2012) Lancet 379:1893–1901

    Article  CAS  Google Scholar 

  18. Rheault TR, Stellwagen JC, Adjabeng GM, Hornberger KR, Petrov KG, Waterson AG, Dickerson SH, Mook RA Jr, Laquerre SG, King AJ (2013) ACS Med Chem Lett 4:358–362

    Article  CAS  Google Scholar 

  19. Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P (2012) Nat Rev Drug Discov 11:873–886

    Article  CAS  Google Scholar 

  20. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M (2011) N Engl J Med 364:2507–2516

    Article  CAS  Google Scholar 

  21. Young K, Minchom A, Larkin J (2012) Future Oncol 8:499–507

    Article  CAS  Google Scholar 

  22. Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH, Kaempgen E (2012) Lancet 380:358–365

    Article  CAS  Google Scholar 

  23. Chu EY, Wanat KA, Miller CJ, Amaravadi RK, Fecher LA, Brose MS, McGettigan S, Giles LR, Schuchter LM, Seykora JT (2012) J Am Acad Dermatol 67:1265–1272

    Article  CAS  Google Scholar 

  24. Anforth R, Fernandez-Peñas P, Long GV (2013) Lancet Oncol 14:e11–e18

    Article  CAS  Google Scholar 

  25. Li X, Shen J, Tan L, Zhang Z, Gao D, Luo J, Cheng H, Zhou X, Ma J, Ding K (2016) Bioorg Med Chem Lett 26:2760–2763

    Article  CAS  Google Scholar 

  26. FDA (2001) Guidance for industry: bioanalytical methods validation, 2001. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070107.pdf. Accessed May 2001

Download references

Acknowledgements

This study was partially supported by the National Natural Science Foundation of China (#21302186); the Guangdong Province Natural Science Foundation (#2014A030313735); the Guangdong Science and Technology Planning Founding (#2013A022100019); and Zhongshan Introducing Talent Award.

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Correspondence to Huimin Cheng or Renke Dai.

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The authors state that there is no conflict of interests in the paper.

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E. Jiang and J. Deng contributed equally to the work.

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Jiang, E., Deng, J., Guo, J. et al. Determination of A Novel Selective B-RafV600E Inhibitor (LXK4) in Dog Plasma by HPLC–MS/MS and its Application in a Pharmacokinetic Study. Chromatographia 80, 71–76 (2017). https://doi.org/10.1007/s10337-016-3195-9

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  • DOI: https://doi.org/10.1007/s10337-016-3195-9

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