Analytical and Bioanalytical Chemistry

, Volume 410, Issue 22, pp 5555–5565 | Cite as

Simultaneous determination of amantadine and rimantadine in feed by liquid chromatography-Qtrap mass spectrometry with information-dependent acquisition

  • Qi Jia
  • Dan Li
  • Xinlu Wang
  • Shuming Yang
  • Yongzhong Qian
  • Jing QiuEmail author
Research Paper
Part of the following topical collections:
  1. Food Safety Analysis


A sensitive method for simultaneous determination of amantadine and rimantadine in feed was developed using an ultra-high-performance liquid chromatography-triple quadrupole linear ion trap mass spectrometry (UHPLC-Qtrap-MS) in the multiple reaction monitoring information-dependent acquisition-enhanced product ion (MRM-IDA-EPI) mode, and employing the mixed cation exchange (MCX) solid-phase extraction column as sample cleanup and amantadine-d15 and rimantadine-d4 as internal standards, respectively. Compared to traditional MRM mode, for the targeted drugs in feed simultaneously both the secondary mass spectra and MRM information can be obtained using UHPLC-Qtrap-MS with MRM-IDA-EPI mode, and thus more accurate qualitative confirmation results achieved even at lower concentration of 0.2 μg/L in acceptable purity fit values. After optimization of sample preparation, good linearities (R > 0.9994) were obtained over the concentration range from 1 to 200 μg/L for amantadine and rimantadine. The precision was validated by intra-day and inter-day, and the relative standard deviations were all within 9.61%. Mean recoveries ranged from 76.1 to 112% at spiked concentrations of 0.5–100 μg/kg in three types of feed samples, including formula feed and complex concentrated feed for pigs and premix feed for chicken. The limits of detection (LODs) and quantification (LOQs) were 0.2 and 0.5 μg/kg for both drugs, respectively. The application in real feed samples further proved the accuracy and reliability of the developed method. This method provides an important tool to detect illegal uses of amantadine and rimantadine in feed.

Graphical abstract

Simultaneous quantitation and qualitative confirmation of amantadine and rimantadine in feed by MRM-IDA-EPI


Amantadine Rimantadine Feed Solid-phase extraction Liquid chromatography-triple Qtrap mass spectrometry 



This work was supported by Central Public-interest Scientific Institution Basal Research Fund (Nos. Y2017JC46 and 1610072016003) and the Special Fund for Agro-scientific Research in the Public Interest (201203023).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Hall CB, Dolin R, Gala CL, Markovitz DM, Zhang YQ, Madore PH, et al. Children with influenza A infection: treatment with rimantadine. Pediatrics. 1987;80(2):275–82.PubMedGoogle Scholar
  2. 2.
    Yun H, Cui F, Yan H, Liu X, He Y, Zhang Z. Determination of ribavirin and amantadine in chicken by ultra performance liquid chromatography-tandem mass spectrometry. Chin J Chromatogr. 2013;31(31):724–8.CrossRefGoogle Scholar
  3. 3.
    Sun L, Zhang L, Qian XU, Wang X, Wang SH. Research development of toxicity and residue detection methods of florfenicol. Chin J Veter Drug. 2009;43(6):49–52.Google Scholar
  4. 4.
    He G, Qiao J, Dong C, He C, Zhao L, Tian Y. Amantadine-resistance among H5N1 avian influenza viruses isolated in northern China. Antivir Res. 2008;77(1):72–6.CrossRefPubMedGoogle Scholar
  5. 5.
    Vitomir Ć, Silva D, Biljana A, Sanja Č. The significance of rational use of drugs in veterinary medicine for food safety. Tehnologija Mesa. 2011;52(1):74–9.Google Scholar
  6. 6.
    Ministry of Agriculture of P.R. China. The abolished directory of local standards for veterinary drugs. Announcement No. 560th, 2005.Google Scholar
  7. 7.
    Lou HG, Yuan H, Ruan ZR, Jiang B. Simultaneous determination of paracetamol, pseudoephedrine, dextrophan and chlorpheniramine in human plasma by liquid chromatography-tandem mass spectrometry. J Chromatogr B. 2010;878(7–8):682–8.CrossRefGoogle Scholar
  8. 8.
    Leis HJ, Windischhofer W. Determination of memantine in human plasma by GC using negative ion chemical ionization MS detection after derivatization with a new reagent. Microchim Acta. 2012;178(3–4):309–14.CrossRefGoogle Scholar
  9. 9.
    Liu Y, Xu C, Yan R, Lim C, Yeh LT, Lin CC. Sensitive and specific LC–MS/MS method for the simultaneous measurements of viramidine and ribavirin in human plasma. J Chromatogr B. 2006;832(1):17–23.CrossRefGoogle Scholar
  10. 10.
    Wang P, Liang YZ, Chen BM, Zhou N, Yi LZ, Yu Y, et al. Quantitative determination of amantadine in human plasma by liquid chromatography–mass spectrometry and the application in a bioequivalence study. J Pharm Biomed Anal. 2007;43(4):1519–25.CrossRefPubMedGoogle Scholar
  11. 11.
    Liu X, Huang YW, Li J, Li XB, Bi KS, Chen XH. Determination of arbidol in human plasma by LC-ESI-MS. J Pharm Biomed Anal. 2007;43(1):371–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Yan H, Liu X, Cui F, Yun H, Li J, Ding S, et al. Determination of amantadine and rimantadine in chicken muscle by QuEChERS pretreatment method and UHPLC coupled with LTQ Orbitrap mass spectrometry. J Chromatogr B. 2013;938(9):8–13.Google Scholar
  13. 13.
    Wu YL, Chen RX, Xue Y, Yang T, Zhao J, Zhu Y. Simultaneous determination of amantadine, rimantadine and memantine in chicken muscle using multi-walled carbon nanotubes as a reversed-dispersive solid phase extraction sorbent. J Chromatogr B. 2014;965:197–205.CrossRefGoogle Scholar
  14. 14.
    Zhao SH, Li D, Qiu J, Wang M, Yang SM, Chen D. Simultaneous determination of amantadine, rimantadine and chlorpheniramine in animal-derived food by liquid chromatography-tandem mass spectrometry after fast sample preparation. Anal Methods. 2014;6(17):7062–7.CrossRefGoogle Scholar
  15. 15.
    Mu PQ, Xu NN, Chai TT, Jia Q, Yin ZQ, Yang SM, et al. Simultaneous determination of 14 antiviral drugs and relevant metabolites in chicken muscle by UPLC–MS/MS after QuEChERS preparation. J Chromatogr B. 2016;1023−1024:17–23.CrossRefGoogle Scholar
  16. 16.
    Tsuruoka Y, Nakajima T, Kanda M, Hayashi H, Matsushima Y, Yoshikawa S, et al. Simultaneous determination of amantadine, rimantadine, and memantine in processed products, chicken tissues, and eggs by liquid chromatography with tandem mass spectrometry. J Chromatogr B. 2017;1044−1045:142.CrossRefGoogle Scholar
  17. 17.
    Revilla A, Hamáček J, Lubal P, Havel J. Determination of rimantadine in pharmaceutical preparations by capillary zone electrophoresis with indirect detection or after derivatization. Chromatographia. 1998;47(7–8):433–9.CrossRefGoogle Scholar
  18. 18.
    Shuangjin C, Fang F, Han L, Ming M. New method for high-performance liquid chromatographic determination of amantadine and its analogues in rat plasma. J Pharm Biomed Anal. 2007;44(5):1100–5.CrossRefPubMedGoogle Scholar
  19. 19.
    VdH FA, Teeuwsen J, Holthuis JJ, Brinkman UA. High-performance liquid chromatographic determination of amantadine in urine after micelle-mediated pre-column derivatization with 1-fluoro-2,4-dinitrobenzene. J Pharm Biomed Anal. 1990;8(8–12):799–804.Google Scholar
  20. 20.
    Stubbings G, Bigwood T. The development and validation of a multiclass liquid chromatography tandem mass spectrometry (LC–MS/MS) procedure for the determination of veterinary drug residues in animal tissue using a QuEChERS (quick, easy, cheap, effective, rugged and safe) approach. Anal Chim Acta. 2009;637(1):68–78.CrossRefPubMedGoogle Scholar
  21. 21.
    Xu M, Ju W, Xia X, Tan H, Chen M, Zhang J, et al. Determination of rimantadine in rat plasma by liquid chromatography/electrospray mass spectrometry and its application in a pharmacokinetic study. J Chromatogr B. 2008;864(1):123–8.CrossRefGoogle Scholar
  22. 22.
    Xing Y, Meng W, Sun W, Li D, Yu Z, Tong L, et al. Simultaneous qualitative and quantitative analysis of 21 mycotoxins in Radix Paeoniae Alba by ultra-high performance liquid chromatography quadrupole linear ion trap mass spectrometry and QuEChERS for sample preparation. J Chromatogr B. 2016;1031:202–13.CrossRefGoogle Scholar
  23. 23.
    Chen D, Miao H, Zhao Y, Wu Y. Dispersive micro solid phase extraction of amantadine, rimantadine and memantine in chicken muscle with magnetic cation exchange polymer. J Chromatogr B. 2017;1051:92–6.CrossRefGoogle Scholar
  24. 24.
    Han M, Tian Y, Li Z, Chen Y, Yang W, Zhang L. Quantitative determination of chromium picolinate in animal feeds by solid phase extraction and liquid chromatography-tandem mass spectrometry. J Chromatogr B. 2017;1070:37–42.CrossRefGoogle Scholar
  25. 25.
    Zhao Z, Zhang Y, Xuan Y, Song W, Si W, Zhao Z, et al. Ion-exchange solid-phase extraction combined with liquid chromatography-tandem mass spectrometry for the determination of veterinary drugs in organic fertilizers. J Chromatogr B. 2016;1022:281–9.CrossRefGoogle Scholar
  26. 26.
    Mol HG, Plaza-Bolaños P, Zomer P, de Rijk TC, Stolker AA, Mulder PP. Toward a generic extraction method for simultaneous determination of pesticides, mycotoxins plant toxins, and veterinary drugs in feed and food matrixes. Anal Chem. 2008;80:9450–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Saleh TA. Sensing of chlorpheniramine in pharmaceutical applications by sequential injector coupled with potentiometer. J Pharm Anal. 2011;1(4):246–50.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Li H, Zhang C, Wang J, Jiang Y, Fawcett JP, Gu J. Simultaneous quantitation of paracetamol, caffeine, pseudoephedrine, chlorpheniramine and cloperastine in human plasma by liquid chromatography-tandem mass spectrometry. J Pharm Biomed Anal. 2010;51(3):716–22.CrossRefPubMedGoogle Scholar
  29. 29.
    Kuroda TNS, Takizawa Y, Tamura N, Kusano K, Mizobe F, Harju K. Pharmacokinetics and pharmacodynamics of d-chlorpheniramine following intravenous and oral administration in healthy thoroughbred horses. Vet J. 2013;197(2):433–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Kaddoumi ANM, Wada M, Nakashima K. Pharmacokinetic interactions between phenylpropanolamine, caffeine and chlorpheniramine in rats. Eur J Pharm Sci. 2004;22(3):209–16.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Qi Jia
    • 1
  • Dan Li
    • 1
  • Xinlu Wang
    • 1
  • Shuming Yang
    • 1
  • Yongzhong Qian
    • 1
  • Jing Qiu
    • 1
    Email author
  1. 1.Institute of Quality Standards & Testing Technology for Agro-Products, Key Laboratory of Agro-product Quality and SafetyChinese Academy of Agricultural Sciences; Key Laboratory of Agri-food Quality and Safety, Ministry of AgricultureBeijingChina

Personalised recommendations