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  • 1 Department of Pharmacy, Ningbo YinZhou No.2 Hospital, Ningbo, , China
  • | 2 School of Basic Medicine, Wenzhou Medical University, Wenzhou, , China
  • | 3 Department of Rehabilitation, Wenzhou Municipal Hospital of Traditional Chinese Medicine, Wenzhou, , China
Open access

Abstract

Narciclasine is a 7-hydroxy derivative of lycorisidine. It was the first alkaloid isolated from the stem of narcissus (Amaryllidaceae) in 1967. Six mice were given narciclasine (5 mg/kg) by intravenous administration. A UPLC-MS/MS method was developed to determine narciclasine in mouse blood. Tectorigenin (internal standard, IS) and narciclasine were gradient eluted by mobile phase of methanol and 0.1% formic acid in a BEH C18 column. The multiple reaction monitoring (MRM) of m/z 308.1→248.1 for narciclasine and m/z 301.1→286.0 for IS with an electrospray ionization (ESI) source was used for quantitative determination. The calibration curve ranged from 1 to 6,000 ng/mL. The accuracy was from 92.5 to 107.3%, and the matrix effect was between 103.6 and 107.4%. The developed UPLC-MS/MS method was successfully applicated to a pharmacokinetic study of narciclasine in mice after intravenous administration (5 mg/kg).

Abstract

Narciclasine is a 7-hydroxy derivative of lycorisidine. It was the first alkaloid isolated from the stem of narcissus (Amaryllidaceae) in 1967. Six mice were given narciclasine (5 mg/kg) by intravenous administration. A UPLC-MS/MS method was developed to determine narciclasine in mouse blood. Tectorigenin (internal standard, IS) and narciclasine were gradient eluted by mobile phase of methanol and 0.1% formic acid in a BEH C18 column. The multiple reaction monitoring (MRM) of m/z 308.1→248.1 for narciclasine and m/z 301.1→286.0 for IS with an electrospray ionization (ESI) source was used for quantitative determination. The calibration curve ranged from 1 to 6,000 ng/mL. The accuracy was from 92.5 to 107.3%, and the matrix effect was between 103.6 and 107.4%. The developed UPLC-MS/MS method was successfully applicated to a pharmacokinetic study of narciclasine in mice after intravenous administration (5 mg/kg).

Introduction

In the history of human search for effective drugs, natural products have played a vital role. Especially in the field of cancer, more than 60% of drugs are derived from natural products. Plants in the Amaryllidaceae family are known for their medicinal effects and toxicity [1–4]. The role has been known for a long time. As far back as ancient Greece, narcissus extracts have been successfully used in cancer treatment. The 48 alkaloids isolated from narcissus have a carbon skeleton, but one group of these alkaloids is represented by the structure of hydroxybenzophenanthridone or isoquinolinone [5, 6]. The most representative compounds are narciclasine, lycoricidine, and pancratistatin. The most commonly used term to define this group of alkaloids in the literature is called isoquinolone [7]. The cytotoxicity of these isoquinolone alkaloids has been confirmed in basic experiments as early as 30 years ago, and was later confirmed by NCI (International Cancer Agency) at the level of MTT colorimetric determination of human cancer cell lines[8, 9].

Narciclasine, lycorisidine (7-deoxynarcissus), squalene and its derivatives have shown effective anti-tumor cell line effects in vitro cytotoxicity experiments and in vivo experiments against mice M-5076 sarcoma and P-388 tumor activity [10, 11]. Therefore, this type of alkaloid with a new main structure is a new resource with potential and development as a future anti-cancer drug. Narciclasine does not affect the activity of proteases in vitro, but inhibits the synthesis of proteases at the ribosome level. Narciclasine is described as an anti-mitotic substance similar to colchicine. Narciclasine is also an inhibitor of peptide bond formation in eukaryotic ribosomes [12, 13]. It inhibits the formation of peptide bonds by combining with 60S ribosomal subunits and peptidyl transferase centers. Unlike other anti-cancer drugs, narcissus does not interact with DNA to affect or form complexes.

To better understand the pharmacokinetics [14, 15], an analytical method for the determination of narciclasine in biological fluids is necessary. Svagrova et al. developed a reversed-phase high-performance liquid chromatography for determination of narciclasine in serum, with the retention time of narciclasine was 5 min, and needed 0.5 mL blood for the sample preparation [16]. Until now, there were no reports about the pharmacokinetics of narciclasine in biological fluids by UPLC-MS/MS. Therefore, it was to develop a UPLC-MS/MS method for determination of narciclasine in mouse blood and used for pharmacokinetics.

Experimental

Chemicals

Narciclasine and tectorigenin (IS) (both purity >98%) were from Chengdu Munster biotechnology Co. Ltd. (Chengdu, China). Milli-Q water system was from Millipore Sigma (Burlington, MA, USA). HPLC grade acetonitrile, formic acid and methanol were from Merck Company (Darmstadt, Germany).

Instrument and condition

An ACQUITY H-Class UPLC equipped with a XEVO TQS-micro triple quadrupole mass spectrometry (Waters Corp, Milford, MA, USA) with electrospray ionization (ESI), was used for analysis.

UPLC BEH C18 (1.7 μm, 2.1 mm × 50 mm) column was used for separation at 30 °C. The mobile phase consisted of methanol and water (0.1% formic acid) with the flow rate of 0.4 mL/min. The gradient conditions with as follows: 0–0.2 min, 10% methanol; 0.2–1.4 min, 10–85% methanol; 1.4–2.4 min, 85% methanol; 2.4–2.5 min, 85–10%, methanol; 2.5–4.5 min, 10% methanol.

Capillary voltage was 2 kV, the temperature of source ionization was 150 °C, dry gas (nitrogen) was 900 L/h, and the temperature for drying gas was 450 °C. The m/z 308.1→248.1 for narciclasine (cone voltage 12 v, collision voltage 18 v) and m/z 301.1→286.0 for IS (cone voltage 52 v, collision voltage 26 v), was used for quantitative analysis, in an ESI positive mode and MRM, Fig. 1.

Fig. 1.
Fig. 1.

Chemical structure and mass spectrum of narciclasine and tectorigenin (IS)

Citation: Acta Chromatographica 34, 2; 10.1556/1326.2021.00865

Calibration standards

The stored solutions of narciclasine (1.0 mg/mL) and tectorigenin (1.0 mg/mL) were prepared in methanol. Working standard solutions were diluted by methanol, including 10, 50, 200, 1,000, 5,000, 15,000, 30,000, 60,000 ng/mL for narciclasine. The working standard solution (100 ng/mL) of tectorigenin was diluted with methanol from the stored solution.

Calibration standards of narciclasine were spiked to blank mouse blood to concentration of 1, 5, 20, 100, 500, 1,500, 3,000, 6,000 ng/mL. Three quality control (QC) samples were 2, 450 and 5,000 ng/mL.

Sample preparation

One hundred microliter acetonitrile (containing IS 100 ng/mL) was added into 20 μL blood, mixed for 1.0 min, and centrifuged at 13,000 rpm for 10 min. The supernate (2 μL) was injected into UPLC-MS/MS for analysis.

Pharmacokinetic study

Six Institute of Cancer Research (ICR) mice (male, 20–22 g) were from Laboratory Animal Center of Wenzhou Medical University (Wenzhou, China). The blood samples (20 μL) were withdrawn from caudal vein after intravenous administration of narciclasine (1 mg/kg) at 0.083, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 h, and stored at −20°C until analysis. The data was fitted by the DSA 2.0 (China Pharmaceutical University, China).

Results

Method validation

Fig. 2 exhibited the UPLC-MS/MS of a blank blood sample, a blank blood sample spiked with narciclasine and IS, and a blood sample obtained after intravenous administration. No interference was found at the retention times of the narciclasine and the IS.

Fig. 2.
Fig. 2.

Narciclasine and IS chromatograms obtained by UPLC/MS/MS in mouse blood. (A) a blank blood sample, (B) the blank blood samples spiked with narciclasine (1 ng/mL) and IS, (C) a blood samples after intravenous administration

Citation: Acta Chromatographica 34, 2; 10.1556/1326.2021.00865

The equation of the calibration curve (1–6,000 ng/mL) of narciclasine was: y = 0.0012x + 0.0012 (r = 0.9994, n = 6), y represented the ratio of the peak area of narciclasine to that of IS, and x was the concentration of narciclasine. The LLOQ was 1 ng/mL, the precision and accuracy of the LLOQ were 13.6 and 107.3%, respectively.

The accuracy ranged from 92.5 to 107.3%, the precision was less than 14%, and the matrix effect was between 103.6% and 107.4%, the recovery was better than 65.7%, in Table 1.

Table 1.

The accuracy, precision, matrix effect and recovery of narciclasine in mouse blood samples (n = 6)

Concentration (ng/mL)Precision (%)Accuracy (RSD%)Metrix effect (%)Recovery (%)
Intra-dayInter-dayIntra-dayInter-day
110.513.692.5107.3104.770.8
23.46.9101.899.4106.667.4
4504.57.3105.2103.9107.466.2
5,0008.42.7101.097.1103.665.7

The stability of narciclasine in variations condition (3 freezing and thawing cycles, −20 °C for 30 days, room temperature for 2 h) was acceptable, the accuracy was within 86% and 114%, and precision was less than 14%.

Pharmacokinetic study

The main pharmacokinetic parameters of narciclasine were fiited by the non-compartment model, Table 2. The blood concentration of narciclasine was showed in Fig. 3.

Table 2.

Main Pharmacokinetic study of narciclasine after intravenous administration

ParametersUnitiv (5 mg/kg)
AUC(0-t)ng/mL×h2448.1 ± 408.6
AUC(0-∞)ng/mL×h2452.5 ± 408.7
MRT(0-t)H0.8 ± 0.2
MRT(0-∞)H0.9 ± 0.2
t1/2zH1.7 ± 0.2
CLz/FL/kg2.1 ± 0.3
Vz/FL/h/kg5.2 ± 1.3
Cmaxng/mL4452.9 ± 996.5

Discussion

We chose the positive mode for the response of the narciclasine was stronger than that in the negative ion mode. Then fragment peaks with relatively high fragments were selected as quantitative ion pairs, m/z308.1→248.1 for narciclasine (cone voltage 12 v, collision voltage 18 v) and m/z 301.1→286.0 for IS (cone voltage 52 v, collision voltage 26 v), were shown in Fig. 1.

Fig. 3.
Fig. 3.

Mean plasma concentration-time profile after intravenous administration of narciclasine (5 mg/kg)

Citation: Acta Chromatographica 34, 2; 10.1556/1326.2021.00865

The different mobile phase was tested, such as acetonitrile, 0.1% formic acid in water, 10 mmol/L ammonium acetate and methanol. The methanol and 0.1% formic acid in water was used as the mobile phase, it achieved the suitable retention time (1.7 min) and better peak.

Choosing sample treatment method was very important in methodology [17–21]. The extraction efficiencies of ethyl acetate, acetonitrile, and methanol were compared. The extraction efficiencies of acetonitrile (around 70%) were better than ethyl acetate (around 50%) and methanol (around 50%). And the matrix effects of acetonitrile were acceptable (around 105%).

To select the internal standard during the method establishment process was very important [22–26]. Several compounds including astragalin, tectorigenin, rubiadin and narciclasine were compared. It was comprehensively shown that tectorigenin had a structure, and the peak time was similar to that of narciclasine.

UPLC-MS/MS was applied to the quantitative analysis of narciclasine in mouse blood, which was much faster than traditional HPLC (retention time of narciclasine was 5.0 min), and needed less blood (20 μL) [16]. No literature has been reported on the pharmacokinetics of narciclasine in rats or mice.

Conclusions

A simple UPLC-MS/MS method was developed for determination of narciclasine in mouse with the LLOQ of 1 ng/mL. The developed UPLC-MS/MS method was successfully applied to the pharmacokinetics in mice.

Acknowledgments

This work was supported by Wenzhou science and Technology Bureau (Y2020882), the second batch of agricultural cooperatives in Yinzhou District in 2018 (NO. 23).

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    Chen, J. F. ; Bao, X. ; Lin, C. L. ; Zhou, G. E. Latin Am. J. Pharm. 2019, 38, 985990.

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    Chen, L. G. ; Weng, Q. H. ; Lin, Y. J. ; Lu, X. J. ; Zhong, Z. Q. , Xiong, J. H. ; Wang, X. Q. Curr. Pharm. Anal. 2020, 16, 705711.

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  • 1.

    Ding, Y. ; Qu, D. ; Zhang, K. M. ; Cang, X. X. ; Kou, Z. N. ; Xiao, W. ; Zhu, J. B. J. Asian Nat. Prod. Res. 2017, 19, 53100.

  • 2.

    Nair, J. J. ; Bastida, J. ; Codina, C. ; Viladomat, F. ; van Staden, J. Nat. Prod. Commun. 2013, 8, 13351350.

  • 3.

    N'Tamon, A. D. ; Okpekon, A. T. ; Bony, N. F. ; Bernadat, G. ; Gallard, J. F. ; Kouame, T. , Seon-Meniel, B. , Leblanc, K. , Rharrabti, S. , Mouray, E. , Grellier, P. , Ake, M. , Amin, N. C. , Champy, P. , Beniddir, M. A. ; Le Pogam, P. Phytochemistry 2020, 179, 112485.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Gasca, C. A. ; Moreira, N. C. S. ; de Almeida, F. C. ; Dutra-Gomes, J. V. ; Castillo, W. O. ; Fagg, C. W. ; Magalhaes, P. O. ; Fonseca-Bazzo, Y. M. ; Sakamoto-Hojo, E. , de Medeiros, Y. K. , de Souza Borges, W. ; Silveira, D. Food Chem. Toxicol. 2020, 111703.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Sibanyoni, M. N. ; Chaudhary, S. K. ; Chen, W. ; Adhami, H. R. ; Combrinck, S. ; Maharaj, V. ; Schuster, D. ; Viljoen, A. Fitoterapia 2020, 146, 104650.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Koutova, D. ; Maafi, N. ; Havelek, R. ; Opletal, L. ; Blunden, G. ; Rezacova, M. ; Cahlikova, L. Molecules 2020, 25, 2337.

  • 7.

    Trujillo-Chacon, L. M. ; Alarcon-Enos, J. E. ; Cespedes-Acuna, C. L. ; Bustamante, L. ; Baeza, M. ; Lopez, M. G. ; Fernandez-Mendivil, C. ; Cabezas, F. ; Pastene-Navarrete, E. R. Food Chem. Toxicol. 2019, 132, 110665.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Cole, E. R. ; de Andrade, J. P. ; Filho, J. F. A. ; Schmitt, E. F. P. ; Alves-Araujo, A. ; Bastida, J. ; Endringer, D. C. ; de, S. B. W. ; Lacerda, V. Anticancer Agents Med. Chem. 2019, 19, 707717.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Nair, J. J. ; Bastida, J. ; van Staden, J. Nat. Prod. Commun. 2016, 11, 121132.

  • 10.

    Isbilen, O. ; Rizaner, N. ; Volkan, E. BMC Complement. Altern. Med. 2018, 18, 30.

  • 11.

    Chen, M. X. ; Huo, J. M. ; Hu, J. ; Xu, Z. P. ; Zhang, X. Fitoterapia 2018, 130, 4853.

  • 12.

    Gopalakrishnan, R. ; Matta, H. ; Choi, S. ; Chaudhary, P. M. Sci. Rep. 2020, 10, 5712.

  • 13.

    Brautigam, J. ; Bischoff, I. ; Schurmann, C. ; Buchmann, G. ; Epah, J. ; Fuchs, S. ; Heiss, E. ; Brandes, R. P. ; Furst, R. J. Mol. Cel Cardiol. 2019, 135, 97108.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Zhang, X. ; Xiang, Q. ; Zhao, X. ; Ma, L. ; Cui, Y. J. Clin. Pharm. Ther. 2019, 44, 163173.

  • 15.

    Millar, S. A. ; Stone, N. L. ; Yates, A. S. ; O'Sullivan, S. E. Front. Pharmacol. 2018, 9, 1365.

  • 16.

    Svagrova, I. ; Stulik, K. ; Pacakova, V. ; Caliceti, P. ; Veronese, F. M. J. Chromatogr. 1991, 563, 95102.

  • 17.

    Qiu, E. J. ; Wang, H. Z. ; Yu, Y. ; Song, D. Z. ; Cai, J. Z. ; Ye, F. F. Latin Am. J. Pharm. 2020, 39, 11711175.

  • 18.

    Liu, Z. Z. ; Liu, H. M. ; Wu, Y. Z. ; Xu, X. X. ; Ma, J. S. Latin Am. J. Pharm. 2020, 39, 11161121.

  • 19.

    Chen, S. J. ; Zhou, C. P. ; Hu, Y. J. ; Wang, H. Z. ; Liu, F. L. Latin Am. J. Pharm. 2020, 39, 208212.

  • 20.

    Ye, W. J. ; Lin, C. L. ; Lin, G. Y. ; Chen, R. J. ; Sun, W. ; Wang, S. H. ; Wang, X. Q. ; Zhou, Y. F. Curr. Pharm. Anal. 2019, 15, 604611.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Song, H. C. ; Huang, Y. W. ; Zhu, D. Q. ; Tong, S. H. ; Zhang, M. L. ; Wang, X. Q. ; Bao, X. Curr. Pharm. Anal. 2019, 15, 194199.

  • 22.

    Li, T. R. ; Ye, W. J. ; Huang, B. G. ; Lu, X. J. ; Chen, X. X. ; Lin, Y. J. ; Wen, C. C. ; Wang, X. Q. J. Pharm. Biomed. Anal. 2019, 168, 133137.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Ren, K. ; Jin, Y. ; Wang, X. Q. ; Wei, Z. Latin Am. J. Pharm. 2019, 38, 991995.

  • 24.

    Chen, L. G. ; Yang, J. Y. ; Chen, D. W. ; Xiong, J. H. ; Wang, X. Q. ; Ying, X. Q. ; Wei, Y. L. ; Lin, Y. P. ; Zhang, S. Z. ; Wu, M. L. Latin Am. J. Pharm. 2019, 38, 855859.

    • Search Google Scholar
    • Export Citation
  • 25.

    Chen, J. F. ; Bao, X. ; Lin, C. L. ; Zhou, G. E. Latin Am. J. Pharm. 2019, 38, 985990.

  • 26.

    Chen, L. G. ; Weng, Q. H. ; Lin, Y. J. ; Lu, X. J. ; Zhong, Z. Q. , Xiong, J. H. ; Wang, X. Q. Curr. Pharm. Anal. 2020, 16, 705711.

    • Crossref
    • Search Google Scholar
    • Export Citation
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Senior editors

Editor(s)-in-Chief: Kowalska, Teresa

Editor(s)-in-Chief: Sajewicz, Mieczyslaw

Editors(s)

  • Danica Agbaba (University of Belgrade, Belgrade, Serbia)
  • Ivana Stanimirova-Daszykowska (University of Silesia, Katowice, Poland)
  • Monika Waksmundzka-Hajnos (Medical University of Lublin, Lublin, Poland)

Editorial Board

  • R. Bhushan (The Indian Institute of Technology, Roorkee, India)
  • J. Bojarski (Jagiellonian University, Kraków, Poland)
  • B. Chankvetadze (State University of Tbilisi, Tbilisi, Georgia)
  • M. Daszykowski (University of Silesia, Katowice, Poland)
  • T.H. Dzido (Medical University of Lublin, Lublin, Poland)
  • A. Felinger (University of Pécs, Pécs, Hungary)
  • K. Glowniak (Medical University of Lublin, Lublin, Poland)
  • B. Glód (Siedlce University of Natural Sciences and Humanities, Siedlce, Poland)
  • U. Hubicka (Jagiellonian University, Kraków, Poland)
  • K. Kaczmarski (Rzeszow University of Technology, Rzeszów, Poland)
  • H. Kalász (Semmelweis University, Budapest, Hungary)
  • I. Klebovich (Semmelweis University, Budapest, Hungary)
  • A. Koch (Private Pharmacy, Hamburg, Germany)
  • Ł. Komsta (Medical University of Lublin, Lublin, Poland)
  • P. Kus (Univerity of Silesia, Katowice, Poland)
  • D. Mangelings (Free University of Brussels, Brussels, Belgium)
  • E. Mincsovics (Corvinus University of Budapest, Budapest, Hungary)
  • G. Morlock (Giessen University, Giessen, Germany)
  • A. Petruczynik (Medical University of Lublin, Lublin, Poland)
  • J. Sherma (Lafayette College, Easton, PA, USA)
  • R. Skibiński (Medical University of Lublin, Lublin, Poland)
  • B. Spangenberg (Offenburg University of Applied Sciences, Germany)
  • T. Tuzimski (Medical University of Lublin, Lublin, Poland)
  • Y. Vander Heyden (Free University of Brussels, Brussels, Belgium)
  • A. Voelkel (Poznań University of Technology, Poznań, Poland)
  • B. Walczak (University of Silesia, Katowice, Poland)
  • W. Wasiak (Adam Mickiewicz University, Poznań, Poland)

 

KOWALSKA, TERESA
E-mail: kowalska@us.edu.pl

SAJEWICZ, MIECZYSLAW
E-mail:msajewic@us.edu.pl

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2020
 
Total Cites
650
WoS
Journal
Impact Factor
1,639
Rank by
Chemistry, Analytical 71/83 (Q4)
Impact Factor
 
Impact Factor
1,412
without
Journal Self Cites
5 Year
1,301
Impact Factor
Journal
0,34
Citation Indicator
 
Rank by Journal
Chemistry, Analytical 75/93 (Q4)
Citation Indicator
 
Citable
45
Items
Total
43
Articles
Total
2
Reviews
Scimago
28
H-index
Scimago
0,316
Journal Rank
Scimago
Chemistry (miscellaneous) Q3
Quartile Score
 
Scopus
393/181=2,2
Scite Score
 
Scopus
General Chemistry 215/398 (Q3)
Scite Score Rank
 
Scopus
0,560
SNIP
 
Days from
58
submission
 
to acceptance
 
Days from
68
acceptance
 
to publication
 
Acceptance
51%
Rate

2019  
Total Cites
WoS
495
Impact Factor 1,418
Impact Factor
without
Journal Self Cites
1,374
5 Year
Impact Factor
0,936
Immediacy
Index
0,460
Citable
Items
50
Total
Articles
50
Total
Reviews
0
Cited
Half-Life
6,2
Citing
Half-Life
8,3
Eigenfactor
Score
0,00048
Article Influence
Score
0,164
% Articles
in
Citable Items
100,00
Normalized
Eigenfactor
0,05895
Average
IF
Percentile
20,349
Scimago
H-index
26
Scimago
Journal Rank
0,255
Scopus
Scite Score
226/167=1,4
Scopus
Scite Score Rank
Chemistry (miscellaneous) 240/398 (Q3)
Scopus
SNIP
0,494
Acceptance
Rate
41%

 

Acta Chromatographica
Publication Model Online only
Gold Open Access
Submission Fee none
Article Processing Charge 400 EUR/article
Regional discounts on country of the funding agency World Bank Lower-middle-income economies: 50%
World Bank Low-income economies: 100%
Further Discounts Editorial Board / Advisory Board members: 50%
Corresponding authors, affiliated to an EISZ member institution subscribing to the journal package of Akadémiai Kiadó: 100%
Subscription Information Gold Open Access
Purchase per Title  

Acta Chromatographica
Language English
Size A4
Year of
Foundation
1992
Publication
Programme
2021 Volume 33
Volumes
per Year
1
Issues
per Year
4
Founder Institute of Chemistry, University of Silesia
Founder's
Address
PL-40-007 Katowice, Poland, Bankowa 12
Publisher Akadémiai Kiadó
Publisher's
Address
H-1117 Budapest, Hungary 1516 Budapest, PO Box 245.
Responsible
Publisher
Chief Executive Officer, Akadémiai Kiadó
ISSN 2083-5736 (Online)

Monthly Content Usage

Abstract Views Full Text Views PDF Downloads
Jun 2021 0 0 0
Jul 2021 0 0 0
Aug 2021 0 0 0
Sep 2021 0 40 40
Oct 2021 0 48 56
Nov 2021 0 55 87
Dec 2021 0 6 6