Authors:
Meifei Lu Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, PR China

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Xiaojie Lu Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, PR China

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Zheng Yu Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, PR China

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Congcong Wen Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, PR China

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https://orcid.org/0000-0001-8413-1697
Open access

Abstract

Calycanthine is an important class of alkaloids extracted and isolated from the roots, leaves, flowers and fruits of Chimonanthus praecox. In this work, the UPLC-MS/MS method was used for determination of calycanthine in rat plasma, and the pharmacokinetics in rats were investigated. Midazolam was used as an internal standard (IS), and methanol precipitation method was used to pretreatment the rat plasma samples. Chromatographic separation was achieved on a UPLC BEH C18 (50 × 2.1 mm, 1.7 μm) column with the mobile phase of methanol- 0.1% formic acid aqueous solution with gradient elution. Multiple reaction monitoring (MRM) mode with positive ionization was applied for quantitative analysis, m/z 347.3 → 246.7 and 326.2 → 291.4 for calycanthine and IS, respectively. The results indicated that within the range of 1–200 ng/mL, linearity of calycanthine in rat plasma was good (r > 0.995), and the lower limit of quantification (LLOQ) was 1 ng/mL. Accuracy range was between 90.6 and 109.4%, precision (RSD) of calycanthine was less than 14%. The matrix effect was between 97.9% and 105.4%, the recovery was better than 85.6%. The developed UPLC-MS/MS method was successfully applied in the pharmacokinetics of calycanthine in rats after oral and intravenous administration. The absolute bioavailability of the calycanthine was 37.5% in rats.

Abstract

Calycanthine is an important class of alkaloids extracted and isolated from the roots, leaves, flowers and fruits of Chimonanthus praecox. In this work, the UPLC-MS/MS method was used for determination of calycanthine in rat plasma, and the pharmacokinetics in rats were investigated. Midazolam was used as an internal standard (IS), and methanol precipitation method was used to pretreatment the rat plasma samples. Chromatographic separation was achieved on a UPLC BEH C18 (50 × 2.1 mm, 1.7 μm) column with the mobile phase of methanol- 0.1% formic acid aqueous solution with gradient elution. Multiple reaction monitoring (MRM) mode with positive ionization was applied for quantitative analysis, m/z 347.3 → 246.7 and 326.2 → 291.4 for calycanthine and IS, respectively. The results indicated that within the range of 1–200 ng/mL, linearity of calycanthine in rat plasma was good (r > 0.995), and the lower limit of quantification (LLOQ) was 1 ng/mL. Accuracy range was between 90.6 and 109.4%, precision (RSD) of calycanthine was less than 14%. The matrix effect was between 97.9% and 105.4%, the recovery was better than 85.6%. The developed UPLC-MS/MS method was successfully applied in the pharmacokinetics of calycanthine in rats after oral and intravenous administration. The absolute bioavailability of the calycanthine was 37.5% in rats.

Introduction

The Chimonanthus belongs to the family Calycanthaceae, which has large fragrant flowers and beautiful leaves [1, 2]. Chimonanthus contains volatile oil, coumarins, alkaloids, alkene, sesquiterpenoids, flavonoids [3–6]. The main medicinal components are alkaloids [7–10]. Calycanthine is an important class of alkaloids extracted and isolated from the roots, leaves, flowers and fruits of Chimonanthus praecox [11, 12]. Calycanthine may mediate its convulsant action predominantly by inhibiting the release of the inhibitory neurotransmitter GABA as a result of interactions with L-type Ca2+ channels and by inhibiting GABA-mediated chloride currents at GABA(A) receptors [13]. In the in vitro tests, calycanthine showed significant inhibitory activities against five plant pathogenic fungi Exserohilum turcicum, Bipolaris maydis, Alternaria solani, Sclerotinia sderotiorum, and Fusarium oxysportium.

Pharmacokinetics is a discipline that quantitatively studies the laws of drug absorption, distribution, metabolism, and excretion in living organisms [14–18]. It has also been extended to the mechanism research of the entire treatment process in vivo absorption, distribution, metabolism, and excretion (ADME), the interaction of complex drug systems, and drug action substances. In order to further understand the absorption and distribution of calycanthine in the body, it is necessary to conduct a systematic study of pharmacokinetics to provide a theoretical basis for drug development. Therefore, the study of the pharmacokinetics of calycanthine is of great significance for the clinical application.

As far as I known, there was no reports about the quantitive analysis and pharmacokinetic study of calycanthine. In this study, an UPLC-MS/MS method was developed for determination of calycanthine in rat plasma, and pharmacokinetics in rats was investigated.

Materials and methods

Chemical and animals

Calycanthine (purity > 98%, Fig. 1A) and midazolam (purity > 98%, Fig. 1B) were purchased from Chengdu Mansite Bio-Technology Co., Ltd (Chengdu, China). Ultrapure water was prepared by Millipore Milli-Q water system (Bedford, MA, USA). HPLC-grade methanol was purchased from Merck (Darmstadt, Germany). HPLC-grade formic acid was obtained from Tedia (Ohio, USA).

Fig. 1.
Fig. 1.

Chemical structure of (A) calycanthine and (B) midazolam

Citation: Acta Chromatographica AChrom 33, 1; 10.1556/1326.2020.00772

Instrument and condition

XEVO TQS-micro triple quadrupole mass spectrometer and ACQUITY H-Class UPLC (Waters Corp, Milford, MA, USA) were used in this study. Masslynx 4.1 software (Waters Corp.) was used to control the equipment and collect data.

UPLC BEH C18 (50 mm × 2.1 mm, 1.7 μm) was used at 40 °C. Mobile phase was composed of methanol and 0.1% formic acid aqueous solution in gradient elution, and the flow rate was set at 0.5 mL/min. The gradient elution was as follows: 0–0.2 min, 10% methanol; 0.2–1.4 min, 10–80% methanol; 1.4–2.0 min, methanol 80%; 2.0–2.1 min, 80–10% methanol; 2.1–3.0 min, 10% methanol. The total run time was 3.0 min.

Capillary voltage was set as 2.4 kV, ion source temperature was 150 °C, and desolvation temperature was 400 °C. Nitrogen was used as desolvation gas (800 L/h) and nebulising gas. ESI in Multiple reaction monitoring (MRM) mode was used in positive mode: m/z 347.3 → 246.7 and 326.2 → 291.4 for calycanthine and internal standard (IS), respectively.

Stock and working solutions

Stock solutions of calycanthine (1.0 mg/mL) and midazolam (1.0 mg/mL) were prepared by methanol. Calycanthine working solutions with different concentrations (10, 50, 100, 200, 500, 1,000, 2,000 ng/mL) were prepared by diluting the stock solutions with methanol. Midazolam working solution of 50 ng/mL was diluted with methanol from midazolam stock solution.

Standard curve

The blank rat plasma was spiked with suitable amounts of working solutions of calycanthine to prepare standard solutions with concentrations of 1, 5, 10, 20, 50, 100, 200 ng/mL. Quality control samples at concentrations of 1, 3, 18, and 180 ng/mL were prepared by the same means.

Plasma pretreatment

In a 1.5 mL centrifuge tube, 50 μL plasma, methanol (200 μL, containing IS 50 ng/mL) was added into plasma, mixed by a vortexer for 1.0 min, and centrifuged at 13,000 rpm for 10 min at 4 °C. The supernate (150 μL) was transferred into a liner pipe in vial, and 2 μL was inject into UPLC-MS/MS for analysis.

Method validation

The validation method was established in accordance with the guidance of the US Food and Drug Administration (FDA) [19, 20].

Pharmacokinetics

Twelve Sprague Dawley (SD) rats (male, body weight 200–220 g) were obtained from Animal Experimental Center of Wenzhou Medical University. Six rats was given calycanthine (10 mg/kg) by oral (po) administration, and the other six rats was given calycanthine (2 mg/kg) by intravenous (iv) administration. The blood (100 μL) was withdrawn from the caudal vein at 5 min, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 h after administration. Plasma (50 μL) was collected after centrifuging at 3,000 rpm for 10 min and stored at −20 °C. DAS 2.0 software (China Pharmaceutical University) was used to analyze pharmacokinetic parameters.

Results and discussion

Method development

The choice of positive and negative ionization mode for electrospray ESI is often evaluated in methodology [21–26]. In positive ion mode the charging generally occurs via protonation, and in negative ion mode charging occurs via deprotonation of the analyte. Calycanthine is an alkaloid compound and belongs to weakly basic drugs. Generally speaking, weakly basic drugs are more suitable for positive ionization mode. In our work, calycanthine has higher sensitivity in positive ionization ESI mode than negative mode. The choice of IS is very important in bioanalytical methodology, related to the quantitative accuracy of the method. Midazolam was selected as IS because it and calycanthine have similar mass spectrometric ionization mode.

UPLC conditions were as far as possible separating endogenous interfering from the analyte and IS [27, 28]. We tried acetonitrile, methanol, 0.1% formic acid aqueous solution, ammonium acetate solution as mobile phase. As a result, the mobile phase of methanl-0.1% formic acid aqueous solution, using gradient elution, could obtain satisfactory chromatographic peaks and retention time. UPLC-MS/MS was faster and higher sensitive than traditional HPLC. It only takes 3 min to analyze one plasma sample, which could save a lot of time and solvents. In addition, the relatively low LLOQ (1 ng/mL) for calycanthine could be used to determine lower plasma concentrations at the last sampling time point.

Method validation

The representative UPLC-MS/MS chromatograms of calycanthine and IS in rat plasma were show in Fig. 2. The absence of obvious endogenous substances interfered with the detection, indicating that the method was specificity.

Fig. 2.
Fig. 2.

UPLC-ESI-MS/MS of calycanthine and midazolam (IS) in rat plasma. (A) blank plasma, (B) blank plasma spiked calycanthine (1 ng/mL) and IS, (C) a rat plasma after oral administration of calycanthine in rats (62.3 ng/mL)

Citation: Acta Chromatographica AChrom 33, 1; 10.1556/1326.2020.00772

The concentration of calycanthine standard curve in rat plasma was within the range of 1–200 ng/mL. Linearity of analytical method was determined by least square linear regression by using 1/x2 as a weighting factor. The equation of standard curve is y = (0.001748 ± 0.000125)x − (0.00763 ± 0.000645), r = 0.9984, where y is the peak area ratio of calycanthine to internal standard and x represents calycanthine concentrations in rat plasma. The LLOQ of calycanthine in rat plasma was 1 ng/mL.

As shown in Table 1, accuracy range was between 90.6 and 109.4%, intra-day and inter-day precision (RSD) were less than 14%, the matrix effect was between 97.9 and 105.4%, the recovery was better than 85.6%.

Table 1.

Accuracy, precision, matrix effect and recovery of calycanthine in rat plasma

Concentration (ng/mL)Accuracy (%)Precision (RSD %)Matrix effect (%)Recovery (%)
Intra-dayInter-dayIntra-dayInter-day
190.6107.913.69.097.987.3
3109.4105.25.97.799.089.9
1898.7100.87.710.1105.485.6
18096.996.78.63.6103.991.2

The rat plasma at room temperature for 2 h, −20 °C for 30 days and freeze-thaw stability test, the variation of calycanthine was within ±12% and CV was less than 13%, it indicated the stability of calycanthine was acceptable.

Pharmacokinetics

UPLC-MS/MS was applied to the quantitative detection of calycanthine in plasma, which was faster and sensitivity than traditional HPLC. The plasma concentration-time curves of calycanthine was shown in Fig. 3. The main pharmacokinetic parameters of calycanthine analyzed by the non-compartment model were listed in Table 2. The bioavailability of calycanthine is 37.5% after oral administration. Calycanthine with t1/2 of intravenous and oral administration were 5.0 ± 3.0 and 3.5 ± 1.8 h, it indicated that calycanthine metabolism was not fast in rats. The AUC(0−t) of intravenous and oral administration were 304.1 ± 108.2 and 570.9 ± 187.9 ng/mL*h, it indicated that the oral absorption was good. The apparent distribution volumes (V) of intravenous and oral administration were 35.9 ± 26.9 and 85.8 ± 23.6 L/kg, it could be speculated that they were widely distributed in the organs. As far as I known, there was no reports about the quantitive analysis and pharmacokinetic study of calycanthine in rats. The study the pharmacokinetics of calycanthine in vivo, it could help to better understand the mechanism of pharmacy.

Fig. 3.
Fig. 3.

Plasma concentration-time curve of calycanthine after oral (10 mg/kg) and intravenous (2 mg/kg) administration

Citation: Acta Chromatographica AChrom 33, 1; 10.1556/1326.2020.00772

Table 2.

Main pharmacokinetic parameters of calycanthine in rats

ParametersUnitiv 2 mg/kgpo 10 mg/kg
AUC(0−t)ng/mL*h304.1 ± 108.2570.9 ± 187.9
AUC(0−∞)ng/mL*h374.9 ± 146.7589.5 ± 217.5
MRT(0−t)h3.7 ± 0.35.6 ± 1.6
MRT(0−∞)h7.2 ± 6.66.1 ± 2.5
t1/2zh5.0 ± 3.03.5 ± 1.8
VzL/kg35.9 ± 26.985.8 ± 23.6
CLzL/h/kg6.0 ± 2.118.8 ± 6.9
Cmaxng/mL90.2 ± 8.281.0 ± 12.4
Bioavailability37.5%

Conclusion

In this study, a simple and fast UPLC-MS/MS method with good selectivity for determination of calycanthine in rat plasma was developed. The linear range was 1–200 ng/mL, and 50 μL plasma was used for sample treatment. This developed UPLC-MS/MS method was applied in pharmacokinetics of calycanthine in rats, and bioavailability was determinated to be 37.5% after oral administration.

Acknowledgments

This study was supported by Natural Science Foundation of Zhejiang Province Grants (LQ19H040010), Students Science and Technology Innovation Activities and Xinmiao Talents Program of Zhejiang Province (2018R413020).

Reference

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  • 1.

    Li, S.; Zou, Z. Pestic. Biochem. Physiol. 2019, 160, 136145.

  • 2.

    Shu, R. G.; Wan, Y. L.; Wang, X. M. Chin. J. Nat. Med. 2019, 17, 161186.

  • 3.

    Lou, H. Y., Zhang, Y.; Ma, X. P.; Jiang, S.; Wang, X. P.; Yi, P.; Liang, G. Y.; Wu, H. M.; Feng, J.; Jin, F. Y.; Pan, W. D. Chin. J. Nat. Med. 2018, 16, 621627.

    • Search Google Scholar
    • Export Citation
  • 4.

    Liu, G.; Fu, J. Bot. Stud. 2018, 59, 30.

  • 5.

    Li, Z., Jiang, Y.; Liu, D.; Ma, J.; Li, J.; Li, M.; Sui, S. Int. J. Mol. Sci. 2018, 19.

  • 6.

    Huang, W. P., Tan, T.; Li, Z. F.; OuYang, H.; Xu, X.; Zhou, B.; Feng, Y. L. J. Pharm. Biomed. Anal. 2018, 154, 236244.

  • 7.

    Chen, H., Xiong, L.; Wang, N.; Liu, X.; Hu, W.; Yang, Z.; Jiang, Y.; Zheng, G.; Ouyang, K.; Wang, W. Food Funct. 2018, 9, 49594967.

  • 8.

    Tan, T., Luo, Y.; Zhong, C. C.; Xu, X.; Feng, Y. J. Pharm. Biomed. Anal. 2017, 141, 140148.

  • 9.

    Sun, Q., Zhu, J.; Cao, F.; Chen, F. PLoS One 2017, 12, e0181094.

  • 10.

    Chen, H., Ouyang, K.; Jiang, Y.; Yang, Z.; Hu, W.; Xiong, L.; Wang, N.; Liu, X.; Wang, W. Int. J. Biol. Macromol. 2017, 98, 829836.

  • 11.

    Zhang, J. W., Gao, J. M.; Xu, T.; Zhang, X. C.; Ma, Y. T.; Jarussophon, S.; Konishi, Y. Chem. Biodivers. 2009, 6, 838845.

  • 12.

    Li, Q. J., Wang, M. L.; Yang, X. S.; Ma, L.; Hao, X.J. J. Asian. Nat. Prod. Res. 2013, 15, 270275.

  • 13.

    Chebib, M., Duke, R. K.; Duke, C. C.; Connor, M.; Mewett, K. N.; Johnston, G. A. Toxicol. Appl. Pharmacol. 2003, 190, 5864.

  • 14.

    Tian, W., Cai, J.; Xu, Y.; Luo, X.; Zhang, J.; Zhang, Z.; Zhang, Q.; Wang, X.; Hu, L.; Lin, G. Int. J. Clin. Exp. Med. 2015, 8, 1516415172.

    • Search Google Scholar
    • Export Citation
  • 15.

    Ma, J., Wang, S.; Huang, X.; Geng, P.; Wen, C.; Zhou, Y.; Yu, L.; Wang, X. J. Pharm. Biomed. Anal. 2015, 111, 131137.

  • 16.

    Hu, L. M., Zhang, M. M.; Qu, M. X.; Wang, X.; Wang, C. J.; Chen, C. M.; Zhou, Y. F. Lat. Am. J. Pharm. 2015, 34, 12521257.

  • 17.

    Zhang, Q., Wen, C.; Xiang, Z.; Ma, J.; Wang, X. J. Pharm. Biomed. Anal. 2014, 90, 134138.

  • 18.

    Huang, T., Liu, Y.; Zhang, C. Eur. J. Drug. Metab. Pharmacokinet. 2019, 44, 159168.

  • 19.

    Zimmer, D. Bioanalysis 2014, 6, 1319.

  • 20.

    FDA. Guidance for Industry Analytical Procedures and Methods Validation for Drugs and Biologics, 2014. https://www.fdanews.com/ext/resources/files/02/02-19-14-Guidance.pdf.

    • Search Google Scholar
    • Export Citation
  • 21.

    Cai, J. Z., Ma, J. S.; Xu, K. Q.; Gao, G.; Xiang, Y. Y.; Lin, C. L. Int. J. Clin. Exp. Med. 2015, 8, 97379743.

  • 22.

    Lei, X. W., Zhou, G. Z.; Fan, L. Y.; Gu, K. W.; Hu, Y.; Zhang, M. L.; Yuan, Q.; Xu, H. Q.; Zhang, K. J.; Ma, J. S. Lat. Am. J. Pharm. 2016, 35, 551557.

    • Search Google Scholar
    • Export Citation
  • 23.

    Tong, S. H., Guo, J. Y.; Song, H. C.; Lv, S. W.; Zhu, Y. L.; Ma, J. S.; Zheng, Y. C. Int. J. Clin. Exp. Med. 2015, 8, 97169722.

  • 24.

    Wang, J. J., Wang, Z. B.; Chen, C.; Wang, Z. Y.; Liu, N. H.; Ma, J. S.; Wang, X. Q.; Hu, L. F. Lat. Am. J. Pharm. 2012, 31, 240244.

  • 25.

    Wang, Y., Cai, J. Z.; Fang, C. B.; Zheng, H. L.; Xu, X.; Chen, D. R.; Zhu, Q.; Zhang, Y. Y.; Zhang, X.; Ma, J. S.; Zhou, H. Int. J. Clin. Exp. Med. 2016, 9, 35933599.

    • Search Google Scholar
    • Export Citation
  • 26.

    Zhang, X. H., Ma, J. S.; Hu, L. F.; Zhang, Q. W.; Wang, X. Q.; Pan, J. C.; Ye, F. Q. J. Liq. Chromatogr. Relat. Technol. 2012, 35, 16271637.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    Chen, L. G., Su, K.; Jiang, Y. Y.; Chen, B. B.; Wen, C. C.; Zeng, M.; Wang, X. C. Lat. Am. J. Pharm. 2016, 35, 14501453.

  • 28.

    Wang, X., Zheng, M.; Liu, J.; Huang, Z.; Bai, Y.; Ren, Z.; Wang, Z.; Tian, Y.; Qiao, Z.; Liu, W.; Feng, F. J. Ethnopharmacol. 2017, 209, 175183.

    • Crossref
    • Search Google Scholar
    • Export Citation
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Senior editors

Editor(s)-in-Chief: Sajewicz, Mieczyslaw, University of Silesia, Katowice, Poland

Editors(s)

  • Danica Agbaba, University of Belgrade, Belgrade, Serbia (1953-2024)
  • Łukasz Komsta, Medical University of Lublin, Lublin, Poland
  • Ivana Stanimirova-Daszykowska, University of Silesia, Katowice, Poland
  • Monika Waksmundzka-Hajnos, Medical University of Lublin, Lublin, Poland

Editorial Board

  • Ravi Bhushan, The Indian Institute of Technology, Roorkee, India
  • Jacek Bojarski, Jagiellonian University, Kraków, Poland
  • Bezhan Chankvetadze, State University of Tbilisi, Tbilisi, Georgia
  • Michał Daszykowski, University of Silesia, Katowice, Poland
  • Tadeusz H. Dzido, Medical University of Lublin, Lublin, Poland
  • Attila Felinger, University of Pécs, Pécs, Hungary
  • Kazimierz Glowniak, Medical University of Lublin, Lublin, Poland
  • Bronisław Glód, Siedlce University of Natural Sciences and Humanities, Siedlce, Poland
  • Anna Gumieniczek, Medical University of Lublin, Lublin, Poland
  • Urszula Hubicka, Jagiellonian University, Kraków, Poland
  • Krzysztof Kaczmarski, Rzeszow University of Technology, Rzeszów, Poland
  • Huba Kalász, Semmelweis University, Budapest, Hungary
  • Katarina Karljiković Rajić, University of Belgrade, Belgrade, Serbia
  • Imre Klebovich, Semmelweis University, Budapest, Hungary
  • Angelika Koch, Private Pharmacy, Hamburg, Germany
  • Piotr Kus, Univerity of Silesia, Katowice, Poland
  • Debby Mangelings, Free University of Brussels, Brussels, Belgium
  • Emil Mincsovics, Corvinus University of Budapest, Budapest, Hungary
  • Ágnes M. Móricz, Centre for Agricultural Research, Budapest, Hungary
  • Gertrud Morlock, Giessen University, Giessen, Germany
  • Anna Petruczynik, Medical University of Lublin, Lublin, Poland
  • Robert Skibiński, Medical University of Lublin, Lublin, Poland
  • Bernd Spangenberg, Offenburg University of Applied Sciences, Germany
  • Tomasz Tuzimski, Medical University of Lublin, Lublin, Poland
  • Adam Voelkel, Poznań University of Technology, Poznań, Poland
  • Beata Walczak, University of Silesia, Katowice, Poland
  • Wiesław Wasiak, Adam Mickiewicz University, Poznań, Poland
  • Igor G. Zenkevich, St. Petersburg State University, St. Petersburg, Russian Federation

 

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

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2023  
Web of Science  
Journal Impact Factor 1.7
Rank by Impact Factor Q3 (Chemistry, Analytical)
Journal Citation Indicator 0.43
Scopus  
CiteScore 4.0
CiteScore rank Q2 (General Chemistry)
SNIP 0.706
Scimago  
SJR index 0.344
SJR Q rank Q3

Acta Chromatographica
Publication Model Online only
Gold Open Access
Submission Fee none
Article Processing Charge 700 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
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Acta Chromatographica
Language English
Size A4
Year of
Foundation
1988
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)

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