The Metabolism and Disposition of Koumine, Gelsemine and Humantenmine from Gelsemium

Author(s): Zi-Yuan Wang, Meng-Ting Zuo, Zhao-Ying Liu*.

Journal Name: Current Drug Metabolism

Volume 20 , Issue 7 , 2019


Graphical Abstract:


Abstract:

Background: Gelsemium is a toxic flowering plant of the Gelsemiaceae family. It is used to treat skin diseases in China, and it is an important medicinal and homeopathic plant in North America. Up to now, more than 200 compounds have been isolated and reported from Gelsemium. More than 120 of these are indole alkaloids, including the main components, koumine, gelsemine and humantenmine which produce the pharmacological and toxicological effects of Gelsemium. However, their clinical application their limited by its narrow therapeutic window. Therefore, it is very important to study the metabolism and disposition of indole alkaloids from Gelsemium before their clinical application. This paper reviews all the reports on the metabolism and disposition of alkaloids isolated from Gelsemium at home and abroad.

Methods: The metabolism and disposition of alkaloids from Gelsemium were searched by the Web of Science, NCBI, PubMed and some Chinese literature databases.

Results: Only koumine, gelsemine and humantenmine have been reported, and few other alkaloids have been described. These studies indicated that the three indole alkaloids are absorbed rapidly, widely distributed in tissues, extensively metabolized and rapidly eliminated. There are species differences in the metabolism of these alkaloids, which is the reason for the differences in their toxicity in animals and humans.

Conclusion: This review not only explains the pharmacokinetics of indole alkaloids from Gelsemium but also facilitates further study on their metabolism and mechanism of toxicity.

Keywords: Gelsemium, koumine, gelsemine, humantenmine, pharmacokinetics, metabolism.

[1]
Xu, Y.K.; Yang, L.; Liao, S.G.; Cao, P.; Wu, B.; Hu, H.B.; Guo, J.; Zhang, P. Koumine, humantenine, and yohimbane alkaloids from Gelsemium elegans. J. Nat. Prod., 2015, 78(7), 1511-1517.
[http://dx.doi.org/10.1021/np5009619] [PMID: 26103517]
[2]
Jin, G.L.; Su, Y.P.; Liu, M.; Xu, Y.; Yang, J.; Liao, K.J.; Yu, C.X. Medicinal plants of the genus Gelsemium (Gelsemiaceae, Gentianales)-a review of their phytochemistry, pharmacology, toxicology and traditional use. J. Ethnopharmacol., 2014, 152(1), 33-52.
[http://dx.doi.org/10.1016/j.jep.2014.01.003] [PMID: 24434844]
[3]
Rujjanawate, C.; Kanjanapothi, D.; Panthong, A. Pharmacological effect and toxicity of alkaloids from Gelsemium elegans Benth. J. Ethnopharmacol., 2003, 89(1), 91-95.
[http://dx.doi.org/10.1016/S0378-8741(03)00267-8] [PMID: 14522437]
[4]
Bellavite, P.; Bonafini, C.; Marzotto, M. Experimental neuropharmacology of Gelsemium sempervirens: Recent advances and debated issues. J. Ayurveda Integr. Med., 2018, 9(1), 69-74.
[http://dx.doi.org/10.1016/j.jaim.2017.01.010] [PMID: 29428604]
[5]
Paris, A.; Schmidlin, S.; Mouret, S.; Hodaj, E.; Marijnen, P.; Boujedaini, N.; Polosan, M.; Cracowski, J.L. Effect of Gelsemium 5CH and 15CH on anticipatory anxiety: A phase III, single-centre, randomized, placebo-controlled study. Fundam. Clin. Pharmacol., 2012, 26(6), 751-760.
[http://dx.doi.org/10.1111/j.1472-8206.2011.00993.x] [PMID: 21954883]
[6]
Bellavite, P.; Magnani, P.; Zanolin, E.; Conforti, A. Homeopathic doses of Gelsemium sempervirens improve the behavior of mice in response to novel environments. Evid. Based Complement. Alternat. Med., 2011, 2011, 362517.
[http://dx.doi.org/10.1093/ecam/nep139] [PMID: 19752165]
[7]
Bellavite, P. Gelsemium sempervirens and animal behavioral models. Front. Neurol., 2011, 2, 56-57.
[http://dx.doi.org/10.3389/fneur.2011.00056] [PMID: 21941520]
[8]
Pascarella, J.B. Mechanisms of prezygotic reproductive isolation between two sympatric species, Gelsemium rankinii and G. sempervirens (Gelsemiaceae), in the southeastern United States. Am. J. Bot., 2007, 94(3), 468-476.
[http://dx.doi.org/10.3732/ajb.94.3.468] [PMID: 21636417]
[9]
Xie, L.J.; Han, X.F. Metabolism, clinical charateristics and management of Gelsemium elegans poisoning. Adverse Drug React. J., 2006, 8, 202-204.
[10]
Yang, Y.; Chen, J.Z.; Wu, S.S.; Liao, H.J.; Chen, W.L.; Li, X.Y. Studies on metabolic characterization of leucorhagins in porcine and rat liver microsomes. J. Fujian Univ. Tradit. Chin. Med., 2012, 22, 47-49.
[11]
Liu, Y.C.; Xiao, S.; Yang, K.; Ling, L.; Sun, Z.L.; Liu, Z.Y. Comprehensive identification and structural characterization of target components from Gelsemium elegans by high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry based on accurate mass databases combined with MS/MS spectra. J. Mass Spectrom., 2017, 52(6), 378-396.
[http://dx.doi.org/10.1002/jms.3937] [PMID: 28444801]
[12]
Liu, Y.C.; Lin, L.; Cheng, P.; Sun, Z.L.; Wu, Y.; Liu, Z.Y. Fingerprint analysis of Gelsemium elegans by HPLC followed by the targeted identification of chemical constituents using HPLC coupled with quadrupole-time-of-flight mass spectrometry. Fitoterapia, 2017, 121, 94-105.
[http://dx.doi.org/10.1016/j.fitote.2017.07.002] [PMID: 28705508]
[13]
Tong, X.L.; Zhen, H.S.; Qin, H.L.; Li, S.M.; Ge, J. Overview of Gelsemium research. Inform. Tradit. Chin. Med., 2007, 24, 16-18.
[14]
Chen, J.Z.; Li, Y.; Xiao, J.P.; Wu, S.S.; Song, H.W. Development of a sensitive and rapid UPLC-MS/MS method for the determination of koumine in rat plasma: Application to a pharmacokinetic study. Biomed. Chromatogr., 2013, 27(6), 736-740.
[http://dx.doi.org/10.1002/bmc.2852] [PMID: 23225577]
[15]
Shi, D.M.; Su, Y.P.; Yu, C.X. Study on intestinal absorption kinetics of koumine in rats. Zhongguo Xin Yao Zazhi, 2017, 26, 1450-1454.
[16]
Wang, L.; Wen, Y.; Meng, F. Simultaneous determination of gelsemine and koumine in rat plasma by UPLC-MS/MS and application to pharmacokinetic study after oral administration of Gelsemium elegans Benth extract. Biomed. Chromatogr., 2018, 32(6), e4201.
[http://dx.doi.org/10.1002/bmc.4201] [PMID: 29388221]
[17]
Wang, L.; Sun, Q.; Zhao, N.; Wen, Y.Q.; Song, Y.; Meng, F.H. Ultra-Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS)-based pharmacokinetics and tissue distribution study of koumine and the detoxification mechanism of Glycyrrhiza uralensis fisch on Gelsemium elegans benth. Molecules, 2018, 23(7), 1693.
[http://dx.doi.org/10.3390/molecules23071693] [PMID: 29997360]
[18]
Xu, Y.; Zheng, M.; Li, S.P.; Yang, Y.P.; Yang, X.; Liu, M.; Yu, C.X. Pharmacokinetics and tissue distribution of koumine in rats. J. Fujian Medical University, 2013, 47, 199-203.
[19]
Cai, J.; Lei, L.S.; Chi, D.B. Antineoplastic effect of koumine in mice bearing H22 solid tumor. Nan Fang Yi Ke Da Xue Xue Bao, 2009, 29(9), 1851-1852.
[PMID: 19778809]
[20]
Huang, J.; Su, Y.P.; Yu, C.X.; Xu, Y.; Yang, J. Cytotoxic effects of alkaloidal compounds from Gelsemium elegans Benth on the tumor cells of digestive system in vitro. Strait Pharm. J., 2010, 22, 197-200.
[21]
Li, Y.; Zeng, R.J.; Zheng, X.Q.; Guo, Y.; Chen, J.Z. Uplc-ms/MS method for the determination and enzymatic reaction kinetics of leucagglutinin in rat liver microsomes. Fujian J. Tradit. Chin. Med., 2013, 44, 50-52.
[22]
Xing, X.D. Enzyme kinetics of koumine metabolism in rat liver microsome. Strait Pharm. J., 2013, 25, 33-36.
[23]
Zhang, L.; Du, L.; Lv, W.W.; Zhao, Q.C.; Hua, W.; An, Y.; Guo, T.; Wu, L.J. Four new koumine metabolites in rat liver microsomes. J. Asian Nat. Prod. Res., 2013, 15(1), 46-52.
[http://dx.doi.org/10.1080/10286020.2012.742511] [PMID: 23323600]
[24]
Xiao, S.; Huang, Y.J.; Sun, Z.L.; Liu, Z.Y. Structural elucidation of koumine metabolites by accurate mass measurements using high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. Rapid Commun. Mass Spectrom., 2017, 31(3), 309-314.
[http://dx.doi.org/10.1002/rcm.7797] [PMID: 27870537]
[25]
Sa, X.; Huang, Y.J.; Liu, Y.C.; Sun, Z.L.; Liu, Z.Y. In vitro metabolism of koumine in pig. Chin. J. Vet. Sci., 2018, 38, 1568-1572.
[26]
Hu, Y.; Wang, Z.; Huang, X.; Xia, B.; Tang, L.; Zheng, Z.; Ye, L. Oxidative metabolism of koumine is mainly catalyzed by microsomal CYP3A4/3A5. Xenobiotica, 2017, 47(7), 584-591.
[http://dx.doi.org/10.1080/00498254.2016.1213925] [PMID: 27499416]
[27]
Wei, W.Z.; Ye, L.X.; Huang, H.L.; Qiu, H.Q.; Lin, J.; Yu, C.X. In vitro koumine metabolism of liver microsomes in humans, minipigs, SD rats, Rhesus monkeys and Beagle dogs. Central South Pharm., 2016, 14, 1045-1049.
[28]
Wei, W.Z.; Huang, H.L.; Ye, L.X.; Lin, J.; Yu, C.X. Metabolism kinetica and subtype analysis of CYP450 of koumine in liver microsomes of human, minipig, rat, monkey and dog. J. Fujian Med. Univ., 2017, 51, 82-87.
[29]
Zhang, S.; Hu, S.; Yang, X.; Shen, J.; Zheng, X.; Huang, K.; Xiang, Z. Development of a liquid chromatography with mass spectrometry method for the determination of gelsemine in rat plasma and tissue: Application to a pharmacokinetic and tissue distribution study. J. Sep. Sci., 2015, 38(6), 936-942.
[http://dx.doi.org/10.1002/jssc.201401168] [PMID: 25580713]
[30]
Zhao, Q.C.; Hua, W.; Zhang, L.; Guo, T.; Zhao, M.H.; Yan, M.; Shi, G.B.; Wu, L.J. Antitumor activity of two gelsemine metabolites in rat liver microsomes. J. Asian Nat. Prod. Res., 2010, 12(9), 731-739.
[http://dx.doi.org/10.1080/10286020.2010.492951] [PMID: 20839118]
[31]
Yang, K.; Huang, Y.J.; Xiao, S.; Liu, Y.C.; Sun, Z.L.; Liu, Y.S.; Tang, Q.; Liu, Z.Y. Identification of gelsemine metabolites in rat liver S9 by high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. Rapid Commun. Mass Spectrom., 2018, 32(1), 19-22.
[http://dx.doi.org/10.1002/rcm.8012] [PMID: 29027298]
[32]
Xiao, S. The content measurement of Gelsemium crude extracts and in vitro metabolism of major Gelsemium alkaloids., 2016. June.
[33]
Hu, Y.; Chen, M.; Wang, Z.; Lan, Y.; Tang, L.; Liu, M.; Zhao, J.; Hu, M.; Zhang, L.; Ye, L. Development of a validated UPLC-MS/MS method for determination of humantenmine in rat plasma and its application in pharmacokinetics and bioavailability studies. Biomed. Chromatogr., 2017, 31(12), 4017.
[http://dx.doi.org/10.1002/bmc.4017] [PMID: 28557019]
[34]
Li, J.; Jin, Y.; Fu, H.; Huang, Y.; Wang, X.; Zhou, Y. Pharmacokinetics and bioavailability of gelsenicine in mice by UPLC-MS/MS. Biomed. Chromatogr., 2019, 33(3), e4418.
[http://dx.doi.org/10.1002/bmc.4418] [PMID: 30367478]


Rights & PermissionsPrintExport Cite as


Article Details

VOLUME: 20
ISSUE: 7
Year: 2019
Page: [583 - 591]
Pages: 9
DOI: 10.2174/1389200220666190614152304
Price: $58

Article Metrics

PDF: 31
HTML: 2