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Current Pharmaceutical Analysis

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ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

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Research Article

Distribution, Metabolism, Excretion and Toxicokinetics of Vitexin in Rats and Dogs

Author(s): Daopeng Tan, Geng Li, Wenying Lv, Xu Shao, Xiaoliang Li, Haijun Niu, Yaoqing Xu, Jianyong Zhang, Lin Qin, Yuqi He*, Min Jiang* and Long Cheng*

Volume 18, Issue 5, 2022

Published on: 09 August, 2021

Page: [553 - 564] Pages: 12

DOI: 10.2174/1573412917666210809154537

Price: $65

Abstract

Background: Vitexin is the main bioactive compound of hawthorn (Crataegus pinnatifida), a famous traditional Chinese medicine, and vitexin for injection is currently in phase I clinical trial in China.

Objective: This investigation systematically evaluated the metabolism and toxicokinetics of vitexin in rats and dogs.

Methods: Rats and beagle dogs were administrated different doses of vitexin, and then the plasma concentration, tissue distribution, excretion, metabolism, pharmacokinetics and plasma protein binding were investigated.

Results: The elimination half-life (t1/2) values in rats after a single intravenous dose of 3, 15 and 75 mg/kg were estimated as 43.53±10.82, 22.86±4.23, and 21.17±8.64 min, and the values of the area under the plasma concentration-time curve (AUC0→∞) were 329.34±144.07, 974.79±177.27, and 5251.49±786.98 mg•min/L, respectively. The plasma protein binding rate in rats was determined as about 65% by equilibrium dialysis after 72 hr. After 24 hr of intravenous administration, 16.30%, 3.47% and 9.72% of the given dose were excreted in urine, feces and bile, respectively. The metabolites of the vitexin were hydrolyzed via deglycosylation. The pharmacokinetics of dogs after intravenous administration revealed t1/2, AUC0-∞ and mean residence time (MRT0-∞) values of 20.43±6.37 min, 227.96±26.68 mg•min/L and 17.12±4.33 min, respectively. The no-observed-adverse- effect level (NOAEL) was 50 mg/kg body weight/day. There was no significant accumulation effect at 8 or 20 mg/kg/day in dogs over 92 days of repeated administration. For the 50 mg/kg/- day dose group, the exposure (AUC, Cmax) decreased significantly with prolonged administration. This trend suggests that repeated administration accelerates vitexin metabolism.

Conclusion: The absorption of vitexin following routine oral administration was very low. To improve the bioavailability of vitexin, the development of an injectable formulation would be a suitable alternative choice.

Keywords: Pharmacokinetics metabolism, toxicokinetics, vitexin, traditional Chinese medicine, hawthorn, liquid chromatography.

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[1]
Commission, CP Chinese Pharmacopoeia. 2020, 33-34.
[2]
Xu, H.; Xu, H.E.; Ryan, D. A study of the comparative effects of hawthorn fruit compound and simvastatin on lowering blood lipid levels. Am. J. Chin. Med., 2009, 37(5), 903-908.
[http://dx.doi.org/10.1142/S0192415X09007302] [PMID: 19885950]
[3]
Huang, W.; Ye, X.; Li, X.; Zhao, Z.; Lan, P.; Wang, L.; Liu, M.; Gao, Y.; Zhu, J.; Li, P.; Feng, P. The inhibition activity of chemical constituents in hawthorn fruit and their synergistic action to HMG-CoA reductase. Chin. J Chin. Mater. med., 2010, 35(18), 2428-2431.
[4]
Diane, A.; Borthwick, F.; Wu, S.; Lee, J.; Brown, P.N.; Dickinson, T.A.; Croft, K.D.; Vine, D.F.; Proctor, S.D. Hypolipidemic and cardioprotective benefits of a novel fireberry hawthorn fruit extract in the JCR:LA-cp rodent model of dyslipidemia and cardiac dysfunction. Food Funct., 2016, 7(9), 3943-3952.
[http://dx.doi.org/10.1039/C6FO01023G] [PMID: 27538786]
[5]
Zhang, Y.; Zhang, L.; Geng, Y.; Geng, Y. Hawthorn fruit attenuates atherosclerosis by improving the hypolipidemic and antioxidant activities in apolipoprotein e-deficient mice. J. Atheroscler. Thromb., 2014, 21(2), 119-128.
[http://dx.doi.org/10.5551/jat.19174] [PMID: 24126122]
[6]
Li, C.; Wang, M.H. Anti-inflammatory effect of the water fraction from hawthorn fruit on LPS-stimulated RAW 264.7 cells. Nutr. Res. Pract., 2011, 5(2), 101-106.
[http://dx.doi.org/10.4162/nrp.2011.5.2.101] [PMID: 21556222]
[7]
Wu, P.; Li, F.; Zhang, J.; Yang, B.; Ji, Z.; Chen, W. Phytochemical compositions of extract from peel of hawthorn fruit, and its antioxidant capacity, cell growth inhibition, and acetylcholinesterase inhibitory activity. BMC Complement. Altern. Med., 2017, 17(1), 151.
[http://dx.doi.org/10.1186/s12906-017-1662-y] [PMID: 28284186]
[8]
Jiang, W.; Zhang, W.G.; Ma, X.S. Clinical and experimental study on jiangzhi tiaoya granule in treating essential hypertension and protecting function of vascular endothelium. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih, 2002, 22(1), 18-20.
[PMID: 12585164]
[9]
Li, S.C.; Huang, H.; Zheng, F.M.; Wen, D.L.; Mo, S.W. Effects of yixintong on regulating cellular calcium channels. Zhongguo Zhongyao Zazhi, 2003, 28(8), 754-756.
[PMID: 15015360]
[10]
Piao, J.H.; Tong, P.Z.; Zhang, H.; Gao, T.H.; Zhang, L.; Lu, X.H. Yixintong tablet’s protection against experimental myocardial ischemia. Zhongguo Zhongyao Zazhi, 2003, 28(5), 442-445.
[PMID: 15139130]
[11]
Dong, L.Y.; Chen, Z.W.; Guo, Y.; Cheng, X.P.; Shao, X. Mechanisms of vitexin preconditioning effects on cultured neonatal rat cardiomyocytes with anoxia and reoxygenation. Am. J. Chin. Med., 2008, 36(2), 385-397.
[http://dx.doi.org/10.1142/S0192415X08005849] [PMID: 18457368]
[12]
Dong, L.; Fan, Y.; Shao, X.; Chen, Z. Vitexin protects against myocardial ischemia/reperfusion injury in Langendorff-perfused rat hearts by attenuating inflammatory response and apoptosis. Food Chem. Toxicol., 2011, 49(12), 3211-3216.
[http://dx.doi.org/10.1016/j.fct.2011.09.040] [PMID: 22001368]
[13]
Dong, L.Y.; Li, S.; Zhen, Y.L.; Wang, Y.N.; Shao, X.; Luo, Z.G. Cardioprotection of vitexin on myocardial ischemia/reperfusion injury in rat via regulating inflammatory cytokines and MAPK pathway. Am. J. Chin. Med., 2013, 41(6), 1251-1266.
[http://dx.doi.org/10.1142/S0192415X13500845] [PMID: 24228599]
[14]
Che, X.; Wang, X.; Zhang, J.; Peng, C.; Zhen, Y.; Shao, X.; Zhang, G.; Dong, L. Vitexin exerts cardioprotective effect on chronic myocardial ischemia/reperfusion injury in rats via inhibiting myocardial apoptosis and lipid peroxidation. Am. J. Transl. Res., 2016, 8(8), 3319-3328.
[PMID: 27648122]
[15]
Abbasi, E.; Nassiri-Asl, M.; Shafeei, M.; Sheikhi, M. Neuroprotective effects of vitexin, a flavonoid, on pentylenetetrazole-induced seizure in rats. Chem. Biol. Drug Des., 2012, 80(2), 274-278.
[http://dx.doi.org/10.1111/j.1747-0285.2012.01400.x] [PMID: 22554436]
[16]
Lu, C.C.; Xu, Y.Q.; Wu, J.C.; Hang, P.Z.; Wang, Y.; Wang, C.; Wu, J.W.; Qi, J.C.; Zhang, Y.; Du, Z.M. Vitexin protects against cardiac hypertrophy via inhibiting calcineurin and CaMKII signaling pathways. Naunyn Schmiedebergs Arch. Pharmacol., 2013, 386(8), 747-755.
[http://dx.doi.org/10.1007/s00210-013-0873-0] [PMID: 23624753]
[17]
Yang, L.; Yang, Z.M.; Zhang, N.; Tian, Z.; Liu, S.B.; Zhao, M.G. Neuroprotective effects of vitexin by inhibition of NMDA receptors in primary cultures of mouse cerebral cortical neurons. Mol. Cell. Biochem., 2014, 386(1-2), 251-258.
[http://dx.doi.org/10.1007/s11010-013-1862-9] [PMID: 24141792]
[18]
Min, J.W.; Hu, J.J.; He, M.; Sanchez, R.M.; Huang, W.X.; Liu, Y.Q.; Bsoul, N.B.; Han, S.; Yin, J.; Liu, W.H.; He, X.H.; Peng, B.W. Vitexin reduces hypoxia-ischemia neonatal brain injury by the inhibition of HIF-1alpha in a rat pup model. Neuropharmacology, 2015, 99, 38-50.
[http://dx.doi.org/10.1016/j.neuropharm.2015.07.007] [PMID: 26187393]
[19]
Chen, L.; Zhang, B.; Shan, S.; Zhao, X. Neuroprotective effects of vitexin against isoflurane-induced neurotoxicity by targeting the TRPV1 and NR2B signaling pathways. Mol. Med. Rep., 2016, 14(6), 5607-5613.
[http://dx.doi.org/10.3892/mmr.2016.5948] [PMID: 27878303]
[20]
Min, J.W.; Kong, W.L.; Han, S.; Bsoul, N.; Liu, W.H.; He, X.H.; Sanchez, R.M.; Peng, B.W. Vitexin protects against hypoxic-ischemic injury via inhibiting Ca2+/Calmodulin-dependent protein kinase II and apoptosis signaling in the neonatal mouse brain. Oncotarget, 2017, 8(15), 25513-25524.
[http://dx.doi.org/10.18632/oncotarget.16065] [PMID: 28424420]
[21]
Borghi, S.M.; Carvalho, T.T.; Staurengo-Ferrari, L.; Hohmann, M.S.; Pinge-Filho, P.; Casagrande, R.; Verri, W.A., Jr Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines. J. Nat. Prod., 2013, 76(6), 1141-1149.
[http://dx.doi.org/10.1021/np400222v] [PMID: 23742617]
[22]
Rosa, S.I.; Rios-Santos, F.; Balogun, S.O.; Martins, D.T. Vitexin reduces neutrophil migration to inflammatory focus by down-regulating pro-inflammatory mediators via inhibition of p38, ERK1/2 and JNK pathway. Phytomedicine, 2016, 23(1), 9-17.
[http://dx.doi.org/10.1016/j.phymed.2015.11.003] [PMID: 26902402]
[23]
Demir Özkay, U.; Can, O.D. Anti-nociceptive effect of vitexin mediated by the opioid system in mice. Pharmacol. Biochem. Behav., 2013, 109, 23-30.
[http://dx.doi.org/10.1016/j.pbb.2013.04.014] [PMID: 23639588]
[24]
Zhu, Q.; Mao, L.N.; Liu, C.P.; Sun, Y.H.; Jiang, B.; Zhang, W.; Li, J.X. Antinociceptive effects of vitexin in a mouse model of postoperative pain. Sci. Rep., 2016, 6, 19266.
[http://dx.doi.org/10.1038/srep19266] [PMID: 26763934]
[25]
Can, O.D.; Demir Özkay, Ü.; Üçel, U.I. Anti-depressant-like effect of vitexin in BALB/c mice and evidence for the involvement of monoaminergic mechanisms. Eur. J. Pharmacol., 2013, 699(1-3), 250-257.
[http://dx.doi.org/10.1016/j.ejphar.2012.10.017] [PMID: 23099258]
[26]
Cuzzolin, L.; Benoni, G. Attitudes and knowledge toward natural products safety in the pharmacy setting: An Italian study. Phytother. Res., 2009, 23(7), 1018-1023.
[http://dx.doi.org/10.1002/ptr.2745] [PMID: 19140118]
[27]
de Souza Nascimento, S.; Desantana, J.M.; Nampo, F.K.; Ribeiro, E.A.; da Silva, D.L.; Araújo-Júnior, J.X.; da Silva Almeida, J.R.; Bonjardim, L.R.; de Souza Araújo, A.A.; Quintans-Júnior, L.J. Efficacy and safety of medicinal plants or related natural products for fibromyalgia: A systematic review. Evid. Based Complement. Alternat. Med., 2013, 2013, 149468.
[http://dx.doi.org/10.1155/2013/149468] [PMID: 23861696]
[28]
Ashihara, H. Metabolism and biological function of natural products in plants preface. Nat. Prod. Commun., 2015, 10(5), 1.
[29]
Xue, H.F.; Ying, Z.M.; Zhang, W.J.; Meng, Y.H.; Ying, X.X.; Kang, T.G. Hepatic, gastric, and intestinal first-pass effects of vitexin in rats. Pharm. Biol., 2014, 52(8), 967-971.
[http://dx.doi.org/10.3109/13880209.2013.874464] [PMID: 24555505]
[30]
He, M.; Min, J.W.; Kong, W.L.; He, X.H.; Li, J.X.; Peng, B.W. A review on the pharmacological effects of vitexin and isovitexin. Fitoterapia, 2016, 115, 74-85.
[http://dx.doi.org/10.1016/j.fitote.2016.09.011] [PMID: 27693342]
[31]
Qu, L.; Zheng, H.S.; Feng, N.P.; Li, S.M. Determination of vitexin-rhamnoside in Beagle dog plasma and preliminary pharmacokinetics of Yixintong sustained release tablets. Zhongguo Zhongyao Zazhi, 2008, 33(10), 1168-1170.
[PMID: 18720869]
[32]
Cui, S.M.; Wei, X.F.; Zhang, J.; Ye, Z.Z.; Liao, H.W. Determination of vitexin in plasma by HPLC-MS/MS method and its pharmacokinetics in rats. Zhong Yao Cai, 2012, 35(7), 1120-1123.
[PMID: 23252280]
[33]
Yan, C.; Liu, H.; Lin, L. Simultaneous determination of vitexin and isovitexin in rat plasma after oral administration of Santalum album L. leaves extract by liquid chromatography tandem mass spectrometry. Biomed. Chromatogr., 2013, 27(2), 228-232.
[http://dx.doi.org/10.1002/bmc.2780] [PMID: 22706896]
[34]
Zhang, Y.Y.; Gan, J.Y.; Lu, C.S.; Ning, X.Y.; Wei, J.H.; Feng, X. Chemical constituents of zhuang medicine Alysicarpus vagnalis herb. Zhong Yao Cai, 2021, 44(05), 1136-1139.
[35]
Di, L.; Umland, J.P.; Trapa, P.E.; Maurer, T.S. Impact of recovery on fraction unbound using equilibrium dialysis. J. Pharm. Sci., 2012, 101(3), 1327-1335.
[http://dx.doi.org/10.1002/jps.23013] [PMID: 22161810]

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