The Influence of Compatibility of Rhubarb and Radix Scutellariae on the Pharmacokinetics of Anthraquinones and Flavonoids in Rat Plasma

Original Research Article
  • 83 Downloads

Abstract

Background and Objectives

Rhubarb–Radix scutellariae is a classic herb pair, which is commonly used to clear away heat and toxin in clinic. The aim of this study was to investigate the influence of compatibility of Rhubarb and Radix scutellariae on the pharmacokinetic behaviors of anthraquinones and flavonoids in rat plasma.

Methods

Eighteen rats were randomly divided into three groups, and were orally administered Rhubarb and/or Radix scutellariae extracts. A sensitive and rapid UPLC–MS/MS method was developed and validated to determine the concentrations of baicalin, baicalein, wogonside, wogonin, rhein, and emodin in rat plasma. The concentrations of phase II conjugates of flavonoid aglycones and anthraquinone aglycones were also determined after hydrolyzing the plasma with sulfatase.

Results

Compared with administration of Radix scutellariae alone, co-administration of Rhubarb significantly decreased the first maximum plasma concentration (C max1) of baicalin, wogonside, and the phase II conjugates of baicalein, wogonin to 46.40, 61.27, 41.49, and 20.50%, respectively. The area under the plasma concentration–time curve from time zero to infinity (AUC0–∞) was significantly decreased from 82.60 ± 20.22 to 51.91 ± 7.46 μM·h for rhein and 276.83 ± 98.02 to 175.42 ± 86.82 μM·h for the phase II conjugates of wogonin after compatibility. The time to reach the first maximum plasma concentration (T max1) of anthraquinones was shortened and the second peak of anthraquinones disappeared after compatibility.

Conclusions

Compatibility of Rhubarb and Radix scutellariae can significantly affect the pharmacokinetic behaviors of characteristic constituents of the two herbs. The cause of these pharmacokinetic differences was further discussed combined with the in vivo ADME (absorption, disposition, metabolism, and excretion) processes of anthraquinones and flavonoids.

Notes

Compliance with Ethical Standards

Funding

This project was financially supported by the National Natural Science Foundation of China (No. 81403314), the Open Project Program of Guangxi Key Laboratory of Traditional Chinese Medicine Quality Standards (No. 201503), and the Natural Research Foundation of Jiangsu Province (No. BK20161456) and the Qing Lan Project of Jiangsu Province (2017).

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical Approval

The ethical committee of China Pharmaceutical University approved the experiment. The experiment was carried out in accordance with the US guidelines for the Care and Use of Laboratory Animals.

Supplementary material

13318_2017_444_MOESM1_ESM.docx (410 kb)
Supplementary material 1 (DOCX 409 kb)

References

  1. 1.
    Jia W, Gao WY, Yan YQ, Wang J, Xu ZH, Zheng WJ, Xiao PG. The rediscovery of ancient chinese herbal formulas. Phytother Res. 2003;18:681–6.CrossRefGoogle Scholar
  2. 2.
    Zhou MM, Hong YL, Lin X, Shen L, Feng Y. Recent pharmaceutical evidence on the compatibility rationality of traditional chinese medicine. J Ethnopharmacol. 2017;206:363–75.CrossRefPubMedGoogle Scholar
  3. 3.
    Wang SP, Hu YY, Tan W, Wu X, Chen R, Cao J, Chen MW, Wang YT. Compatibility art of traditional chinese medicine: from the perspective of herb pairs. J Ethnopharmacol. 2012;143:412–23.CrossRefPubMedGoogle Scholar
  4. 4.
    Hong JY, Chung HJ, Bae SY, Trung TN, Bae K, Lee SK. Induction of cell cycle arrest and apoptosis by physcion, an anthraquinone isolated from rhubarb (rhizomes of Rheum tanguticum), in MDA-MB-231 human breast cancer cells. J Cancer Prev. 2014;19:273–8.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tan L, Geng DD, Hu FZ, Dong Q. Rapid identification and quantification of natural antioxidants in the seeds of rhubarb from different habitats in china using accelerated solvent extraction and HPLC-DAD-ESI–MSN-DPPH assay. J Chromatogr Sci. 2016;54:48–57.PubMedGoogle Scholar
  6. 6.
    Lee W, Ku SK, Lee D, Lee T, Bae JS. Emodin-6-O-β-d-glucoside inhibits high-glucose-induced vascular inflammation. Inflamm. 2014;37:306–13.CrossRefGoogle Scholar
  7. 7.
    Lu K, Zhang C, Wu WJ, Zhou M, Tang YM, Peng Y. Rhubarb extract has a protective role against radiation-induced brain injury and neuronal cell apoptosis. Mol Med Rep. 2015;12:2689–94.CrossRefPubMedGoogle Scholar
  8. 8.
    Shang XF, He XR, He XY, Li MX, Zhang RX, Fan PC, Zhang QL, Jia ZP. The genus scutellaria an ethnopharmacological and phytochemical review. J Ethnopharmacol. 2010;128:279–313.CrossRefPubMedGoogle Scholar
  9. 9.
    Shia CS, Juang SH, Tsai SY, Chang PH, Kuo SC, Hou YC, Chao PDL. Metabolism and pharmacokinetics of anthraquinones in Rheum palmatum in rats and ex vivo antioxidant activity. Planta Med. 2009;75:1386–92.CrossRefPubMedGoogle Scholar
  10. 10.
    Wu WJ, Yan R, Yao MC, Zhan Y, Wang YT. Pharmacokinetics of anthraquinones in rat plasma after oral administration of a rhubarb extract. Biomed Chromatogr. 2014;28:564–72.CrossRefPubMedGoogle Scholar
  11. 11.
    Shai CS, Tsai SY, Lin JC, Li ML, Ko MH, Chao PDL, Huang YC, Hou YC. Steady-state pharmacokinetics and tissue distribution of anthraquinones of Rhei rhizoma in rats. J Ethnopharmacol. 2012;137:1388–94.CrossRefGoogle Scholar
  12. 12.
    Srinivas NR. Baicalin, an emerging multi-therapeutic agent: pharmacodynamics, pharmacokinetics, and considerations from drug development perspectives. Xenobiotica. 2010;40:357–67.CrossRefPubMedGoogle Scholar
  13. 13.
    Wang ZG, Hu HL, Chen F, Lan K, Wang AQ. Reduced system exposures of total rhein and baicalin after combinatory oral administration of rhein, baicalin and berberine to beagle dogs and rats. J Ethnopharmacol. 2013;145:442–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Qu HB, Ma YH, Yu K, Cheng YY. Simultaneous determination of eight active components in chinese medicine ‘yiqing’ capsule using high-performance liquid chromatography. J Pharm Biomed Anal. 2007;43:66–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Zan B, Shi R, Wang TM, Wu JS, Ma YM, Cheng NN. Simultaneous quantification of multiple active components from xiexin decoction in rat plasma by LC-ESI–MS/MS: application in pharmacokinetics. Biomed Chromatogr. 2011;25:816–26.CrossRefPubMedGoogle Scholar
  16. 16.
    Tong L, Wan MX, Zhang LH, Zhu YH, Sun H, Bi KS. Simultaneous determination of baicalin, wogonoside, baicalein, wogonin, oroxylin A and chrysin of Radix scutellariae extract in rat plasma by liquid chromatography tandem mass spectrometry. J Pharm Biomed Anal. 2012;70:6–12.CrossRefPubMedGoogle Scholar
  17. 17.
    Wen ZM, Dumas TE, Schrieber SJ, Hawke RL, Fried MW, Smith PC. Pharmacokinetics and metabolic profile of free, conjugated, and total silymarin flavonolignans in human plasma after oral administration of milk thistle extract. Drug Metab Dispos. 2008;36:65–72.CrossRefPubMedGoogle Scholar
  18. 18.
    Yan DM, Ma YM, Shi R, Xu DS, Zhang N. Pharmacokinetics of anthraquinones in Xiexin decoction and in different combinations of its constituent herbs. Phytother Res. 2009;23:317–23.CrossRefPubMedGoogle Scholar
  19. 19.
    Zhang L, Lin G, Chang Q, Zuo Z. Role of intestinal first-pass metabolism of baicalein in its absorption process. Pharm Res. 2005;22:1050–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Kang MJ, Ko GS, Oh DG, Kim JS, Noh K, Kang W, Yoon WK, Kim HC, Jeong HG, Jeong TC. Role of metabolism by intestinal microbiota in pharmacokinetics of oral baicalin. Arch Pharmacal Res. 2014;37:371–8.CrossRefGoogle Scholar
  21. 21.
    Xing J, Chen XY, Zhong DF. Absorption and enterohepatic circulation of baicalin in rats. Life Sci. 2005;78:140–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Shi R, Zhou H, Liu ZM, Ma YM, Wang TM, Liu YY, Wang CH. Influence of Coptis chinensis on pharmacokinetics of flavonoids after oral administration of Radix scutellariae in Rats. Biopharm Drug Dispos. 2009;30:398–410.CrossRefPubMedGoogle Scholar
  23. 23.
    Lu T, Song J, Huang F, Deng YX, Xie L, Wang GJ, Liu XD. Comparative pharmacokinetics of baicalin after oral administration of pure baicalin, Radix scutellariae extract and huang-lian-jie-du-tang to rats. J Ethnopharmacol. 2007;110:412–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Lai MY, Hsiu SL, Tsai SY, Hou YC, Chao PDL. Comparison of metabolic pharmacokinetics of baicalin and baicalein in rats. J Pharm Pharmacol. 2003;55:205–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Dahms M, Lotz R, Lang W, Renner U, Bayer E, Spahn-Langguth H. Elucidation of phase I and phase II metabolic pathways of rhein: species differences and their potential relevance. Drug Metab Dispos. 1997;25:442–52.PubMedGoogle Scholar
  26. 26.
    Shia CS, Hou YC, Juang SH, Tsai SY, Hsieh PH, Ho LC, Chao PDL. Metabolism and pharmacokinetics of san-huang-xie-xin-tang, a polyphenol-rich chinese medicine formula, in rats and ex vivo antioxidant activity. Evid Based Complement Altern Med. 2011;2011:1–9.CrossRefGoogle Scholar
  27. 27.
    Meng Q, Liu KX. Pharmacokinetic interactions between herbal medicines and prescribed drugs: focus on drug metabolic enzymes and transporters. Curr Drug Metab. 2014;15:791–807.CrossRefPubMedGoogle Scholar
  28. 28.
    Ye L, Lu LL, Li Y, Zeng S, Yang XS, Chen WY, Feng Q, Liu W, Tang L, Liu ZQ. Potential role of ATP-binding cassette transporters in the intestinal transport of rhein. Food Chem Toxicol. 2013;58:301–5.CrossRefPubMedGoogle Scholar
  29. 29.
    Li Z, Ge L, Kovács B, Jani M, Krajcsi P, Zhong Z. Mechanistic study on the intestinal absorption and disposition of baicalein. Eur J Pharm Sci. 2007;31:221–31.CrossRefGoogle Scholar
  30. 30.
    Akao T, Sakashita Y, Hanada M, Goto H, Shimada Y, Terasawa K. Enteric excretion of baicalein, a flavone of Scutellariae radix, via glucuronidation in rat: involvement of multidrug resistance-associated protein 2. Pharm Res. 2004;21:2120–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Akao T, Sato K, Hanada M. Hepatic contribution to a marked increase in the plasma concentration of baicalin after oral administration of its aglycone, baicalein, in multidrug resistance-associated protein 2-deficient rat. Biol Pharm Bull. 2009;32:2079–82.CrossRefPubMedGoogle Scholar
  32. 32.
    Liu W, Feng Q, Li Y, Ye L, Hu M, Liu ZQ. Coupling of UDP-glucuronosyltransferases and multidrug resistance-associated proteins is responsible for the intestinal disposition and poor bioavailability of emodin. Toxicol Appl Pharmacol. 2012;265:316–24.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Key Laboratory of Drug Quality Control and PharmacovigilanceChina Pharmaceutical UniversityNanjingChina
  2. 2.State Key Laboratory of Natural MedicineChina Pharmaceutical UniversityNanjingChina

Personalised recommendations