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.
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References
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Srinivas NR. Baicalin, an emerging multi-therapeutic agent: pharmacodynamics, pharmacokinetics, and considerations from drug development perspectives. Xenobiotica. 2010;40:357–67.
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.
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.
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.
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.
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.
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.
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.
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.
Xing J, Chen XY, Zhong DF. Absorption and enterohepatic circulation of baicalin in rats. Life Sci. 2005;78:140–6.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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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).
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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.
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Zhang, Y., Zhang, Z. & Song, R. The Influence of Compatibility of Rhubarb and Radix Scutellariae on the Pharmacokinetics of Anthraquinones and Flavonoids in Rat Plasma. Eur J Drug Metab Pharmacokinet 43, 291–300 (2018). https://doi.org/10.1007/s13318-017-0444-8
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DOI: https://doi.org/10.1007/s13318-017-0444-8