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Current Pharmaceutical Analysis

Author(s): Ya-Nan Zhu, Shuo Zhang, Min Zhang, Xiao-Xia Meng, Peng-Jiao Wang, Rong-Ping Zhang and Xiu-Li Gao*

DOI: 10.2174/1573412916666200206141439

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Study of Pharmaceutical Excipient PEG400 Alteration of Pharmacokinetics and Tissue Distribution of Main Flavonoids Metabolites of Baicalin

Page: [609 - 623] Pages: 15

  • * (Excluding Mailing and Handling)

Abstract

Background: Polyethylene glycol 400 (PEG400), as a good traditional Chinese medicine solvent, diluent and solubilizer, is widely used as a main pharmaceutical excipient in traditional Chinese medicine compound preparations containing active ingredient baicalin. PEG400 could increase the solubility and release of baicalin in vivo, but it was unknown that PEG400 affected the absorption and distribution of baicalin or not.

Objective: At present, the effects of PEG400 on the pharmacokinetic characteristics and tissue distribution behaviors of the main flavonoid metabolites baicalin, baicalein 6-O-β-D-glucopyranoside (B6G) and baicalein after oral administration of baicalin were investigated by a rapid, efficient and sensitive ultra- high performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method. Moreover, we respectively studied the effects of PEG400 on the activities and protein expressions of two subtypes UDP-glucuronyltransferase 1 A8/A9 (UGT1A8 and UGT1A9) of UDP-glucuronosyltransferases (UGTs) in vitro and in vivo experiments to determine the partial mechanisms by which PEG400 altered the pharmacokinetics and tissue distribution behaviors of the three flavonoid metabolites.

Methods: A rapid, efficient and sensitive ultra-high performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method and ELISA and so on.

Results: The results showed that PEG400 significantly increased the Cmax and AUC0-t values (P < 0.05 or P < 0.01) of baicalin and B6G while baicalein could not be quantified due to its extremely low concentration (lower the LLOQ) in plasma. Baicalin, B6G and baicalein were mainly distributed in the stomach, small intestine, kidney and liver. PEG400 changed the distribution of three flavonoid metabolites in various tissues and also increased the activities and expressions of UGT1A8 and UGT1A9.

Conclusion: In conclusion, PEG400 significantly altered the pharmacokinetic characteristics and tissue distribution behaviors of three flavonoid metabolites may partly result from PEG400 upregulated the activities and expressions of the drug biphasic metabolic enzymes UGT1A8 and UGT1A9, which provided a material basis and useful information to reveal the mechanism of action and clinical application of PEG400.

Keywords: Polyethylene glycol 400, baicalin, baicalein 6-O-β-D-glucopyranoside, tissue distribution, pharmacokinetics, UGT1A8, UGT1A9.

Graphical Abstract

[1]
Lu, Y.; Joerger, R.; Wu, C. Study of the chemical composition and antimicrobial activities of ethanolic extracts from roots of Scutellaria baicalensis Georgi. J. Agric. Food Chem., 2011, 59(20), 10934-10942.
[http://dx.doi.org/10.1021/jf202741x] [PMID: 21866919]
[2]
Lai, W.; Jia, J.; Yan, B.; Jiang, Y.; Shi, Y.; Chen, L.; Mao, C.; Liu, X.; Tang, H.; Gao, M.; Cao, Y.; Liu, S.; Tao, Y. Baicalin hydrate inhibits cancer progression in nasopharyngeal carcinoma by affecting genome instability and splicing. Oncotarget, 2017, 9(1), 901-914.
[PMID: 29416665]
[3]
Ni, H.; Wu, Z.; Muhammad, I. Optimization of baicalin water extraction process from Scutellaria baicalensis (a traditional Chinese medicine) by using orthogonal test and HPLC. Rev. Bras. Farmacogn., 2018, 28, 151-155.
[http://dx.doi.org/10.1016/j.bjp.2018.02.001]
[4]
Guo, Y.R. Research progress of immunomodulation effects of huangqin (Radix Scutellariae). Guide. Chin. Med., 2013, 11, 77-78.
[5]
Liu, X.N.; Yang, Y.J.; Lu, Q.Z. Density functional theory investigation of scutellarin. J. Shandong. Univ., 2012, 47, 20-25.
[6]
Akao, T.; Kawabata, K.; Yanagisawa, E.; Ishihara, K.; Mizuhara, Y.; Wakui, Y.; Sakashita, Y.; Kobashi, K. Baicalin, the predominant flavone glucuronide of scutellariae radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form. J. Pharm. Pharmacol., 2000, 52(12), 1563-1568.
[http://dx.doi.org/10.1211/0022357001777621] [PMID: 11197087]
[7]
Zhang, L.; Lin, G.; Chang, Q.; Zuo, Z. Role of intestinal first-pass metabolism of baicalein in its absorption process. Pharm. Res., 2005, 22(7), 1050-1058.
[http://dx.doi.org/10.1007/s11095-005-5303-7] [PMID: 16028005]
[8]
Liu, Z.; Zhou, S.Y.; Li, W.; Wen, H.M.; Bian, H.M.; Chen, L. Liguzinediol induced positive inotropic effect in normal isolated rat hearts. Chin. J. New. Drugs. Clin. Remed, 2009, 28, 293-296.
[9]
Giacomini, K.M.; Huang, S.M.; Tweedie, D.J.; Benet, L.Z.; Brouwer, K.L.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.; Hillgren, K.M.; Hoffmaster, K.A.; Ishikawa, T.; Keppler, D.; Kim, R.B.; Lee, C.A.; Niemi, M.; Polli, J.W.; Sugiyama, Y.; Swaan, P.W.; Ware, J.A.; Wright, S.H.; Yee, S.W.; Zamek-Gliszczynski, M.J.; Zhang, L. Membrane transporters in drug development. Nat. Rev. Drug Discov., 2010, 9(3), 215-236.
[http://dx.doi.org/10.1038/nrd3028] [PMID: 20190787]
[10]
Hillgren, K.M.; Keppler, D.; Zur, A.A.; Giacomini, K.M.; Stieger, B.; Cass, C.E.; Zhang, L. Emerging transporters of clinical importance: an update from the International Transporter Consortium. Clin. Pharmacol. Ther., 2013, 94(1), 52-63.
[http://dx.doi.org/10.1038/clpt.2013.74] [PMID: 23588305]
[11]
Kochling, J.D.; Miao, H.; Young, C.R.; Looker, A.R.; Shannon, M.; Montgomery, E.R. Understanding the degradation pathway of a poorly water-soluble drug formulated in PEG-400. J. Pharm. Biomed. Anal., 2007, 43(5), 1638-1646.
[http://dx.doi.org/10.1016/j.jpba.2006.12.011] [PMID: 17224256]
[12]
Vasconcelos, T.; Sarmento, B.; Costa, P. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discov. Today, 2007, 12(23-24), 1068-1075.
[http://dx.doi.org/10.1016/j.drudis.2007.09.005] [PMID: 18061887]
[13]
Court, M.H.; Zhang, X.; Ding, X.; Yee, K.K.; Hesse, L.M.; Finel, M. Quantitative distribution of mRNAs encoding the 19 human UDP-glucuronosyltransferase enzymes in 26 adult and 3 fetal tissues. Xenobiotica, 2012, 42(3), 266-277.
[http://dx.doi.org/10.3109/00498254.2011.618954] [PMID: 21995321]
[14]
Mazerska, Z.; Mróz, A.; Pawłowska, M.; Augustin, E. The role of glucuronidation in drug resistance. Pharmacol. Ther., 2016, 159, 35-55.
[http://dx.doi.org/10.1016/j.pharmthera.2016.01.009] [PMID: 26808161]
[15]
Ohno, S.; Nakajin, S. Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metab. Dispos., 2009, 37(1), 32-40.
[http://dx.doi.org/10.1124/dmd.108.023598] [PMID: 18838504]
[16]
Rowland, A.; Miners, J.O.; Mackenzie, P.I. The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int. J. Biochem. Cell Biol., 2013, 45(6), 1121-1132.
[http://dx.doi.org/10.1016/j.biocel.2013.02.019] [PMID: 23500526]
[17]
Ma, J.; Zheng, L.; Deng, T.; Li, C.L.; He, Y.S.; Li, H.J.; Li, P. Stilbene glucoside inhibits the glucuronidation of emodin in rats through the down-regulation of UDP-glucuronosyltransferases 1A8: application to a drug-drug interaction study in Radix Polygoni Multiflori. J. Ethnopharmacol., 2013, 147(2), 335-340.
[http://dx.doi.org/10.1016/j.jep.2013.03.013] [PMID: 23523942]
[18]
Wu, B.; Kulkarni, K.; Basu, S.; Zhang, S.; Hu, M. First-pass metabolism via UDP-glucuronosyltransferase: a barrier to oral bioavailability of phenolics. J. Pharm. Sci., 2011, 100(9), 3655-3681.
[http://dx.doi.org/10.1002/jps.22568] [PMID: 21484808]
[19]
Guidance for Industry: Bioanalytical Method Validation. U.S. Department of Health and Human Services, FDA Rockville, . 2001.
[20]
Zhang, Z.; Ma, G.; Xue, C.; Sun, H.; Wang, Z.; Xiang, X.; Cai, W. Establishment of rat liver microsome-hydrogel system for in vitro phase II metabolism and its application to study pharmacological effects of UGT substrates. Drug Metab. Pharmacokinet., 2019, 34(2), 141-147.
[http://dx.doi.org/10.1016/j.dmpk.2019.01.005] [PMID: 30744936]
[21]
Cai, Y.; Li, S.; Li, T.; Zhou, R.; Wai, A.T.; Yan, R. Oral pharmacokinetics of baicalin, wogonoside, oroxylin A 7-O-β-d-glucuronide and their aglycones from an aqueous extract of Scutellariae Radix in the rat. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2016, 1026, 124-133.
[http://dx.doi.org/10.1016/j.jchromb.2015.11.049] [PMID: 26809374]
[22]
Zhang, X.J.; Liu, S.; Xing, J.P. Effect of type 2 diabetes mellitus on flavonoid pharmacokinetics and tissue distribution after oral administration of Radix Scutellaria extract in rats., Chin. J. Nat. Med., 2018, 16, 0418-0427..
[23]
Wang, L.; Shen, X.; Mi, L.; Jing, J.; Gai, S.; Liu, X.; Wang, Q.; Zhang, S. Simultaneous determinations of four major bioactive components in Acacia catechu (L.f.) Willd and Scutellaria baicalensis Georgi extracts by LC-MS/MS: Application to its herb-herb interactions based on pharmacokinetic, tissue distribution and excretion studies in rats. Phytomedicine, 2019, 56, 64-73.
[http://dx.doi.org/10.1016/j.phymed.2018.09.239] [PMID: 30668355]
[24]
Zhang, S.; Xie, Y.; Wang, J. Simultaneous determination of six bioactive components of total flavonoids of Scorzonera austriaca in rat tissues by LC-MS/MS: application to a tissue distribution study. Rev. Bras. Farmacogn., 2018, 28, 156-164.
[http://dx.doi.org/10.1016/j.bjp.2018.01.004]
[25]
Akao, T.; Hanada, M.; Sakashita, Y.; Sato, K.; Morita, M.; Imanaka, T. Efflux of baicalin, a flavone glucuronide of Scutellariae Radix, on Caco-2 cells through multidrug resistance-associated protein 2. J. Pharm. Pharmacol., 2007, 59(1), 87-93.
[http://dx.doi.org/10.1211/jpp.59.1.0012] [PMID: 17227625]
[26]
Zhao, T.H.; Wen, S.; Deng, S.H.; Yang, H.S.; Cao, K. Analgesic activity and biodistribution of polyethylene glycol conjugation to enkephalin. Chin. Pharmacol. Bull., 2013, 1, 703-707.