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Study of pharmaceutical excipient PEG400 alteration of pharmacokinetics and tissue distribution of main flavonoids metabolites of baicalin

Author(s):

Ya-nan Zhu, Shuo Zhang, Min Zhang, Xiao-xia Meng, Peng-jiao Wang, Rong-ping Zhang and Xiu-li Gao*  

Abstract:


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 if PEG400 affected the absorption and distribution of baicalin or not. At present, the effects of PEG400 after oral administration of baicalin on the pharmacokinetic characteristics and tissue distribution behaviors of baicalin itself and its main flavonoid metabolites baicalein-6-O-β-glucopyranoside (B6G) and baicalein were investigated by a rapid, efficient and sensitive ultra-high performance liquid chromatography coupled 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 vivo experiments to determine the partial mechanisms by which PEG400 altered the pharmacokinetics and tissue distribution behaviors of the three flavonoid metabolites. 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. In conclusion, PEG400 significantly altered the pharmacokinetic characteristics and tissue distribution behaviors of three flavonoid metabolites. This may partly result from PEG400 upregulation of the activities and expressions of the drug biphasic metabolic enzymes UGT1A8 and UGT1A9, which provided a material basis.

Keywords:

Polyethylene glycol 400, Baicalin; Baicalein, Baicalein-6-O-β-D-glucopyranoside, Tissue distribution, Pharmacokinetics, UGT1A8, UGT1A9

Affiliation:

State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guiyang 550025, State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guiyang 550025, State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guiyang 550025, Microbiology and Biochemical Pharmaceutical Engineering Research Center of Guizhou Provincial Department of Education, Guizhou Medical University, Guiyang 550004, State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guiyang 550025, School of Pharmacy, Kunming Medical University, Kunming 650500, State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmacy, Guizhou Medical University, Guiyang 550025



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