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

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.