title: Improvement of intestinal absorption of forsythoside A in weeping forsythia extract by various absorption enhancers based on tight junctions.
abstract: Forsythoside A (FTA), one of the main active ingredients in weeping forsythia extract, possesses strong antibacterial, antioxidant and antiviral effects, and its content was about 8% of totally, higher largely than that of other ingredients, but the absolute bioavailability orally was approximately 0.5%, which is significant low influencing clinical efficacies of its oral preparations. In the present study, in vitro Caco-2 cell, in situ single-pass intestinal perfusion and in vivo pharmacokinetics study were performed to investigate the effects of absorption enhancers based on tight junctions: sodium caprate and water-soluble chitosan on the intestinal absorption of FTA, and the eventual mucosal epithelial damage resulted from absorption enhancers was evaluated by MTT test, measurement of total amount of protein and the activity of LDH and morphology observation, respectively. The pharmacological effects such as antioxidant activity improvement by absorption enhancers were verified by PC12 cell damage inhibition rate after H₂O₂ insults. The observations from in vitro Caco-2 cell showed that the absorption of FTA in weeping forsythia extract could be improved by absorption enhancers. Meanwhile, the absorption enhancing effect of water-soluble chitosan may be almost saturable up to 0.0032% (w/v), and sodium caprate at concentrations up to 0.64 mg/ml was safe for the Caco-2 cells, but water-soluble chitosan at different concentrations was all safe for these cells. The observations from single-pass intestinal perfusion in situ model showed that duodenum, jejunum, ileum and colon showed significantly concentration-dependent increase in P(eff)-value, and that P(eff)-value in the ileum and colon groups, where sodium caprate was added, was higher than that of duodenum and jejunum groups, but P(eff)-value in the jejunum group was higher than that of duodenum, ileum and colon groups where water-soluble chitosan was added. Intestinal mucosal toxicity studies showed no significant toxicity below 800 μg/ml sodium caprate and water-soluble chitosan at different concentrations. In pharmacokinetics study, water-soluble chitosan at dosage of 50mg/kg improved the bioavailability of FTA in weeping forsythia extract to the greatest extent, and was safe for gastrointestine from morphological observation. Besides, treatment with weeping forsythia extract with water-soluble chitosan at dosage of 50 mg/kg prevented PC12 cell damage upon H₂O₂ stimulation better than that of control. All findings above suggested that water-soluble chitosan at dosage of 50 mg/kg might be safe and effective absorption enhancer for improving the bioavailability of FTA and the antioxidant activity in vivo in weeping forsythia extract.
authors.affiliation: College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210046, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Kun Ming
authors.initials: KM
authors.lastname: Qin
authors.forename: Jin Jun
authors.initials: JJ
authors.lastname: Shan
authors.forename: Wen Zheng
authors.initials: WZ
authors.lastname: Ju
authors.forename: Shi Jia
authors.initials: SJ
authors.lastname: Liu
authors.forename: Bao Chang
authors.initials: BC
authors.lastname: Cai
authors.forename: Liu Qing
authors.initials: LQ
authors.lastname: Di
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics* / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D048271:Chitosan / Q000494:pharmacology*; D003652:Decanoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D031657:Forsythia / Q000737:chemistry*; D006027:Glycosides / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D016716:PC12 Cells; D010936:Plant Extracts / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000975:Antioxidants; D003652:Decanoic Acids; D006027:Glycosides; D010936:Plant Extracts; C031071:decanoic acid; D048271:Chitosan; D006861:Hydrogen Peroxide; C058049:forsythiaside