Improvement of Intestinal Absorption of Forsythoside A and Chlorogenic Acid by Different Carboxymethyl Chitosan and Chito-oligosaccharide, Application to Flos Lonicerae - Fructus Forsythiae Herb Couple Preparations

Abstract

The current study aims to investigate the effect of chitosan derivatives on the intestinal absorption and bioavailabilities of forsythoside A (FTA) and Chlorogenic acid (CHA), the major active components in Flos Lonicerae - Fructus Forsythiae herb couple. Biopharmaceutics and pharmacokinetics properties of the two compounds have been characterized in vitro, in situ as well as in rats. Based on the identified biopharmaceutics characteristics of the two compounds, the effect of chitosan derivatives as an absorption enhancer on the intestinal absorption and pharmacokinetics of FTA and CHA in pure compound form as well as extract form were investigated in vitro, in situ and in vivo. Both FTA and CHA demonstrated very limited intestinal permeabilities, leading to oral bioavailabilities being only 0.50% and 0.13% in rats, respectively. Results from both in vitro, in situ as well as in vivo studies consistently indicated that Chito-oligosaccharide (COS) at dosage of 25 mg/kg could enhance intestinal permeabilities significantly as well as the in vivo bioavailabilities of both FTA and CHA than CMCs in Flos Lonicerae - Fructus Forsythiae herb couple preparations, and was safe for gastrointestine from morphological observation. Besides, treatment with Flos Lonicerae - Fructus Forsythiae herb couple preparations with COS at the dosage of 25 mg/kg prevented MDCK damage after influenza virus propagation, which was significantly better than control. The current findings not only identified the usefulness of COS for the improved delivery of Flos Lonicerae - Fructus Forsythiae preparations but also demonstrated the importance of biopharmaceutical characterization in the dosage form development of traditional Chinese medicine.

Transepithelial transport of phenolic acids in Flos Lonicerae Japonicae in intestinal Caco-2 cell monolayers

“…7 Briefly, after culture medium was aspirated, the cell monolayers were washed three times with blank HBSS ( pH 6.0). 7 Briefly, after culture medium was aspirated, the cell monolayers were washed three times with blank HBSS ( pH 6.0).…”

“…in Flos Lonicerae Japonicae, had good positive correlation between dose and effects via pharmacokinetic/pharmacodynamic (PK/PD) models combined with PLS ( partial least squares) 3 and drug-drug interaction (DDI) combined with hierarchical cluster analysis (HCA) and principal component analysis (PCA). 7,8 Chen (2009) 9 conducted physicochemical studies of phenolic acids, showing that they were highly hydrophilic compounds almost dissociated in biological fluids, which lead us to postulate that the low permeability in the intestinal mucosa was one of the important reasons for their reported low bioavailabilities. Besides, the content of phenolic acids in Flos Lonicerae Japonicae was largely higher than that of other ingredients, such as flavones, isoflavones, triter- penoid saponins and iridoids.…”

Antiviral activity of chlorogenic acid against influenza A (H1N1/H3N2) virus and its inhibition of neuraminidase

“…These data show a lower dosage than those of previous reports23. Oral administration of 960 mg/kg/d CHA caused a survival rate of 56%, in comparison with model group23, which could be attributed to the low oral bioavailability (0.13%) of CHA29. Thus, it was reasonable that intravenous injection of 100 mg/kg/d CHA caused a similar inhibition of influenza with oral administration of 960 mg/kg/d CHA.…”

“…However, evidence for the antiviral effects and potential mechanisms is very limited. Moreover, it was administered orally in previous experiments23, which could not confirm CHA is an effective component in blood, due to its low oral bioavailability (0.13%)29. Thus, the anti-influenza effects should be checked by intravenous injection.…”

Simultaneous determination of phenolic acids by UPLC–MS/MS in rat plasma and its application in pharmacokinetic study after oral administration of Flos Lonicerae preparations

“…It was reported that, more than 500 prescriptions containing Flos Lonicerae have been used to treat various diseases in China [3], and its preparations, such as Jin-Yin-Huang oral liquid composed of Flos Lonicerae alone, Shuang-Huang-Lian tablet, Yin-Qiao-Jie-Du tablet, Fufang Jin-Huang-Lian Granule, Qing-Re-Jie-Du oral liquid and Fufang Qin-Lan oral liquid, etc. [4], in which Flos Lonicerae was the main and active composition, were extensively used for treating acute upper respiratory tract infection caused by virus or bacterial infection in clinical practice. It was found that those phenolic acids especially isochlorogenic acids in Flos Lonicerae were the main bioactive components for antioxidant, antiviral and antibacterial effects by "Spectrum-activity relationship" and "Knock-out/Knock-in" methods [5,6].…”