Intestinal metabolism and absorption mechanism of multi-components in Gaultheria leucocarpa var. yunnanensis - An assessment using in situ and in vitro models, comparing gut segments in pathological with physiological conditions. (25th March 2022)

• Record Type: Journal Article
• Authors: Wang, Xiuhuan; Dong, Ying; Song, Ruolan; Yu, Axiang; Wei, Jing; Fan, Qiqi; Yao, Jianling; Shan, Dongjie; Zhong, Xiangjian; Lv, Fang; She, Gaimei
• Is Part Of: Journal of ethnopharmacology. Volume 286(2022)
• Publication Date: 2022-03-25
• Subjects: Gaultheria leucocarpa var. Yunnanensis -- P-glycoprotein -- Absorption mechanism -- Everted gut sacs -- In situ single-pass intestinal perfusion; ARF anti-rheumatic arthritis fraction -- ADME absorption distribution metabolism, and elimination -- MSTG-B methyl benzoate-2-O-β-D-glucopyranosyl (1→2)-[O-β-D-xylopyranosyl (1→6)]-O-β-D-glucopyranoside -- MSTG-A methyl salicylate-2-O-β-D-xylopyranosyl (1→2)-[O-β-D-xylopyranosyl (1→6)]-O-β-D-glucopyranoside -- Gualtherin methyl salicylate-2-O-β-D-xylopyranosyl (1→6)-O-β-D-glucopyranoside; Ethnopharmacology -- Periodicals; Pharmacognosy -- Periodicals; Herbs -- Periodicals; Herbs -- Periodicals; Pharmacognosy -- Periodicals; Pharmacognosie -- Périodiques; Herbes -- Périodiques; 615.1
• DOI: 10.1016/j.jep.2021.114844
• Languages: English
• ISSNs: 0378-8741

Abstract

Abstract: Ethnopharmacological relevance: Dianbaizhu ( Gaultheria leucocarpa var. yunnanensis ) as a Chinese folk medicine exerts significant treatment effects on rheumatoid arthritis (RA) with a long historical time. Our previous reports showed that the anti-rheumatic arthritis fraction (ARF) extracted and enriched from Dianbaizhu possessed good druggability, which was better than its single active ingredients. However, the intestinal transport characteristics and mechanism of ARF have not been elucidated to date. Aim of the study: In order to illustrate the role of active ingredients of ARF in alleviating RA and promoting the development of dosage forms, the intestinal metabolism, absorption properties and mechanism of ARF in vitro and in situ models were investigated. Materials and methods: Firstly, after incubating with 4 intestinal segments (duodenum, jejunum, ileum, and colon), 7 key components in ARF, including MATG-B, (+)-catechin, MSTG-A, Gaultherin, chlorogenic acid, quercetin, and kaempferol were quantitatively analyzed by a high-performance liquid chromatography (HPLC). Secondly, combining the physiological and pathological rats, the in situ single-pass intestinal perfusion and in vitro everted gut sacs of rats were performed to investigate the absorption features and transport mechanisms of ARF using HPLC and HPLC-Q-TOF-MS/MS. Subsequently, in situ studies were employed to determine the effect of P-glycoprotein (P-gp) inhibitor (verapamil) on the transport characteristics of ARF in RA model rats. Results: Comparing the absorption parameters of ARF incubated in different intestinal segments, data showed that the absorption of ARF in the small intestine was significantly stronger than that of the colon ( P < 0.01). The number of characterized prototype components was subjected to the incubation time, drug concentration and rat body condition, but not the intestinal segments. There were no significant differences in the number of metabolites among different intestinal segments, administration concentrations and incubation time. The best small intestinal absorption site of ARF was duodenum and ileum in normal and model rats, respectively. The P eff values of 7 index compounds were all higher than 0.2 × 10 −4 cm/s, and the F a values of 7 index compounds were all greater than 20% in the in situ perfusion investigation. The results showed that MSTG-B, MSTG-A and Gaultherin were likely to be substrates of P-gp as verapamil significantly enhanced their P eff and K a values, while other ingredients were not P-gp substrates. Conclusions: The intestinal membrane permeability of ARF was good. Its intestinal absorption mechanisms mainly involved active transportation processes and passive diffusion. Besides, this report provided data support and basis for clinical development, bioavailability improvement and formulation design. Graphical abstract: Image 1 Highlights: 7 components were determined to evaluate the gut absorption characteristics of ARF. The gut transport mechanism of ARF was explored by in vitro and in situ models. The best absorption segment of ARF was ileum. MSTG-A, MST-B and Gaultherin in ARF might be P-gp subtracts.