Comparative Studies On Intestinal Absorption Of Three Gastrodin Analogues Via Glucose Transport Pathway

Gastrodin is derived from Gastrodia elata Blume(Tianma in Chinese)and is the main active constituent.Gastrodin is a water-soluble drug.However,it can be absorbed completely and rapidly in the intestine.The oral bioavailability of gastrodin in rats as high as approximate reached 86.1%.The previous researches of our group found that gastrodin was absorbed by the glucose transport pathway.According to the current report,gastrodin is the best drug to be absorbed via this pathway.This indicates that glucose transporter is an important pathway for gastrodin intestinal absorption.In this paper,we selected the similar structure compounds of gastrodin:salicin,arbutin and 4methoxypheny1-β-D-glucoside.The chemical structures of these three compounds have slight difference with gastrodin:salicin and gastrodin are isomers with different substituents;compared with gastrodin,the arbutin is lack of‘-CH2-’group;the 4methoxyphenyl-β-D-glucoside has a different position of the substituent‘O’atom.This paper studies on the absorptive capacity of these three gastrodin-like compounds mediated by glucose transporters,and investigates the effect of chemical structure on intestinal absorption via glucose transport pathway.The water-solubility and lipo-solubility of these three compounds were determined.The intestinal absorption characteristics of these three compounds were studied by Caco-2 cell transport model,in situ perfusion experiment and in vivo pharmacokinetics experiments in rats.The effects of glucose and glucose transporter SGLT 1 inhibitor phlorizin on the intestinal absorption of the compounds were investigated.The expression level of SGLT 1 in each intestinal segment of rats was detected by molecular biological technique.The relationship between compounds and glucose transporters was investigated by computer-aided drug design.The three compounds have good water-solubility and suitable lipo-solubility.The watersolubility of arbutin was significantly higher than that of salicin and 4-methoxyphenylβ-D-glucoside.The Caco-2 cell transport experiments showed that the apparent permeability of these three compounds was different,and the transport capacity of salicin was lower than that of arbutin and 4-methoxyphenyl-β-D-glucoside.The in situ intestinal perfusion experiments in rats showed that the absorption of these three compounds in duodenum,jejunum and ileum was better than that in colon.The q-PCR experiments showed that the expression level of SGLT 1 in duodenum,jejunum and ileum was significantly higher than that in colon.When phlorizin present,the effective permeability coefficients of intestinal segments were decreased.The inhibitory effect of phlorizin on arbutin was stronger than that of salicin and 4-methoxyphenyl-β-Dglucoside.The in vivo pharmacokinetic experiments in rats showed that the bioavailability of salicin was lower than that of arbutin and 4-methoxyphenyl-β-Dglucoside;glucose could competitively inhibit the absorption of these compounds,and the inhibition effect was increased with the increase of glucose dose.However,the molecular docking experiments showed that the binding ability of salicin to vSGLT was stronger than that of arbutin and 4-methoxyphenyl-β-D-glucoside.In conclusion,the results showed that salicin,arbutin and 4-methoxyphenyl-β-Dglucoside are water-soluble compounds.The glucose transporter SGLT 1 play a role in the intestinal absorption of these three compounds.These three compounds are well absorbed in the small intestine and poorly absorbed in the colon.The glucose could competitively inhibit the absorption of compounds.The oral absorption of salicin was lower than that of arbutin and 4-methoxyphenyl-β-D-glucoside.The slight difference of chemical structure,especially in substitution positions,has great influence on the oral absorption of compound via glucose transport pathway.The para-position is better than ortho-position.There are significant differences between computer-aided drug design and traditional drug absorption models when evaluating absorptive capacity of these compounds via glucose transport pathway.It is hard to replace traditional biopharmaceutical research methods at present.