Comparative study on the intestinal absorption of three gastrodin analogues via the glucose transport pathway.

Gastrodin is the main active constituent of Tianma, a famous traditional Chinese herbal medicine. Our previous research has found that gastrodin is absorbed rapidly in the intestine by the sodium-dependent glucose transporter 1 (SGLT1). In the current report, gastrodin is the best glycoside compound absorbed via the glucose transport pathway. This study aimed to investigate the effect of the slight difference in chemical structure on the drug intestinal absorption via the glucose transport pathway. Traditional biopharmaceutical and computer-aided molecular docking methods were used to evaluate the intestinal absorption characteristics of three gastrodin analogues, namely, salicin, arbutin and 4-methoxyphenyl-ß-D-glucoside (4-MG). The oil-water partition coefficient (logP) experiments showed that the logP values of the gastrodin analogues followed the order: 4-MG > salicin > arbutin. In vitro Caco-2 cell transport experiments demonstrated that the apparent permeability coefficient (Papp) value of arbutin was higher than those of salicin and 4-MG. In situ single-pass intestinal perfusion experiments showed that the absorption of arbutin and 4-MG was better than that of salicin and that the absorption of the three compounds in the colon was lower than that in the small intestine. Quantitative real-time polymerase chain reaction results confirmed that the SGLT1 mRNA expression in the small intestine of rats was obviously higher than that in the colon of rats. In vivo pharmacokinetic experiments demonstrated that the oral bioavailability of salicin was lower than those of arbutin and 4-MG. In vitro and in vivo experiments showed that glucose or phlorizin (SGLT1 inhibitor) could decrease the intestinal absorption of the three compounds. Contrary to the above biopharmaceutical experiments, the computer-aided molecular docking test showed that the affinity of salicin to the vSGLT receptor was stronger than those of arbutin and 4-MG. In conclusion, the SGLT1 can facilitate the intestinal absorption of salicin, arbutin and 4-MG, and the slight difference in chemical structure can affect absorption.

Improved in vitro and in vivo properties of telmisartan in the co-amorphous system with hydrochlorothiazide: A potential drug-drug interaction mechanism prediction.

The aim of this study is to improve in vitro and in vivo properties of an antihypertensive poorly soluble drug Telmisartan (TEL) by co-amorphization with a pharmacologically relevant drug Hydrochlorothiazide (HCT), and to improve the stability of single amorphous drugs. Herein, TEL-HCT co-amorphous systems (CAMs) (1:1, 2:3, 1:2, 1:3) were prepared by solvent evaporation. The apparent solubility and the dissolution of TEL in the TEL-HCT CAM (1:3) were increased by 79 times and 10 times compared to crystalline TEL, which showed the optimal properties. Cmax and AUC0-48h value of TEL-HCT CAM (1:3) were 10-fold and 3-fold as the crystalline state. Moreover, TEL-HCT CAM (1:3) remained stable in 60 °C, 0 % RH (30 days), 40 °C, 75 % RH (90 days) and 25 °C, 0 % RH (180 days). Positive ΔTgs were observed in all CAMs, suggesting the existence of potential intermolecular force. Fourier Transform-Infrared and Raman spectra were used to further prove the drug-drug interaction and predict potential mechanisms. Therefore, in the strategy of combined medication, CAM provides a promising way to transfer drugs with poor properties into systems with enhanced dissolution, greater bioavailability, and stabilized amorphous state, which has been proven in this study.