Résumé
In this report, highly water soluble esters of scutellarin with different molecular weight polyethylene glycol (PEG) were synthesized in order to improve the bioavailability of scutellarin. The physicochemical properties, the stabilities under different conditions and the in situ intestinal absorption in rats of the conjugates were investigated. By PEG modification, the greatly increased water solubility and desirable partition coefficient of scutellarin were obtained. These compounds function as prodrugs i. e. breakdown occurred in a predictable fashion: the t1/2 of them in PBS buffer at pH7.4 was above 12 h (37 degrees C) in vitro, while in plasma a rapid breakdown was observed, with a t1/2 of about 1. 5-3 h. The stabilities of the prodrugs were improved according to the increase of the molecular weight of PEG, thus, PEGylated prodrugs with desirable rates of hydrolysis could be obtained by the use of variable molecular weight PEGs. The PEGylation could enhance the absorption of scutellarin in rat intestine, and the absorption of scutellarin and its PEG conjugates by intestine was mainly via passive transport, for when the concentration was raised, the uptake did not appear saturable, and the permeability coefficient kept at an equilibrium level. When the molecular weight of PEG increased from 200 to 1000 Da, the absorption of the conjugates decreased. In conclusion, by overall consideration of the yield, stability and absorption, the present authors estimate that the PEG molecular weight used for the PEGylation of scutellarin should be within the range of 400-1 000 Da.