Prodrugs of scutellarin:: Ethyl, benzyl and N,N-diethylglycolamide ester synthesis, physicochemical properties, intestinal metabolism and oral bioavailability in the rats

In an effort to enhance the oral bioavailability of scutellarin, ethyl, benzyl and N,N-diethylglycolamide ester of scutellarin were synthesized. The hydrolysis of the prodrugs follows first-order kinetics in aqueous solution, and produced a V-shaped pH profile. The N,N-diethylglycolamide ester is highly susceptible to enzymatic hydrolysis in human plasma (t(1/2) approximate to 7 min) with a high stability in aqueous solution (t(1/2) approximate to 16 day, pH 4.2). Compared with the solubility of scutellarin, the solubility of glycolamide ester was about ten times in pH 4.0 buffer, and about thirty five times in water. Its apparent partition coefficient increased significantly from -2.56 to 1.48. Glycolamide ester of scutellarin was chosen to investigate the intestinal metabolism and in vivo bioavailability Degradation studies in the intestinal tract content and homogenates indicated intestinal metabolism before absorption was a crucial obstacle for the prodrug. N,N-Diethylglycolamide ester can be protected from the degradation in the intestinal lumen by an emulsion. A significant increase in the plasma AUC and C-max of the prodrug emulsion was observed in rats, compared with that of the scutellarin-cyclodextrin complex (P < 0.01). The emulsion of N,N-diethylglycolamide ester produces a 1.58-fold enhancement in apparent bioavailability and 1.4-fold increase in the absolute bioavailability compared to the scutallarin-cyclodextrin complex. (c) 2006 Published by Elsevier B.V.