Cao Feng, Guo Jian-Xin, Ping Qi-Neng, Liao Zheng-Gen
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Eur J Pharm Sci. 2006 Dec;29(5):385-93. doi: 10.1016/j.ejps.2006.07.007. Epub 2006 Aug 7.
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) approximately 7 min) with a high stability in aqueous solution (t(1/2) approximately 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.
为提高灯盏花素的口服生物利用度，合成了灯盏花素的乙酯、苄酯和N，N -二乙基甘醇酰胺酯。前体药物在水溶液中的水解遵循一级动力学，并呈现V形pH曲线。N，N -二乙基甘醇酰胺酯在人血浆中极易被酶水解（半衰期约7分钟），而在水溶液中具有较高的稳定性（半衰期约16天，pH 4.2）。与灯盏花素的溶解度相比，甘醇酰胺酯在pH 4.0缓冲液中的溶解度约为其10倍，在水中约为35倍。其表观分配系数从-2.56显著增加到1.48。选择灯盏花素的甘醇酰胺酯来研究肠道代谢和体内生物利用度。在肠道内容物和匀浆中的降解研究表明，吸收前的肠道代谢是前体药物的一个关键障碍。N，N -二乙基甘醇酰胺酯可通过乳剂保护其在肠腔内不被降解。与灯盏花素-环糊精复合物相比，在大鼠中观察到前体药物乳剂的血浆AUC和C(max)显著增加（P<0.01）。与灯盏花素-环糊精复合物相比，N，N -二乙基甘醇酰胺酯乳剂的表观生物利用度提高了1.58倍，绝对生物利用度提高了1.4倍。
