肠道中胆酸盐及脂类对难溶性药物蒿甲醚的增溶作用

Effect of Bile Salts and Lipids in Intestine on Solubility of Artemether as a Poorly Water-soluble Drug

目的:考察肠道中胆酸盐及脂类对难溶性药物蒿甲醚溶解度的影响。方法:测定蒿甲醚在不同p H磷酸盐缓冲液、胆酸盐溶液及胆酸盐/脂类混合胶束溶液中的平衡溶解度。考察的肠道中胆酸盐包括牛磺胆酸盐(TC),牛磺脱氧胆酸盐(TDC),牛磺鹅脱氧胆酸盐(TCDC),甘氨胆酸盐(GC),甘氨脱氧胆酸盐(GDC)和甘氨鹅脱氧胆酸盐(GCDC)。外源性脂肪的水解产物脂肪酸和单甘油酸酯用于评价食物中脂肪对蒿甲醚的增溶作用。结果:p H对蒿甲醚溶解度的影响不大,其在磷酸盐缓冲液(p H 2~12)中的溶解度96.0~109.6 mg·L^(-1)。混合胆酸盐能明显增溶蒿甲醚,当胆酸盐达到生理浓度(15 mmol·L^(-1))时,蒿甲醚的溶解度增加了近4倍。各单一胆酸盐对蒿甲醚的增溶作用不尽相同,其中TC和GC的增溶作用较小,而TDC,TCDC,GDC与GCDC增溶作用均较强。加入外源性脂类(脂肪酸和单甘油酸酯)能进一步增加蒿甲醚的溶解度。结论:蒿甲醚在进食状态下的溶解度更高。肠道中的胆酸盐与外源性脂类均能显著增加蒿甲醚的溶解度,促进其在肠道的吸收。

Objective： To investigate the effects of bile salts and lipids in the intestine on the solubility of artemether,a poorly water-soluble drug. Method： Equilibrium solubility of artemether in phosphate buffers with different p H,bile salts and bile salts/lipids mixed micelle solution were determined,bile salts in the intestine included taurocholate（ TC）,taurodeoxycholate（ TDC）,taurochenodeoxycholate（ TCDC）,glycocholate（ GC）,glycodeoxycholate（ GDC） and glycochenodeoxycholate（ GCDC）. Fatty acids and monoglycerides, the main hydrolytic products of the exogenous fat,were used to evaluate effect of fat in food on the solubility of artemether.Result： Effect of p H on the solubility of artemether was not significant. The solubility of artemether in buffer phosphate（ p H 2-12） 96. 0-109. 6 mg·L^-1. Artemether was solubilized by mixed bile salts micelles,when the physiological concentration reached 15 mmol·L^-1,the solubility of artemether increased by nearly four times.There was some difference in solubilization of various bile salts, TC and GC had slightly effect on the solubilization; however,TDC,TCDC,GDC and GCDC could significantly influence the solubility of artemether.Addition of fatty acid and monoglycerides to simulate fat in food resulted in significantly increase in solubilization.Conclusion： The solubility of artemether can be substantially increased by fat in food. Bile salts and exogenous lipids can significantly increase the solubility of artemether and promote its intestinal absorption.