目的 考察膽酸偶聯(lián)喜樹堿衍生物20（S）-O-甘氨酸-脫氧膽酸喜樹堿（E2）、20（S）-O-醋酸-脫氧膽酸喜樹堿（G2）在大鼠血漿和人工胃腸液中的穩(wěn)定性。方法 建立并優(yōu)化高效液相色譜法，測定并比較E2、G2和喜樹堿在大鼠血漿和人工胃腸液中的穩(wěn)定性。結(jié)果 在血漿和人工胃腸液中三者均有不同程度的減少，但E2、G2減少量均低于喜樹堿。相對于人工胃腸液，三者在大鼠血漿中減少最為明顯。三者在3種生物基質(zhì)中發(fā)生了相似的降解，E2、G2主要發(fā)生水解生成喜樹堿，而喜樹堿則主要發(fā)生了內(nèi)酯環(huán)開環(huán)。結(jié)論 通過偶聯(lián)膽酸合成得到的喜樹堿衍生物在生物基質(zhì)中具有明顯高于喜樹堿的穩(wěn)定性，有助于維持喜樹堿藥效團內(nèi)酯環(huán)的穩(wěn)定。

Objective To investigate the stability of the two novel camptothecin analogues conjugated with bile acid, 20(S)-O-glycine-deoxycholate camptothecin (E2) and 20(S)-O-acetate-deoxycholate camptothecin (G2), in the rat plasma, simulated gastric fluid, and simulated intestinal fluid. Methods HPLC-UV methods were optimized, and the changes of the content of the compound in biological matrix were detected. Results The contents of E2, G2 and camptothecin in the three biological matrixs were decreased with varying degrees, but decrements of E2 and G2 were lower than those of camptothecin. Compared to those in simulated gastric fluid and simulated intestinal fluid, the reductions were most obvious in rat plasma. The related chromatograms revealed a similar degradation of E2, G2, and camptothecin, through which the lactone in camptothecin were hydrolyzed, and E2 and G2 were hydrolyzed to produce camptothecin with a lactone. Conclusion The synthesis of camptothecin derivatives obtained by coupling cholic acid would significantly improve the stability of camptothecin in the biological matrixs, and remains a E-ring form of camptothecin, which keeps the antitumor activity.

國家自然科學(xué)基金資助項目（31270397）