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抗肿瘤候选药物Gedatolisib在体外血浆和人工胃/肠液中的稳定性研究及其降解产物分析
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| 篇名： | 抗肿瘤候选药物Gedatolisib在体外血浆和人工胃/肠液中的稳定性研究及其降解产物分析 |
| TITLE： | Study on the Stability of Antitumor Candidate Gedatolisib in Plasma in vitro and Simulated Gastric/intestinal Fluid and Its Catabolites Analysis |
| 摘要： | 目的：考察抗肿瘤候选药物Gedatolisib在体外血浆和人工胃/肠液中的稳定性，并分析其在体外血浆中可能的降解产物。方法：采用高效液相色谱法，以吲哚美辛为内标，分别检测Gedatolisib在SD大鼠（雄性）血浆中孵育0、0.5、1.0、1.5、2.0、3.0h和在空白人工胃液（pH1.3，不含酶）、空白人工肠液（pH6.8，不含酶）、人工胃液（pH1.3，含胃蛋白酶）、人工肠液（pH6.8，含胰蛋白酶）中孵育0、0.5、1.0、2.0、3.0、4.0、6.0h的含量变化，计算其剩余百分比；利用超高效液相色谱-四极杆-飞行时间质谱（UPLC-Q-TOF/MS）技术分析空白血浆和血浆孵育样品的总离子流图，比较差异峰并通过MS图推测降解产物。结果：Gedatolisib在大鼠血浆中孵育2.0h时的剩余百分比约为63％，继续孵育无明显变化；在空白人工肠液中孵育不同时间的剩余百分比均在（99.18±2.15）％～（103.20±3.41）％范围内；在人工肠液中孵育2.0h的剩余百分比降至（88.76±1.53）％，在空白人工胃液中孵育2.0h的剩余百分比降至（85.63±1.55）％，继续孵育均无明显变化；在人工胃液中孵育的剩余百分比从0h的（94.94±3.52）％降至6.0h的（16.19±1.17）％。UPLC-Q-TOF/MS的总离子流图显示，血浆孵育样品与空白血浆的差异峰出现在正离子模式扫描下的6.42min处，该峰扫描通道可见m/z616.3351、632.3277、630.3170、602.2786[M+H]+的分子离子峰，推测Gedatolisib在大鼠血浆中可能生成1-（4-（3-（4，6-双吗啉-1，3，5-三嗪-2-基）苯基）脲基）苯甲酰基）-N，N-二甲基哌啶-4-氧化胺、1-（4-（4-（二甲基氨基）哌啶-1-羰基）苯基）-3-（4-（4-吗啉-6-（3-氧代吗啉）-1，3，5-三嗪-2-基）苯基）脲和1-（4-（3-（4-（4，6-双吗啉-1，3，5-三嗪-2-基）苯基）脲基）苯甲酰基）-N-甲基哌啶等3个降解产物。结论：Gedatolisib在大鼠血浆中不稳定，可能发生末端氮原子氧化、吗啉环氧化和末端氮脱甲基化等反应；在人工肠液和空白人工胃/肠液中稳定性良好，在胃蛋白酶存在下发生明显降解。 |
| ABSTRACT： | OBJECTIVE：To investigate th e stabilities of antitumor candid ate Gedatolisib in plasma in vitro and simulated gastric/intestinal fluids ，and to analyze the possible catabolites in plasma. METHODS ：HPLC method was adopted. Using indometacin as internal standard ，the contents of Gedatolisib incubated in plasma of SD rats （male）for 0，0.5，1.0，1.5，2.0，3.0 h and blank simulated gastric fluid （pH 1.3，no enzyme ），blank simulated intestinal fluid （pH 6.8，no enzyme ），simulated gastric fluid（pH 1.3，containing pepsin ）and simulated intestinal fluid （pH 6.8，containing trypsin ）for 0，0.5，1.0，2.0，3.0，4.0，6.0 h were determined. The remaining percentage of Gedatolisib was calculated. UPLC-Q-TOF/MS was used to analyze the TIC of blank plasma and incubated samples. The differential peaks were compared， and catabolites were inferred by MS 1Z073）.gzwjkj2019-1- chromatograms. RESULTS ： The remaining percentage in plasma of rats for 2.0 h was about 63％，and there was nosignificant change after continued incubation. The remaining percentage of Gedatolisib incubated in blank simulated intestinal fluid for different time ranged （99.18 ± 2.15）％ -（103.20 ± 3.41）％ . The remaining percentage in simulated com intestinal fluids for 2.0 h ranged （88.76 ± 1.53）％ . The remaining percentage in blank simulated gastric fluids for 2.0 h was ranged （85.63±1.55）％，and there was no significant change after continued incubation. The remaining percentage in simulated gastric fluid was from （94.94±3.52）％（0 h）to（16.19±1.17）％ （6.0 h）. TIC of UPLC-Q-TOF/MS showed that the differential peaks of incubated samples and blank plasma was 6.42 min under positive mode scanning ，molecular ion peak of m/z 616.335 1，simulated 632.327 7，630.317 0，602.278 6 [M+H]+ could be found in scanning channel. It was speculated that Gedatolisib could generate 1-（4-（3-（4，6-dimorpholino-1，3，5-triazin-2-yl）phenyl）urea） benzoyl）-N，N-dimethylpiperidin-4-amine oxide ，1-（4-（4-（dimethylamino）piperidine-1-carbonyl）phenyl）-3-（4-（4-morpholino-6- （3-oxomorpholino）-1，3，5-triazin-2-yl）phenyl）urea and 1-（4-（3-（4-（4，6-dimorpholino-1，3，5-triazin-2-yl）phenyl）urea） benzoyl）-N-methylpiperidine. CONCLUSIONS ：Gedatolisib is not stable in rat plasma ，and it may undergo terminal N oxidation， morpholine ring oxidation and terminal N demethylation. Gedatolisib is stable in artificial intestinal fluid and blank artificial gastric/ intestinal fluid ，and degrades obviously in the presence of pepsin. |
| 期刊： | 2020年第31卷第12期 |
| 作者： | 武婷婷，张宇，杜瑶，陈瑞，王丽丽，彭鸿曼，汤磊，王颖，张吉泉 |
| AUTHORS： | WU Tingting， ZHANG Yu，DU Yao，CHEN Rui，WANG Lili，PENG Hongman，TANG Lei，WANG Ying，ZHANG Jiquan |
| 关键字： | 抗肿瘤候选药物；Gedatolisib；体外血浆；人工胃液；人工肠液；稳定性；降解产物 |
| KEYWORDS： | Antitumor candidate ；Gedatolisib；Plasma；Simulated gastric fluid ；Simulated intestinal fluid ；Stability；Catabolite |
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