Study on the Stability of Antitumor Candidate Gedatolisib in Plasma in vitro and Simulated Gastric/intestinal Fluid and Its Catabolites Analysis
- VernacularTitle: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
- Author:
Tingting WU
1
;
Yu ZHANG
1
;
Yao DU
1
;
Rui CHEN
2
;
Lili WANG
3
;
Hongman PENG
4
;
Lei TANG
2
;
Ying WANG
1
;
Jiquan ZHANG
1
Author Information
1. College of Pharmacy，Guizhou Medical University，Guiyang 550025，China
2. Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D，Guizhou Medical University，Guiyang 550025，China
3. School of Medicine and Health Management，Guizhou Medical University，Guiyang 550025，China
4. Dept. of Clinical Teaching，Guiyang Maternal and Child Health Hospital，Guiyang 550003，China
- Publication Type:Journal Article
- Keywords:
Antitumor candidate;
Gedatolisib;
Plasma;
Simulated gastric fluid;
Simulated intestinal fluid;
Stability;
Catabolite
- From:
China Pharmacy
2020;31(12):1452-1445
- CountryChina
- Language:Chinese
-
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.
