Zhou Yuqin, Hu Weitong, Zhang Xiangli, Wang Yi, Zhuang Wenya, Li Fengzhi, Li Qingyong
College of Pharmaceutical Science & Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Key Laboratory of Marine Fishery Resources Exploitment & Utilization of Zhejiang Province, Zhejiang University of Technology.
Faculty of Life Sciences and Medicine, King's College London.
Chem Pharm Bull (Tokyo). 2021;69(11):1054-1060. doi: 10.1248/cpb.c21-00467.
In the evaluation of the druggability of candidate compounds, it was vital to predict the oral bioavailability of compounds from apparent permeability (Papp) across Caco-2 cell-culture model of intestinal epithelium cultured on commercial transwell plate inserts. The study was to investigate the transport characteristics and permeability of FL118 (10, 11-Methylenedioxy-20(S)-camptothecin) derivatives 7-Q6 (7-(4-Ethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin) and 7-Q20 (7-(4-Trifluoromethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin). Transport characteristics and permeability of the tested compounds to the small intestine were assessed at different concentrations (0.5, 1 µM) via Caco-2 cell monolayers model in vitro. Uptake studies based on Caco-2 cells, including temperatures, concentrations, and the influence of efflux transporters, were combined to confirm the transport characteristics of the tested compounds. Furthermore, cytotoxicity results showed that the concentrations used in the experiments were non-toxic and harmless to cells. In addition, The Papp of 7-Q6 was (3.69 ± 1.07) × 10 cm/s with efflux ratio (ER) 0.98, while the Papp of 7-Q20 was (7.78 ± 0.89) × 10 cm/s with ER 1.05 for apical-to-basolateral (AP→BL) at 0.5 µM, suggesting that 7-Q20 might possess higher oral bioavailability in vivo. Furthermore, P-glycoprotein (P-gp) was proved to slightly affect the accumulations of 7-Q20, while the absorption of 7-Q6 was irrelevant with P-gp and breast cancer resistant protein (BCRP) based on the cellular uptake assays. Accordingly, 7-Q6 was completely absorbed by passive diffusion, and 7-Q20 was mainly dependent on passive diffusion with being effluxed by P-gp slightly. Meanwhile, both 7-Q6 and 7-Q20 were potential antitumor drugs that might exhibit high oral bioavailability in the body.
在评估候选化合物的成药可能性时，通过在商业转孔板插入物上培养的Caco-2肠上皮细胞培养模型，根据表观渗透率（Papp）预测化合物的口服生物利用度至关重要。本研究旨在考察FL118（10,11-亚甲二氧基-20(S)-喜树碱）衍生物7-Q6（7-(4-乙基苯基)-10,11-亚甲二氧基-20(S)-喜树碱）和7-Q20（7-(4-三氟甲基苯基)-10,11-亚甲二氧基-20(S)-喜树碱）的转运特性和渗透率。通过体外Caco-2细胞单层模型，在不同浓度（0.5、1µM）下评估受试化合物对小肠的转运特性和渗透率。结合基于Caco-2细胞的摄取研究，包括温度、浓度以及外排转运体的影响，以确认受试化合物的转运特性。此外，细胞毒性结果表明实验中所用浓度对细胞无毒无害。另外，在0.5µM时，7-Q6从顶端到基底外侧（AP→BL）的Papp为(3.69±1.07)×10 cm/s，外排率（ER）为0.98，而7-Q20的Papp为(7.78±0.89)×10 cm/s，ER为1.05，这表明7-Q20在体内可能具有更高的口服生物利用度。此外，基于细胞摄取试验证明P-糖蛋白（P-gp）对7-Q20的蓄积有轻微影响，而7-Q6的吸收与P-gp和乳腺癌耐药蛋白（BCRP）无关。因此，7-Q6通过被动扩散完全吸收，7-Q20主要依赖被动扩散，同时有轻微的P-gp外排。同时，7-Q6和7-Q20都是潜在的抗肿瘤药物，在体内可能表现出较高的口服生物利用度。
