中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Mechanistic Study on the Species Differences in Excretion Pathway of HR011303 in Humans and Rats

文献类型:期刊论文

作者Guo, Zitao3,4; Liu, Mengling2,3; Meng, Jian3; Xue, Yaru3; Huang, Qi1; Zheng, Yuandong3; Wu, Yali2,3; Chen, Zhendong3; Yu, Jinghua3; Zhong, Dafang2,3
刊名DRUG METABOLISM AND DISPOSITION
出版日期2022-06-01
卷号50期号:6页码:809-818
ISSN号0090-9556
DOI10.1124/dmd.121.000582
通讯作者Diao, Xingxing(xxdiao@simm.ac.cn)
英文摘要Excretion of [C-14]HR011303-derived radioactivity showed significant species difference. Urine (81.50% of dose) was the main excretion route in healthy male subjects, whereas feces (87.16% of dose) was the main excretion route in rats. To further elucidate the underlying cause for excretion species differences of HR011303, studies were conducted to uncover its metabolism and excretion mechanism. M5, a glucuronide metabolite of HR011303, is the main metabolite in humans and rats. Results of a rat microsome incubation study suggested that HR011303 was metabolized to M5 in the rat liver. According to previous studies, M5 is produced in both human liver and kidney microsomes. We found that M5 in the human liver can be transported to the blood by multidrug resistance-associated protein (MRP) 3, and then the majority of M5 can be hydrolyzed to HR011303. HR011303 enters the human kidney or liver through passive diffusion, whereas M5 is taken up through organic anion transporter (OAT) 3, organic anion-transporting polypeptide (OATP) 1B1, and OATP1B3. When HR011303 alone is present, it can be metabolized to M5 in both sandwich-cultured rat hepatocytes (SCRH) and sandwich-cultured human hepatocytes (SCHH) and excreted into bile as M5 in SCRH. Using transporter inhibitors in sandwich-cultured model and membrane vesicles expressing MRP2 or Mrp2, we found that M5 was a substance of MRP2/Mrp2, and the bile efflux of M5 was mainly mediated by MRP2/Mrp2. Considering the significant role of MRP3/Mrp3 and MRP2/Mrp2 in the excretion of glucuronides, the competition between them for M5 was possibly the determinant for the different excretion routes in humans and rats. SIGNIFICANCE STATEMENT Animal experiments are necessary to predict dosage and safety of candidate drugs prior to clinical trials. However, extrapolation results often differ from the actual situation. For HR011303, excretory pathways exhibited a complete reversal, through urine in humans and feces in rats. Such phenomena have been observed in several drugs, but no in-depth studies have been conducted to date. In the present study, the excretion species differences of HR011303 can be explained by the competition for M5 between MRP2/Mrp2 and MRP3/Mrp3.
WOS关键词DRUG-DRUG INTERACTION ; ORGANIC ANION ; IN-VIVO ; HEPATOBILIARY DISPOSITION ; EFFLUX TRANSPORTERS ; BILIARY CLEARANCE ; HEPATIC-UPTAKE ; METABOLISM ; PHARMACOKINETICS ; ABSORPTION
资助项目National Natural Science Foundation of China[81903701]
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号WOS:000811854900008
源URL[http://119.78.100.183/handle/2S10ELR8/301605]  
专题中国科学院上海药物研究所
通讯作者Diao, Xingxing
作者单位1.Jiangsu Hengrui Med Co Ltd, Lianyungang, Peoples R China
2.Univ Chinese Acad Sci, Beijing, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China
4.Shanghai Univ, Shanghai, Peoples R China
推荐引用方式
GB/T 7714
Guo, Zitao,Liu, Mengling,Meng, Jian,et al. Mechanistic Study on the Species Differences in Excretion Pathway of HR011303 in Humans and Rats[J]. DRUG METABOLISM AND DISPOSITION,2022,50(6):809-818.
APA Guo, Zitao.,Liu, Mengling.,Meng, Jian.,Xue, Yaru.,Huang, Qi.,...&Diao, Xingxing.(2022).Mechanistic Study on the Species Differences in Excretion Pathway of HR011303 in Humans and Rats.DRUG METABOLISM AND DISPOSITION,50(6),809-818.
MLA Guo, Zitao,et al."Mechanistic Study on the Species Differences in Excretion Pathway of HR011303 in Humans and Rats".DRUG METABOLISM AND DISPOSITION 50.6(2022):809-818.

入库方式: OAI收割

来源:上海药物研究所

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