Mechanistic Studies on the Absorption and Disposition of Scutellarin in Humans: Selective OATP2B1-Mediated Hepatic Uptake Is a Likely Key Determinant for Its Unique Pharmacokinetic Characteristics
文献类型：期刊论文
| 作者 | Gao, Chunying2; Zhang, Hongjian1; Guo, Zitao2; You, Tiangeng3; Chen, Xiaoyan2 ; Zhong, Dafang2
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2012-10 |
| 卷号 | 40期号:10页码:2009-2020 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.112.047183 |
| 文献子类 | Article |
| 英文摘要 | Scutellarin [scutellarein-7-O-glucuronide (S-7-G)] displayed a unique pharmacokinetic profile in humans after oral administration: the original compound was hardly detected, whereas its isomeric metabolite isoscutellarin [scutellarein-6-O-glucuronide (S-6-G)] had a markedly high exposure. Previous rat study revealed that S-7-G and S-6-G in the blood mainly originated from their aglycone in enterocytes, and that the S-7-G/S-6-G ratio declined dramatically because of a higher hepatic elimination of S-7-G. In the present study, metabolite profiling in human excreta demonstrated that the major metabolic pathway for S-6-G and S-7-G was through further glucuronidation. To further understand the cause for the exposure difference between S-7-G and S-6-G in humans, studies were conducted to uncover mechanisms underlying their formation and elimination. In vitro metabolism study suggested that S-7-G was formed more easily but metabolized more slowly in human intestinal and hepatic microsomes. Efflux transporter study showed that S-6-G and S-7-G were good substrates of breast cancer resistance protein and multidrug resistance-associated protein (MRP) 2 and possible substrates of MRP3; however, there was no preference great enough to alter the S-7-G/S-6-G ratio in the blood. Among the major hepatic anion uptake transporters, organic anion-transporting polypeptide (OATP) 2B1 played a predominant role in the hepatic uptake of S-6-G and S-7-G and showed greater preference for S-7-G with higher affinity than S-6-G (Km values were 1.77 and 43.9 mu M, respectively). Considering the low intrinsic permeability of S-6-G and S-7-G and the role of OATP2B1 in the hepatic clearance of such compounds, the selective hepatic uptake of S-7-G mediated by OATP2B1 is likely a key determinant for the much lower systemic exposure of S-7-G than S-6-G in humans. |
| WOS关键词 | INTESTINAL-ABSORPTION ; TRANSPORTERS ; FLAVONOIDS ; METABOLISM ; BAICALEIN ; EFFLUX ; GENE ; RATS |
| 资助项目 | National Natural Science Foundation of China[30271525] ; National Natural Science Foundation of China[81173117] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000309001400017 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277925]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Zhong, Dafang |
| 作者单位 | 1.Soochow Univ, Coll Pharmaceut Sci, Suzhou, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Shanghai E Hosp, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Gao, Chunying,Zhang, Hongjian,Guo, Zitao,et al. Mechanistic Studies on the Absorption and Disposition of Scutellarin in Humans: Selective OATP2B1-Mediated Hepatic Uptake Is a Likely Key Determinant for Its Unique Pharmacokinetic Characteristics[J]. DRUG METABOLISM AND DISPOSITION,2012,40(10):2009-2020. |
| APA | Gao, Chunying,Zhang, Hongjian,Guo, Zitao,You, Tiangeng,Chen, Xiaoyan,&Zhong, Dafang.(2012).Mechanistic Studies on the Absorption and Disposition of Scutellarin in Humans: Selective OATP2B1-Mediated Hepatic Uptake Is a Likely Key Determinant for Its Unique Pharmacokinetic Characteristics.DRUG METABOLISM AND DISPOSITION,40(10),2009-2020. |
| MLA | Gao, Chunying,et al."Mechanistic Studies on the Absorption and Disposition of Scutellarin in Humans: Selective OATP2B1-Mediated Hepatic Uptake Is a Likely Key Determinant for Its Unique Pharmacokinetic Characteristics".DRUG METABOLISM AND DISPOSITION 40.10(2012):2009-2020. |
入库方式： OAI收割
来源：上海药物研究所
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