Cytochrome P450 2B6 and UDP-Glucuronosyltransferase Enzyme-Mediated Clearance of Ciprofol (HSK3486) in Humans: The Role of Hepatic and Extrahepatic MetabolismS
文献类型：期刊论文
| 作者 | Zhou, Yufan5,6; Dong, Hongjiao4; Fan, Jiang4; Zhu, Mingshe3,4; Liu, Lu6; Wang, Yongbin6; Tang, Pingming1,4; Chen, Xiaoyan2,5,6
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2024-02-01 |
| 卷号 | 52期号:2页码:106-117 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.123.001484 |
| 通讯作者 | Tang, Pingming(tangpm@haisco.com) ; Chen, Xiaoyan(xychen@simm.ac.cn) |
| 英文摘要 | Ciprofol (HSK3486) is a novel intravenous agent for general anesthesia. In humans, HSK3486 mainly undergoes glucuronidation to form M4 [fraction of clearance (fCL): 62.6%], followed by the formation of monohydroxylated metabolites that further undergo glucuronidation and sulfation to produce M5-1, M5-2, M5-3, and M3 (summed fCL: 35.2%). However, the complete metabolic pathways of HSK3486 in humans remain unclear. In this study, by comparison with chemically synthesized reference standards, three monohydroxylated metabolites [M7-1, 4 -hydroxylation with an unbound intrinsic clearance (CLint,u) of 2211 pl/min/mg; M7-2, a) -hydroxylation with a CLint,u of 600 pl/min/mg; and M7-3, (a) -1) -hydroxylation with a CLint,u of 78.4 pl/min/mg] were identified in human liver microsomes, and CYP2B6 primarily catalyzed their formation. In humans, M7-1 was shown to undergo glucuronidation at the 4 -position and 1 -position by multiple UDP-glucuronosyltransferases (UGTs) to produce M5-1 and M5-3, respectively, or was metabolized to M3 by cytosolic sulfotransferases. M7-2 was glucuronidated at the a) position by UGT1A9, 2B4, and 2B7 to form M5-2. UGT1A9 predominantly catalyzed the glucuronidation of HSK3486 (M4). The CLint,u values for M4 formation in human liver and kidney microsomes were 1028 and 3407 pl/min/mg, respectively. In vitro to in vivo extrapolation analysis suggested that renal glucuronidation contributed approximately 31.4% of the combined clearance. In addition to HSK3486 glucuronidation (M4), 4 -hydroxylation (M7-1) was identified as another crucial oxidative metabolic pathway (fCL: 34.5%). Further attention should be paid to the impact of CYP2B6and UGT1A9-mediated drug interactions and gene polymorphisms on the exposure and efficacy of HSK3486. SIGNIFICANCE STATEMENT This research elucidates the major oxidative metabolic pathways of HSK3486 (the formation of three monohydroxylated metabolites: M7-1, M7-2, M7-3) as well as definitive structures and formation pathways of these monohydroxylated metabolites and their glucuronides or sulfate in humans. This research also identifies major metabolizing enzymes responsible for the glucuronidation (UGT1A9) and oxidation (CYP2B6) of HSK3486 and characterizes the mechanism of extrahepatic metabolism. The above information is helpful in guiding the safe use of HSK3486 in the clinic. |
| WOS关键词 | IN-VIVO EXTRAPOLATION ; UNSATURATED FATTY-ACIDS ; MOLECULAR-MECHANISMS ; ALBUMIN ; KIDNEY ; UGT ; QUANTIFICATION ; BINDING ; PROTEIN ; UTILITY |
| 资助项目 | National Natural Science Foundation of China[82073924] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001171839400008 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/311004]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Tang, Pingming; Chen, Xiaoyan |
| 作者单位 | 1.Haisco Pharmaceut Grp Co Ltd, 136 Baili Rd, Chengdu 611130, Sichuan, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China 3.MassDefect Technol, Princeton, NJ USA 4.Haisco Pharmaceut Grp Co Ltd, Chengdu, Sichuan, Peoples R China 5.Univ Chinese Acad Sci, Beijing, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Yufan,Dong, Hongjiao,Fan, Jiang,et al. Cytochrome P450 2B6 and UDP-Glucuronosyltransferase Enzyme-Mediated Clearance of Ciprofol (HSK3486) in Humans: The Role of Hepatic and Extrahepatic MetabolismS[J]. DRUG METABOLISM AND DISPOSITION,2024,52(2):106-117. |
| APA | Zhou, Yufan.,Dong, Hongjiao.,Fan, Jiang.,Zhu, Mingshe.,Liu, Lu.,...&Chen, Xiaoyan.(2024).Cytochrome P450 2B6 and UDP-Glucuronosyltransferase Enzyme-Mediated Clearance of Ciprofol (HSK3486) in Humans: The Role of Hepatic and Extrahepatic MetabolismS.DRUG METABOLISM AND DISPOSITION,52(2),106-117. |
| MLA | Zhou, Yufan,et al."Cytochrome P450 2B6 and UDP-Glucuronosyltransferase Enzyme-Mediated Clearance of Ciprofol (HSK3486) in Humans: The Role of Hepatic and Extrahepatic MetabolismS".DRUG METABOLISM AND DISPOSITION 52.2(2024):106-117. |
入库方式： OAI收割
来源：上海药物研究所
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