Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors
文献类型：期刊论文
| 作者 | Tang, Chongzhuang1,2; Chen, Zhaoqiang1,2; Dai, Xiaojian1,2 ; Zhu, Weiliang1; Zhong, Dafang1,2; Chen, Xiaoyan1,2
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| 刊名 | DRUG METABOLISM AND DISPOSITION
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| 出版日期 | 2019-06-01 |
| 卷号 | 47期号:6页码:657-664 |
| ISSN号 | 0090-9556 |
| DOI | 10.1124/dmd.118.086090 |
| 通讯作者 | Chen, Xiaoyan(xychen@simm.ac.cn) |
| 英文摘要 | Racemic proton pump inhibitors (PPIs) have been developed into pure enantiomers given superior pharmacokinetic profiles. However, after doses of single enantiomer PPIs, different degrees of chiral inversion were observed. We investigated the relationship between chiral inversion and reductive metabolism of PPIs, as well as the mechanismof reductive metabolism. In liver microsomes and Sprague-Dawley rats, PPI thioethers were stereoselectively oxidized to (R)- and (S)-PPIs, indicating that thioethers could be the intermediates of chiral inversion. By comparing the area under the plasma concentration-time curve ratios of thioether to rabeprazole under different routes of administration and blood sampling site, it was determined that thioether was mainly formed in the liver rather than the intestine. The formation rate of PPI thioethers in liver subcellular fractions was significantly higher than that in buffers. Sulfhydryl-blocking agents, such as N-ethylmaleimide, menadione, and ethacrynic acid, inhibited the reductive metabolism of PPIs in vitro, and their corresponding glutathione conjugates were observed. Similar amounts of thioethers were formed in glutathione solutions as in liver subcellular fractions, indicating that biologic reducing agents, instead of reductases, accelerated the reductive metabolism of PPIs. The reduction rates in glutathione solutions were ordered as follows: rabeprazole > omeprazole > lansoprazole > pantoprazole, which was consistent with the natural bond orbital charges of sulfur atoms in these compounds. In conclusion, PPIs were transformed into thioethers by biologic reducing agents in liver, and thioethers continued to be oxidized to two enantiomers, leading to chiral inversion. Furthermore, inhibiting oxidative metabolism of PPIs enhanced reductive metabolism and chiral inversion. |
| WOS关键词 | PERFORMANCE LIQUID-CHROMATOGRAPHY ; RABEPRAZOLE ; PHARMACOKINETICS ; PLASMA ; LIVER ; DRUG ; CYTOCHROME-P450 ; LANSOPRAZOLE ; GLUTATHIONE ; HYDROLYSIS |
| 资助项目 | National Natural Science Foundation of China[81573500] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12050306] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000469878500004 |
| 出版者 | AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/289630]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Chen, Xiaoyan |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, 501 Haike Rd, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tang, Chongzhuang,Chen, Zhaoqiang,Dai, Xiaojian,et al. Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors[J]. DRUG METABOLISM AND DISPOSITION,2019,47(6):657-664. |
| APA | Tang, Chongzhuang,Chen, Zhaoqiang,Dai, Xiaojian,Zhu, Weiliang,Zhong, Dafang,&Chen, Xiaoyan.(2019).Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors.DRUG METABOLISM AND DISPOSITION,47(6),657-664. |
| MLA | Tang, Chongzhuang,et al."Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors".DRUG METABOLISM AND DISPOSITION 47.6(2019):657-664. |
入库方式： OAI收割
来源：上海药物研究所
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