Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors

doi:10.1124/dmd.118.086090

	Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors
	Tang, Chongzhuang 1,2; Chen, Zhaoqiang 1,2; Dai, Xiaojian 1,2; Zhu, Weiliang 1; Zhong, Dafang 1,2; Chen, Xiaoyan 1,2
刊名	DRUG METABOLISM AND DISPOSITION
	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.
资助项目	National Natural Science Foundation of China[81573500] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA 12050306]
WOS关键词	PERFORMANCE LIQUID-CHROMATOGRAPHY ; RABEPRAZOLE ; PHARMACOKINETICS ; PLASMA ; LIVER ; DRUG ; CYTOCHROME-P450 ; LANSOPRAZOLE ; GLUTATHIONE ; HYDROLYSIS
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000469878500004
内容类型	期刊论文
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.