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题名: Metabolic profiling of praziquantel enantiomers
作者: Wang, Haina1, 2;  Fang, Zhong-Ze2, 3, 4;  Zheng, Yang5;  Zhou, Kun3, 4, 6;  Hu, Changyan5;  Krausz, Kristopher W.2;  Sun, Dequn5;  Idle, Jeffrey R.2, 7;  Gonzalez, Frank J.2
关键词: Cytochromes P450 ;  Enantioselective metabolism ;  In silica metabolomics ;  Praziquantel
刊名: BIOCHEMICAL PHARMACOLOGY
发表日期: 2014-07-15
DOI: 10.1016/j.bcp.2014.05.001
卷: 90, 期:2, 页:166-178
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
英文摘要: Praziquantel (PZQ), prescribed as a racemic mixture, is the most readily available drug to treat schistosomiasis. In the present study, ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) based metabolomics was employed to decipher the metabolic pathways and enantioselective metabolic differences of PZQ. Many phase I and four new phase II metabolites were found in urine and feces samples of mice 24 h after dosing, indicating that the major metabolic reactions encompassed oxidation, dehydrogenation, and glucuronidation. Differences in the formation of all these metabolites were observed between (R)-PZQ and (S)-PZQ In an in vitro phase I incubation system, the major involvement of CYP3A, CYP2C9, and CYP2C19 in the metabolism of PZQ and CYP3A, CYP2C9, and CYP2C19 exhibited different catalytic activity toward the PZQ enantiomers. Apparent K-m and V-max differences were observed in the catalytic formation of three mono-oxidized metabolites by CYP2C9 and CYP3A4 further supporting the metabolic differences for PZQ enantiomers. Molecular docking showed that chirality resulted in differences in substrate location and conformation, which likely accounts for the metabolic differences. In conclusion, in silico, in vitro, and in vivo methods revealed the enantioselective metabolic profile of praziquantel. Published by Elsevier Inc.
关键词[WOS]: SCHISTOSOMA-MANSONI ;  HEALTHY-VOLUNTEERS ;  ACYL GLUCURONIDE ;  DRUG-RESISTANCE ;  EFFICACY ;  STEREOSELECTIVITY ;  PHARMACOKINETICS ;  FLURBIPROFEN ;  DISPOSITION ;  INHIBITION
语种: 英语
WOS记录号: WOS:000337781700008
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/145885
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Shandong Univ, Coll Pharmaceut Sci, Jinan 250012, Peoples R China
2.NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
3.Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China
4.Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China
5.Shandong Univ Weihai, Marine Coll, Weihai 264209, Peoples R China
6.Liaoning Univ Tradit Chinese Med, Coll Pharm, Dept Basic Chem, Dalian 116600, Peoples R China
7.Univ Bern, Dept Clin Res, CH-3010 Bern, Switzerland

Recommended Citation:
Wang, Haina,Fang, Zhong-Ze,Zheng, Yang,et al. Metabolic profiling of praziquantel enantiomers[J]. BIOCHEMICAL PHARMACOLOGY,2014,90(2):166-178.
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