title: Metabolic profiling of praziquantel enantiomers.
abstract: 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 24h 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 Km and Vmax 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.
authors.affiliation: College of Pharmaceutical Sciences, Shandong University, Jinan 250012, PR China; Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Haina
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States; Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning Medical University, Dalian 116023, China.
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.affiliation: Marine College, Shandong University at Weihai, Weihai 264209, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Joint Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences and First Affiliated Hospital of Liaoning Medical University, Dalian 116023, China; Department of Basic Chemistry, College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhou
authors.affiliation: Marine College, Shandong University at Weihai, Weihai 264209, PR China.
authors.forename: Changyan
authors.initials: C
authors.lastname: Hu
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Kristopher W
authors.initials: KW
authors.lastname: Krausz
authors.affiliation: Marine College, Shandong University at Weihai, Weihai 264209, PR China. Electronic address: dequn.sun@sdu.edu.cn.
authors.forename: Dequn
authors.initials: D
authors.lastname: Sun
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States; Department of Clinical Research, University of Bern, Bern 3010, Switzerland.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Idle
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: gonzalef@mail.nih.gov.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008297:Male; D050216:Metabolic Detoxication, Phase I; D050217:Metabolic Detoxication, Phase II; D055442:Metabolome; D051379:Mice; D062105:Molecular Docking Simulation; D011223:Praziquantel / Q000008:administration & dosage / Q000737:chemistry / Q000652:urine*; D011487:Protein Conformation; D012556:Schistosomicides / Q000008:administration & dosage / Q000737:chemistry / Q000652:urine*; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D013379:Substrate Specificity; D008565:Membrane Proteins
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D007527:Isoenzymes; D011223:Praziquantel; D012556:Schistosomicides; C105144:cytochrome P-450 CYP2D19 (marmoset); C496508:Cyp3a11 protein, mouse; D008565:Membrane Proteins
keywords: Cytochromes P450; Enantioselective metabolism; In silico metabolomics; Praziquantel