Metabolic profiling of praziquantel enantiomers

Wang, Haina; Fang, Zhong-Ze; Zheng, Yang; Zhou, Kun; Hu, Changyan; Krausz, Kristopher W.; Sun, Dequn; Idle, Jeffrey; Gonzalez, Frank J. (2014). Metabolic profiling of praziquantel enantiomers. Biochemical pharmacology, 90(2), pp. 166-178. Elsevier 10.1016/j.bcp.2014.05.001

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Hepatologie

UniBE Contributor:

Idle, Jeffrey

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0006-2952

Publisher:

Elsevier

Language:

English

Submitter:

Lilian Karin Smith-Wirth

Date Deposited:

16 Apr 2015 12:54

Last Modified:

06 Nov 2015 09:40

Publisher DOI:

10.1016/j.bcp.2014.05.001

PubMed ID:

24821110

Uncontrolled Keywords:

Cytochromes P450; Enantioselective metabolism; In silico metabolomics; Praziquantel

BORIS DOI:

10.7892/boris.66932

URI:

https://boris.unibe.ch/id/eprint/66932

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