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Metabolic profiling of praziquantel enantiomers.

Biochemical pharmacology (2014-05-14)
Haina Wang, Zhong-Ze Fang, Yang Zheng, Kun Zhou, Changyan Hu, Kristopher W Krausz, Dequn Sun, Jeffrey R Idle, Frank J Gonzalez
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Adenine, BioReagent, suitable for cell culture
Sigma-Aldrich
Adenine, ≥99%
Sigma-Aldrich
Adenine, BioReagent, suitable for plant cell culture, ≥99%
Adenine, European Pharmacopoeia (EP) Reference Standard
Praziquantel for system suitability, European Pharmacopoeia (EP) Reference Standard
Supelco
Adenine, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Praziquantel, VETRANAL®, analytical standard
Praziquantel, European Pharmacopoeia (EP) Reference Standard
Supelco
Praziquantel, Pharmaceutical Secondary Standard; Certified Reference Material