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 reaction 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 towards 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 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.

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

“…Therefore, the results were strongly empirical and dependent on the investigator’s level of knowledge. However, metabolomics-guided drug metabolism studies have not focused on specific metabolic pathways; therefore, this non-targeted approach facilitates the identification of novel metabolites, the characterization of metabolic enzymes, and the profiling of reactive metabolites [32,36,37,38,39,40,41,42]. This approach is complementary to conventional drug metabolism studies.…”

Praziquantel for Schistosomiasis: Single-Drug Metabolism Revisited, Mode of Action, and Resistance

“…Moreover, PZQ derivatives have generally not achieved improved activity compared to that of the parent drug. Furthermore, in most cases, the promising in vitro activity of candidate drugs cannot be extrapolated to good in vivo activity since their pharmacokinetics and metabolic profiles are key determinants of their in vivo efficacy (53). Much remains to be done to develop an improved and effective derivative of PZQ1.…”

“…Although the enzymes that metabolize PZQ1 are not fully known, PZQ1 is primarily metabolized by CYP 3A and to a lesser extent by CYP 2D6 (35). Several studies have been performed to clarify the metabolic profile of PZQ1, as well as the enzymes involved and the identities of the phase II metabolites (48)(49)(50)(51)(52)(53).…”

Chiral Inhibition of Rivaroxaban Derivatives Towards UDP‐Glucuronosyltransferase (UGT) Isoforms

“…For example, intestinal UGT1A1 protects irinotecan‐induced diarrhea through catalyzing the glucuronidation of SN‐38, which is the active substance of irinotecan . The inhibition of the SN‐38 glucuronidation process by xenobiotics can result in the elevation of the toxicity intensity of irinotecan . The inhibition towards the UGTs‐catalyzed reaction can also disrupt the metabolism of endogenous substances, such as the influence of indinavir and sorafenib towards the metabolism of bilirubin .…”

“…For example, terazosin enantiomers exhibited different pharmacokinetic behaviors in healthy Chinese male subjects . A completely different metabolic pathway was elucidated for praziquantel (PZQ), which is a prevalent drug to treat schistosomiasis . Drug metabolism‐related drug–drug interaction can also be affected by chiral properties.…”