Comparative metabolism of cyclophosphamide and ifosfamide in the mouse using UPLC-ESI-QTOFMS-based metabolomics

Li, Fei; Patterson, Andrew D; Höfer, Constance C; Krausz, Kristopher W; Gonzalez, Frank J; Idle, Jeffrey R (2010). Comparative metabolism of cyclophosphamide and ifosfamide in the mouse using UPLC-ESI-QTOFMS-based metabolomics. Biochemical pharmacology, 80(7), pp. 1063-74. New York, N.Y.: Elsevier 10.1016/j.bcp.2010.06.002

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Ifosfamide (IF) and cyclophosphamide (CP) are common chemotherapeutic agents. Interestingly, while the two drugs are isomers, only IF treatment is known to cause nephrotoxicity and neurotoxicity. Therefore, it was anticipated that a comparison of IF and CP drug metabolites in the mouse would reveal reasons for this selective toxicity. Drug metabolites were profiled by ultra-performance liquid chromatography-linked electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS), and the results analyzed by multivariate data analysis. Of the total 23 drug metabolites identified by UPLC-ESI-QTOFMS for both IF and CP, five were found to be novel. Ifosfamide preferentially underwent N-dechloroethylation, the pathway yielding 2-chloroacetaldehyde, while cyclophosphamide preferentially underwent ring-opening, the pathway yielding acrolein (AC). Additionally, S-carboxymethylcysteine and thiodiglycolic acid, two downstream IF and CP metabolites, were produced similarly in both IF- and CP-treated mice. This may suggest that other metabolites, perhaps precursors of thiodiglycolic acid, may be responsible for IF encephalopathy and nephropathy.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology

UniBE Contributor:

Idle, Jeffrey

ISSN:

0006-2952

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:11

Last Modified:

04 May 2014 23:05

Publisher DOI:

10.1016/j.bcp.2010.06.002

PubMed ID:

20541539

Web of Science ID:

000281428800014

URI:

https://boris.unibe.ch/id/eprint/1733 (FactScience: 203673)

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