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Pharmacokinetics of N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in the rat

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Abstract

Objectives: The objectives of this study were to characterize pharmacokinetics of N-2-chloroethylaziridine (CEA) in the rat model and assess the in vivo fraction of total clearance of phosphoramide mustard (PM) that furnished CEA to circulation. Methods: The disposition of CEA was investigated following separate intravenous (iv) administrations of PM, synthetic CEA, and their combination to the Sprague-Dawley rats. In addition, in rats receiving prodrug cyclophosphamide (CP), plasma concentrations of CP and its metabolites, 4-hydroxycyclophosphamide (HOCP), PM, and CEA, were simultaneously quantified using GC/MS and stable isotope dilution techniques. Results: Following iv administration of synthetic CEA, concentrations of CEA declined biexponentially with the mean terminal half-life and total body clearance of 47.5 min and 167 ml/min/kg, respectively. Urinary excretion of unchanged CEA was 0.164% of the administered dose. CEA was found to be the major circulating metabolite after iv administration of precursor PM to rats. The fraction of total clearance of PM that furnished CEA to circulation was estimated to be 100%, indicating virtually complete availability of the metabolite to circulation once formed. In rats administered with CP, PM exhibited the highest plasma and urinary concentrations compared to HOCP and CEA. Conclusions: For the first time, CEA was demonstrated to be an important in vivo metabolite of CP in the present study. In light of the poor permeability and in vivo stability of PM, the ultimate DNA alkylator, the findings obtained in this study suggested that CEA may contribute significantly to the overall antitumor activity of prodrug CP.

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Abbreviations

CP:

Cyclophosphamide

HOCP:

4-hydroxycyclophosphamide

PM:

Phosphoramide mustard

CEA:

N-2-chloroethylaziridine

NNM:

Nornitrogen mustard

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Acknowledgements

This work was conducted in Kenneth Chan’s laboratory and supported by Biomedical Mass Spectrometry Laboratory, College of Pharmacy, The Ohio State University

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  1. Hong Lu

    Present address: Worldwide Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, PO Box 13398, Research Triangle Park, NC, 27709-3398, USA

Authors and Affiliations

  1. Colleges of Pharmacy and Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA

    Hong Lu & Kenneth K. Chan

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Correspondence to Hong Lu.

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Lu, H., Chan, K.K. Pharmacokinetics of N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in the rat. Cancer Chemother Pharmacol 58, 532–539 (2006). https://doi.org/10.1007/s00280-006-0196-7

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