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Preclinical pharmacokinetics and stability of isophosphoramide mustard

  • Original Articles
  • Isophosphoramide Mustard, Pharmacokinetics, Stability
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Abstract

Stability and preclinical pharmacokinetics of isophosphoramide mustard (IPM), an active metabolite of ifosphamide, were investigated using analytical methods developed in this laboratory. For stability evaluation of IPM we used a rapid, high-pressure liquid chromatographic (HPLC) method by which IPM is analyzed directly from aqueous solutions without derivatization on a 10-μm C-18 reversed-phase column with theophylline as the internal standard. IPM in sodium phosphate buffers was found to undergo pH-dependent first-order degradations. At pH 7.4 and 38° C, the IPM solution showed a half-life of 45 min. A gas chromatographic-mass spectrometry (GC/MS) method for the analysis of IPM in plasma was also developed. This method utilized solid-phase extraction with deuterium-labeled IPM as the internal standard. The routine detection limit for the assay was 50 ng/ml with within-run and between-run coefficients of variation of 6% and 11%, respectively. By this method, stability of IPM in plasma and in RPMI 1640 tissue culture medium was evaluated, and its pharmacokinetics in the Sprague-Dawley rat following i.v. administration at 40 mg/kg were investigated. IPM was found to be more stable in these media, with half-lives in the range of 100 min. IPM plasma pharmacokinetics were found to decline monoexponentially with terminal halflives ranging from 6.8 to 18.7 min and total clearance between 6.0 and 18.3 ml/min. Plasma protein binding of IPM was found to be 55%, and the partition ratio between plasma and red blood cells of 4.9 to 1, respectively. Cytotoxicity of IPM to L1210 cells was evaluated, and the results indicated that the IC50 with 1-h and 4-h exposure was 33 and 15 μm, respectively. Based on these data, IPM plasma levels in the rat declined below the IC50 in about 1 h at this dose. More frequent dosing or infusion may be necessary to maintain adequate drug levels for antitumor activity when IPM is administered directly.

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Authors and Affiliations

  1. School of Pharmacy, University of Southern California, 90033, Los Angeles, CA, USA

    Jenny Jingwen Zheng & Kenneth K. Chan

  2. Comprehensive Cancer Center, School of Medicine, University of Southern California, 90033, Los Angeles, CA, USA

    Franco Muggia

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  1. Jenny Jingwen Zheng
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  2. Kenneth K. Chan
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  3. Franco Muggia
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The work reported was supported by USC Cancer Center Core grant CA 14089 from the National Cancer Institute

Present address: Room 308, Comprehensive Cancer Center, The Ohio State University, 410 W. 12th Avenue, Columbus, Ohio 43210, USA

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Zheng, J.J., Chan, K.K. & Muggia, F. Preclinical pharmacokinetics and stability of isophosphoramide mustard. Cancer Chemother. Pharmacol. 33, 391–398 (1994). https://doi.org/10.1007/BF00686268

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  • DOI: https://doi.org/10.1007/BF00686268

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