Comparative disposition of phosphoramide mustard and other cyclophosphamide metabolites in the mouse using the Salmonella/mutagenesis assay
Suling, W.J.; Struck, R.F.; Woolley, C.W.; Shannon, W.M.
Cancer Treatment Reports 62(9): 1321-1328
1978
ISSN/ISBN: 0361-5960 PMID: 356985 Document Number: 129201
The Salmonella/mutagenesis assay was used to compare the disposition of phosphoramide mustard (PM), an active metabolite of cyclophosphamide (CPA), and other mutagenic CPA metabolites in the mouse. A mutant strain of S. typhimurium, TA-1535, which reverts from a histidine requirement to prototrophy in the presence of mutagens causing DNA base-pair substitutions, was used to measure the mutagenic activity in tissues and urine of BDF1 mice given single i.p. doses of PM (180 mg/kg) or CPA (342 mg/kg). Assuming that mutagenic activity in tissues and body fluids was due to unchanged drug and/or its metabolites PM was rapidly absorbed by the tissues and drug levels were initially high in plasma, kidney, liver and pancreas, but were not detectable in lung, spleen and brain. These levels rapidly decreased with time. The apparent plasma half-life of PM was 20 min. Mutagenic metabolites of CPA disappeared less rapidly from tissues than did PM. Peak levels of CPA metabolites in tissues were reached after 30 min. and were high in plasma, liver, kidney, lung, spleen and pancreas, but were not detectable in brain. The apparent plasma half-life of the CPA metabolites was 34 min. Approximately 34% of the dose of PM was recovered, as drug equivalents, in the urine within 6 h after injection. TLC of the urine of PM-treated mice indicated the presence of PM and nor-nitrogen mustard.