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Metabolism of Iphosphamide [2-(2-Chloroethylamino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine 2-Oxide] and Production of a Toxic Iphosphamide Metabolite¹

Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35205

Iphosphamide [2 - (2 - chloroethylamino) - 3 - (2 - chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide] is metabolized by mouse liver microsomes in the presence of reduced triphosphopyridine nucleotide and oxygen. When purified aldehyde oxidase is added, the initial metabolites do not appear in quantity; but a single, anionic product is present. After chemical methylation, the mass spectrum of the product of the aldehyde oxidase reaction is identical to that of 2-carbomethoxyethyl N,N'-bis(2-chloroethyl)phosphorodiamidate.

The initial oxidation reaction for Iphosphamide has a K_m of 1.0 mM, and cyclophosphamide is a competitive inhibitor with a K₁ of 1.1 mM. Iphosphamide is a competitive inhibitor of cyclophosphamide oxidation, with a K₁ of 1.0 mM compared to a K_m of 0.5 mM.

The initial metabolites of Iphosphamide are toxic to L1210 cells. Mice given injections of these cells, which have been exposed to the initial metabolites, have a longer life-span than those inoculated with untreated cells. The product of the aldehyde oxidase reaction is not toxic in such tests.

Dogs rapidly metabolize Iphosphamide, and only a small amount of unchanged compound appears in the urine. Metabolites that have been isolated from dog urine are 4-keto-Iphosphamide and (after chemical methylation) 2-carbomethoxyethyl N,N'-bis(2-chloroethyl)phosphorodiamidate.

¹ This work was presented in part at the Annual Meetings of the American Association for Cancer Research, May 1972. The investigation was supported by Contracts PH43-66-29. NIH-71-2021, and PH43-65-654 with Division of Cancer Treatment, National Cancer Institute, NIH, Department of Health, Education, and Welfare.

Received 12/11/72. Accepted 1/26/73.