STUDIES ON METABOLISM OF ACNU, A NEW WATER-SOLUBLE ANTI-TUMOR NITROSOUREA .2. DISTRIBUTION, EXCRETION, AND METABOLISM OF 3-[(4-AMINO-2-METHYL-5-PYRIMIDINYL)METHYL]-1-(2-CHLOROETHYL)-1-NITROSOUREA (ACNU) IN RATS AND MICE AFTER IV ADMINISTRATION

  • 1 January 1980
    • journal article
    • research article
    • Vol. 64  (4-5) , 575-580
Abstract
The distribution, excretion and metabolism of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) in healthy rats and mice or tumor-bearing mice were studied with the 14C label in each of 2 positions of the molecule, the ethylene and pyrimidine moieties. After i.v. injection of 4 mg/kg of ACNU-14C, radioactivity was distributed widely and disappeared rapidly from the body. The half-life of intact ACNU in rat plasma was about 12 min. In both animal species, 72-95% of the radioactivity was excreted into urine within 24 h. Early dissociation of renal clearance rate was observed between pyrimidine-14C and ethylene-14C, the former being more rapidly excreted than the latter. Ethylene-14C of ACNU was distributed into tumor tissues of [mouse] X-5563 plasmacytoma cell-bearing mice; a tumor level of radioactivity was 2-fold higher than the blood level at 3 h after injection. The concentrations of several metabolites in plasma and urine were determined. Among these compounds, an intramolecular carbamoylating product of ACNU was found. The isocyanate derived from ACNU probably does not react with any biologic macromolecules; the chloroethyl moiety of ACNU probably has a very important role in the manifestation of the antitumor activity.

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