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.

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 two positions of the molecule, the ethylene and pyrimidine moieties. After iv 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 minutes. In both animal species, 72%-95% of the radioactivity was excreted into urine within 24 hours. 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 X-5563 plasmacytoma-bearing mice, and a tumor level of radioactivity was observed to be twofold higher than the blood level at 3 hours after injection. The concentrations of several metabolites in plasma and urine were determined. Among these compounds, we found an intramolecular carbamoylating product of ACNU. These results suggest that the isocyanate derived from ACNU does not react with any biologic macromolecules, and that the chloroethyl moiety of ACNU has a very important role in the manifestation of the antitumor activity.