Studies on the disposition of 2,3-dihydro-1H-imidazo [1,2-b] pyrazole in rodents

2,3-Dihydro-1H-imidazo [1,2-b] pyrazole (IMPY, NSC-51143) is a new ribonucleotide reductase inhibitor, presently undergoing clinical evaluation, that exhibits prolonged in vivo antitumor activity in experimental animals. Disposition studies were initiated to determine if the prolonged in vivo antitumor activity of IMPY could be explained by its pharmacologic properties. Plasma disappearance curves of radioactivity were biphasic after the i.v. administration of 100, 250 or 500 mg/kg to rats and 250 mg/kg to mice. The distribution phase was rapid in each case ($\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of approximately 30 min or less), followed by a prolonged elimination phase. Radioactivity was distributed to all tissues of rats and mice including brain after an i.v. dose of 250 mg/kg. In rats, 67.8% of the administered radioactivity was excreted in the urine during the first 24 hr. By 120 hr 74.3% had been excreted via the urine compared with 11.1% in the fees, the latter by biliary excretion. The chromatographic profile of the urine collected from rats and mice 4 hr after drug administration indicated extensive metabolism. Thus, the prolonged plasma and tissue levels of parent IMPY and its metabolites can account for the prolonged duration of cytotoxic activity in vivo.