Physiological disposition of 1-acetyl-2-picolinoylhydrazine (NSC68626) in rats bearing Walker carcinosarcoma 256.

The purpose of the study was to investigate distribution and metabolism of l-acetyl-2-picolinoylhydrazine in tissues of tumor-bearing rats in order to understand the basis of its toxicity and antitumor activity. Drug labeled with 14Cin the carbonyl moiety was used to determine drug-derived radio activity. A procedure involving chloroform extraction and paper chromatography was used to determine the un changed drug. Peak levels of radioactivity were attained in all organs within 4 hr after a therapeutic i.p. dose and within 15 min after a low i.v. dose. Although no preferential uptake of l-acetyl-2-picolinoylhydrazine was found in any organ, the uptake by brain was high and comparable to that seen in spleen and tumor and may account for the neurotoxicity and antitumor activity. Disappearance of l-acetyl-2-picolinoylhydrazine from tissues was rapid; more than 90% was removed within 6 hr after the i.p. therapeutic dose adminis tration. Metabolism of the drug was rapid regardless of the route or dose. More than 50% of the drug-derived label in plasma was found to be in the form of metabolites within 2 min after i.v. administration. Fifty-five % of the injected radioactivity was excreted in urine within 6 hr and 95% was excreted by the end of 24 hr; only trace amounts (2 to 4%) of the unchanged drug were found in urine at any time interval. Several metabolites were detected in urine by paper chro matography, and one of them appeared to be picolinic acid.