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Physiological Disposition of 1-Acetyl-2-picolinoylhydrazine (NSC 68626) in Rats Bearing Walker Carcinosarcoma 256¹

Microbiological Associates, Inc. [L. C. M.], and National Cancer Institute [J. A. R. M.], NIH, Bethesda, Maryland 20014

The purpose of the study was to investigate distribution and metabolism of 1-acetyl-2-picolinoylhydrazine in tissues of tumor-bearing rats in order to understand the basis of its toxicity and antitumor activity. Drug labeled with ¹⁴C in the carbonyl moiety was used to determine drug-derived radioactivity. A procedure involving chloroform extraction and paper chromatography was used to determine the unchanged 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 1-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 1-acetyl-2-picolinoylhydrazine from tissues was rapid; more than 90% was removed within 6 hr after the i.p. therapeutic dose administration. 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 chromatography, and one of them appeared to be picolinic acid.

¹ This work supported in part by Contract NO1-CM-33728 with Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Md. 20014.

² To whom requests for reprints should be addressed, at Microbiological Associates, Inc., 5221 River Road, Bethesda, Md. 20016.

Received 3/ 7/73. Accepted 6/14/73.