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N-Demethylation of the Antineoplastic Agent 4(5)-(3,3-Dimethyl-1-triazeno)imidazole-5(4)-carboxamide by Rats and Man¹

The Division of Clinical Oncology, University of Wisconsin Medical School, Madison, Wisconsin 53706

4(5)-(3,3-Dimethyl-1-triazeno)imidazole-5(4)-carboxamide (DIC) was N-demethylated in vitro by rat liver microsomes resulting in the formation of 20.5 mµmoles of formaldehyde/mg microsomal protein/30 min. 4(5)-Aminoimidazole-5(4)-carboxamide was recovered in vitro as a major metabolic product following N-demethylation resulting in the formation of 14.9 mµmoles/mg microsomal protein/30 min. The administration of ¹⁴C-methyl-labeled DIC intraperitoneally to rats was followed by the recovery of 4.0% of the dose as ¹⁴CO₂ within 6 hr. When ¹⁴C-methyl-labeled DIC was administered intraperitoneally to rats pretreated with prochlorperazine or phenobarbital, increased amounts (8.1% and 10.5% respectively) of DIC were N-demethylated to ¹⁴CO₂ within 6 hr. One patient given ¹⁴C-methyl-labeled DIC orally expired 21.4% of the radioactivity as ¹⁴CO₂ within 6 hr. N-Demethylation appears to be a major metabolic pathway of DIC in rats and man. This reaction is mediated by liver microsomal enzymes that can be induced by barbiturates and perhaps prochlorperazine.

¹ Supported in part by Grant CA-06749-0552 from the National Cancer Institute, USPHS, A preliminary report of this work has been made (25).

² Postdoctoral Research Fellow of the National Cancer Institute (1-FO2-CA-39, 136-01).

³ Career Development Awardee of the National Cancer Institute (1-K4 CA-8245-01).

Received 3/21/69. Accepted 6/ 2/69.

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