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Preliminary Clinical Trial and the Physiologic Disposition of 4(5)-(3,3-Dimethyl-1-triazeno)imidazole-5(4)-carboxamide in 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, NSC 45388) was administered i.v. to 15 patients with malignant melanoma and to 17 patients with other tumors at a dosage of 4.5 mg/kg/day for 10 days. In the melanoma group, 5 patients responded to therapy. No responses were seen in the 17 patients with other tumors. Toxicity was manifested by nausea and vomiting, leukopenia, and thrombocytopenia.

The plasma levels and urinary excretion patterns of DIC, administered to patients with cancer, were determined by a revised colorimetric assay. Rapid i.v. injection of 4.5 mg/kg of DIC resulted in initial plasma concentrations of 8.8 ± 1.8 (S.D.) µg/ml which fell to zero within 6 hr. About 30% of the dose was excreted in the urine as DIC 0–6 hr after administration. Plasma levels following multiple daily doses of i.v. therapy varied with dosage, and the amount excreted in the urine 0–6 hr after each dose was about 30%. Intravenous infusion of 4.5 mg/kg of DIC over a 24-hr period produced no detectable plasma levels, while infusion of the same dose over an 8-hr period resulted in a plasma level of nearly 1.0 µg/ml after 7 hr. In both cases, urinary excretion during the infusion period was about 30% of the dose. Following a single oral dose of 4.5 mg/kg, plasma DIC levels were highest [2.4 ± 0.9 (S.D.) µg/ml] 30 min after administration, and fell to zero within 6 hr. Peak plasma DIC levels following multiple daily oral doses of 1.5 mg/kg every 6 hr varied with each dose, but fell to zero before the next dose was given. Following either oral dosage schedule, 14–23% of the dose was excreted into the urine 0–6 hr after administration. The renal clearance of DIC exceeded the glomerular filtration rate. These data suggest that high and sustained plasma levels of DIC can be achieved by either i.v. or oral, multiple daily dose therapy, and that these may be worthy of consideration for clinical trial of this drug.

¹ Supported in part by Grant No. CA-06749-0552 from the National Cancer Institute, USPHS.

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

³ Career Development Awardee (1-K4-CA-8245-01A1) of the National Cancer Institute.

Received 2/ 3/69. Accepted 4/11/69.