Pharmacologic studies of the antitumor agent 5-(dimethyltriazeno)imidazole-4-carboxamide.

Abstract

Summary In the dog, after an intravenous injection of 5-(dimethyltriazeno)imidazole-4-carboxamide (DIC) at 20 mg/kg (400 mg/sq m), the plasma clearance of the drug was fairly fast, with a half-life of about 36 min. The volume of distribution exceeded total-body water content. Excretion was complete in 6 hr, at which time the cumulative excretion was 17% of the injected dose. DIC appeared in the cerebrospinal fluid (CSF) of the dog 10 min after injection. When the drug was administered to the dog by constant intravenous infusion, an average CSF to plasma concentration ratio of 1:7 was obtained at steady state. When administered intravenously to man at a dose ranging from 133 mg/sq m to 270 mg/sq m, the plasma clearance of DIC was similar to that seen in the dog: the plasma half-life was 35 min. The volumes of distribution likewise exceeded total-body water content. However, in 6 hr 43% of the dose was excreted as unchanged DIC. At least 1 unidentified biotransformation product was found in trace amounts in the urine of man and dogs treated with DIC. The plasma half-time of DIC was 111 min when the drug was administered by mouth to patients at a dosage ranging from 30 mg/sq m to 260 mg/sq m. The drug persisted in the plasma for up to 6 hr following ingestion. The cumulative excretion of DIC when given orally was variable; on the average, 19% of the dose was found in the urine in 6 hr. These results suggest that gastrointestinal absorption of DIC was slow, incomplete, and variable.