The objective of these studies was to evaluate the potential toxicity of Triapine (a ribonucleotide reductase inhibitor with potential antitumor activity) in dogs and rats. Various doses (1–20 mg/kg) of Triapine were administered intravenously (IV), once daily for 1, 3, or 5 consecutive days, to Beagle dogs or Albino Sprague-Dawley rats. Control animals were treated with vehicle, with an amount equivalent to a dose of 20 mg/kg of Triapine. Data collected included body weights, clinical signs, clinical pathology (serum chemistry and hematology), and gross and microscopic pathology. In dogs, the no-observed-adverse-effect level (NOAEL) of Triapine, when administered once daily for 5 consecutive days, was 1 mg/kg. For 5 daily doses at 3 mg/kg, or a single dose at 10 mg/kg, Triapine induced only limited toxicity (emesis and diarrhea, causing inappetence and body weight loss). The intensities/frequencies of the clinical signs were greater when Triapine was administered over 15 minutes than 120 minutes. Ondansetron (an antiemetic agent due to its H2 antagonistic properties) delayed, but did not eliminate, emesis induced by 10 mg/kg of Triapine. In rats, the NOAEL of Triapine, when administered once daily for 5 consecutive days, was not determined. However, when administered once daily for 3 consecutive days, 1 mg/kg was considered the NOAEL. Five to 20 mg/kg of Triapine (and its vehicle) induced a wide-range of toxicity. Toxicity related to the vehicle (as reflected by the similar or greater intensity/frequency of these effects in vehicle-treated rats than Triapine-treated rats) were reduced activity, discolored urine, discolored tails, and the accompanying gross and histopathological findings. Triapine-related effects were mortality; reductions in total protein and albumin levels; reductions in red blood cell, white blood cell, and platelet counts; reductions in body and thymic weights; increases in the liver and lung weights (and the corresponding microscopic findings of these organs); and microscopic findings of the adrenal cortex, testes, bone marrow, and kidney. These effects generally increased in a dose-related manner between 5–15 mg/kg, and leveled off at 15 and 20 mg/kg. Essentially all effects induced by Triapine and/or vehicle had returned, or were returning, to normal during a 30-day recovery period. In conclusion, the NOAEL of Triapine was 1 mg/kg, when administered daily for 5 consecutive days, in dogs. Five daily doses at 3 mg/kg or a single dose at 10 mg/kg Triapine-induced emesis and diarrhea. The toxicity was greater when Triapine was administered over 15 minutes than over 120 minutes. Ondansetron had limited efficacy in attenuating the emetic effects of the high dose (10 mg/kg) of Triapine. In rats, the NOAEL of Triapine was 1 mg/kg when administered once daily for 3 consecutive days. At 5–20 mg/kg, Triapine induced a broad spectrum of toxicological effects, which is consistent with its ribonucleotide reductase inhibitory properties. Essentially all effects induced by Triapine and/or vehicle were reversible within 30 days.
A ribonucleotide reductase inhibitor with deoxyribonucleoside-reversible cytotoxicity
