Single and Five Daily Dose Acute Toxicity in Mice and Infusion Dose Range-Findingand Pharmacokinetics in Dogs of Penclomedine (NSC-338720)

摘要

The antineoplastic Penclomedine (NSC-338720) was given intravenously as a singledose (x1) to male CD2F1 mice, as five consecutive daily doses (x5) to male CD2F1 abd B6C3F1 mice, and as 1-hour continuous infusion to male and female beagle dogs. Continuous intravenous infusion in beagle dogs, at dose levels of 31.2 mg/kg (infused over 1 hour) and 46.5 mg/kg (infused over 26-28 minutes) resulted in plasma drug levels of 5.2-7.5 microgram/mL, and 9.1-23.4 microgram/mL, respectively. The elimination of Penclomedine from dog plasma appeared to be biphasic. Severe neurological clinical signs were observed during or immediately after dosing. In dogs treated with 46.5 mg/kg, the infusion was discontinued after 26-28 minutes due toneurological signs. In mice, animals either died from neurological toxicity (x1) immediately after dosing or recovered and developed delayed toxicity (x5). The maximally tolerated dose was 150 mg/kg in x1 CD2F1 mice, 80 mg/kg/day in x5 CD2F1 mice, and 100 mg/kg/day in x5 B6C3F1 mice. Clinical pathologic and histopathologic data indicated target organ toxicity to the bone marrow and thymus in both species of mice and dogs and to the spleen, lymph node, heart, intenstinal tract, kidney, and testis in mice.