Five Daily 1-Hour Continuous Intravenous Infusions of Penclomedine (NSC-338720)in Beagle Dogs

摘要

The target organ toxicity and its reversibility of penclomedine (NSC-338720) wasexamined in male and female beagle dogs following five consecutive daily 1-h i.v. infusion of the drug at doses of 2.5 and 25 mg/kg/h (50 and 500 mg/sq m/h). A vehicle control group received diluted oillecithin emulsion. Clinical signs of toxicity were observed in dogs receiving penclomedine at 25 mg/kg/h but were limited to a few episodes of vomiting or abnormal stools seen only within a few hours after completion of dosing. Hematology results indicated a drug-induced, dose-dependent, progressive leukopenia and thrombocytopenia, most severe on study day 19; a recovery was apparent by day 22. Dogs treated with 25 mg/kg/h and sacrificed on day 10 showed marked bone marrow atrophy. Lung lesions were observed in dogs receiving 25 mg/kg/h and were considered a secondary effect of the drug formulation. Maximal blood concentrations of penclomedine in dogs treated at 25 mg/kg/h ranged from 3.1 to 5.8 microgram/mL. Plasma concentrations of penclomedine were 57% to 81% of respective blood levels. A large volume of distribution and fast clearance rate suggested rapid tissue distribution or metabolism of the drug.