Phase 2 Report of Preclinical Bioavailability and Continuous Intravenous Infusion Toxicity Studies of 2', 3'-Dideoxycytidine (NSC-606170) in Beagle Dogs

摘要

2',3'-Dideoxycytidine (DDO-C, NSC-606170) was given to dogs intravenously and orally at a dose of 100 mg/kg (2,000 mg/sq. cm.). The highest plasma concentration was 304-307 micrograms DDO-C/ml at 2 min after an intravenous dose. The drug was eliminated in two phases following an intravenous dose with a half-life of 10-13 min for the distribution phase and 124-140 min for the elimination phase. The drug was completely absorbed from the gastrointestinal tract (bioavailability = 100%) after an oral dose with a peak plasma concentration of 114-172 micrograms DDO-C/ml occurring at 30-60 min postdose. At least one metabolite was detected in the plasma, the identity of which is unknown. A continuous 120-hour infusion of DDO-C at 0.0353-3.530 mg/kg/hr caused very few toxic effects to the dogs. Mild gastro-intestinal disturbance, elevated body temperature, and decreased body weight were readily reversible. Clinical pathology data suggested a slight possibility of toxicity to the liver and kidney. However, neither drug-related gross nor histopathologic lesions were detected. Steady-state plasma concentrations of approx. 12 micrograms DDO-C/ml for 3.530 mg/kg/hr and approx. 1.1 microgram DDO-C/ml for 0.3530 mg/kg/hr were maintained 8-120 hr after the start of infusion. In the dose group of 3.530 mg/kg/hr, 3-7% of plasma DDO-C penetrated to the cerebrospinal fluid during the 24-48 hr period after the start of infusion reaching a concentration of 0.40-0.96 micrograms/ml.