Preclinical Pharmacokinetics and Toxicity Studies in Beagle Dogs with 5-Azacytosine Arabinoside (NSC-281272). Volume 2

摘要

5-Azacytosine arabinoside (ARC-AC) (NSC-281272) was given to beagle dogs as a single intravenous (IV) or oral (PO) dose (400 mg/kg) or as a continuous IV infusion (16.7 mg/kg/hour for 24, 12, 6, and 3 hours; 5.4 mg/kg/hour for 119, 48, 24, and 12 hours; 0.54 mg/kg/hour for 168, 120, and 72 hours; 0.21 mg/kg/hour for 120 hours; 0.054 mg/kg/hour for 168 and 120 hours; 0.0 mg/kg/hour for 168 and 48 hours). Drug bioavailability after a PO dose was 22% of that after an IV dose. The half-life of drug clearance from plasma ranged from 1.47 to 2.26 hours. The area under the plasma concentration curve versus the time curve was proportional to the dose; elimination was dose independent. All dogs treated at or above 0.21 mg/kg/hour for 48 or more hours, and at 16.7 mg/kg/hour for 24 hours, were found dead or became moribund and were sacrificed. Drug-related clinical observations were consistent with neurologic and gastrointestinal toxicity. A drug-related reduction in hematocrit and hemoglobin concentrations, and red blood cell count occurred in dogs given the single dose.