Infusion Dose Range-Finding of 8-Chloroadenosine-3',5'-Cyclic Monophosphate (NSC-614491) in Beagle Dogs

摘要

The toxicity and pharmacokinetics of 8-chloroadenosine-3',5'-cyclic monophosphate (8-Cl-cAMP, NSC 614491) were evaluated in beagle dogs treated with 24-h i.v. infusions at rates of 2.4, 4.8, and 9.6 mg/kg/h. One male and one female were treated at each dose. Clinical signs of toxicity occurred mostly following the 9.6 mg/kg/h dose and included vomiting and diarrhea which were essentially observed only during the infusion period. Clinical pathology changes occurring in dogs treated at 4.8 and 9.6 mg/kg/h included elevated leukocyte counts and decreased lymphocytes; decreases in RBC, HGB, and HCT; increased BUN and creatinine levels; and increased alkaline phosphatase activity. Increased leukocyte counts were either directly drug-related or secondary to stress produced by gastrointestinal toxicity. Increased alkaline phosphatase suggested tissue damage to the hepato-biliary secretory system or the intestinal epithelium. BUN and creatinine elevations may have been due to renal toxicity. Steady-state plasma concentrations were achieved by about 90 min following initiation of infusion. The pharmacokinetics appeared to be linear, although some discrepancies were apparent in animals treated with 4.8 mg/kg/h.