Subacute Toxicity of a Purine Nucleoside Phosphorylase Inhibitor in Rats

Rats received daily oral doses of 15, 50, 150, or 200 mg/kgCI-1000 for 4 weeks. Doses were selected based on findings froma 2-week range-finding study where doses of 250 and 500 mg/kgresulted in mortality. In the 4-week study, females given 200mg/kg were sacrificed during Week 2 due to poor condition. Serumcreatinine and urea nitrogen increased 2- to 2.5-fold in femalesgiven 200 mg/kg. Dose-related increases in urine volume, urinaryprotein excretion, and osmolar excretion occurred in both sexesbeginning at 50 mg/kg. Kidney weights increased 9–40%in both sexes at 50 mgkg; histopathologic changes were confinedto the 150 and 200 mg/kg groups. At Week 4, T-suppressor/cytotoxiclymphocytes were reduced 43% and T-helper/inducer lymphocyteswere reduced 22% in males given 200 mg/kg. In females, T-suppressor/cytotoxic lymphocytes were significantly decreased (approximately40%) at 50 and 150 mg/kg, with no significant effects on T-helper/inducerlymphocyte populations. At Week 8, following 4 weeks withouttreatment, T-lymphocyte subpopulations were similar in controland drug-treated groups. B-lymphocyte counts and percentageswere increased at Weeks 4 and 8 in males receiving 150 or 200mg/kg. Thymic weights decreased at Week 4 at doses of 150 and200 mg/kg. Plasma CI-1000 levels were higher in females thanin males at all doses except 15 mg/kg; C_max and AUC values werelargely dose proportional in both sexes. In summary, CI-1000was well-tolerated at doses of 15, 50, and 150 mg/ kg with noadverse effects occurring at 15 mg/kg. Drug-induced changesin the kidney were mild and reversible. Immunomodulatory effectswere noted at doses of 50 mg/kg or higher.