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© 1995 Oxford University Press

research-article

Subacute Toxicity of a Purine Nucleoside Phosphorylase Inhibitor in Rats

GRUSHENKA H. I. WOLFGANG, MICHAEL R. BLEAVINS, HUSSEIN HALLAK*, OLAJIDE B. KASALI and ELLEN URDA

Departments of Pathology and Experimental Toxicology Ann Arbor, Michigan 48105 *Pharmacokinetics and Drug Metabolism, Parke–Davis Pharmaceutical Research, Division of Warner–Lambert Company Ann Arbor, Michigan 48105

Received October 17, 1994; accepted March 30, 1995

Rats received daily oral doses of 15, 50, 150, or 200 mg/kg CI-1000 for 4 weeks. Doses were selected based on findings from a 2-week range-finding study where doses of 250 and 500 mg/kg resulted in mortality. In the 4-week study, females given 200 mg/kg were sacrificed during Week 2 due to poor condition. Serum creatinine and urea nitrogen increased 2- to 2.5-fold in females given 200 mg/kg. Dose-related increases in urine volume, urinary protein excretion, and osmolar excretion occurred in both sexes beginning at 50 mg/kg. Kidney weights increased 9–40% in both sexes at ≥50 mg≥kg; histopathologic changes were confined to the 150 and 200 mg/kg groups. At Week 4, T-suppressor/cytotoxic lymphocytes were reduced 43% and T-helper/inducer lymphocytes were reduced 22% in males given 200 mg/kg. In females, T-sup pressor/cytotoxic lymphocytes were significantly decreased (approximately 40%) at 50 and 150 mg/kg, with no significant effects on T-helper/inducer lymphocyte populations. At Week 8, following 4 weeks without treatment, T-lymphocyte subpopulations were similar in control and drug-treated groups. B-lymphocyte counts and percentages were increased at Weeks 4 and 8 in males receiving 150 or 200 mg/kg. Thymic weights decreased at Week 4 at doses of 150 and 200 mg/kg. Plasma CI-1000 levels were higher in females than in males at all doses except 15 mg/kg; Cmax and AUC values were largely dose proportional in both sexes. In summary, CI-1000 was well-tolerated at doses of 15, 50, and 150 mg/ kg with no adverse effects occurring at 15 mg/kg. Drug-induced changes in the kidney were mild and reversible. Immunomodulatory effects were noted at doses of 50 mg/kg or higher.


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