Subacute toxicity of a purine nucleoside phosphorylase inhibitor in rats.
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 > or = 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-suppressor/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.
Wolfgang
G H
GH
Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Bleavins
M R
MR
Hallak
H
H
Kasali
O B
OB
Urda
E
E
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D003681:Dehydration / Q000139:chemically induced / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D007684:Kidney Tubules / Q000473:pathology; D018655:Lymphocyte Count / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D011683:Purine-Nucleoside Phosphorylase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D016482:Urinalysis; D015430:Weight Gain / Q000187:drug effects
D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; C076778:9-deaza-9-(3-thienylmethyl)guanine; D006147:Guanine; D003404:Creatinine; D011683:Purine-Nucleoside Phosphorylase