Thirteen-week oral toxicity study of propiverine hydrochloride in rats

Abstract

A subacute toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out using male and female Wistar rats. P-4 was orally administered to rats at dose levels of 2, 10, 50 and 150 mg/kg/day for 13 weeks, followed by 5 weeks recovery period. The results obtained are as follows: 1. In the general conditions, transient salivation was observed immediately after administration and blotted fur at lower abdomen was noted in rats given 50 mg/kg/day or more. There were no deaths related to P-4. 2. Body weight gain was depressed in males given 50 mg/kg/day or more and females given 150 mg/kg/day. No significant changes in food consumption were observed. Water consumption increased in the groups of 50 mg/kg/day or more. 3. Urinalysis revealed an increase of urine volume, decreases of osmotic pressure, protein and urobilinogen, and a slight increase in excretion of electrolyte in rats given 50 mg/kg/day or more. 4. Hematological examinations revealed slight changes such as an increase in erythrocyte count and a shortening of APTT in rats given 150 mg/kg/day. 5. Serum biochemical examinations showed a decrease in triglyceride and increases in gamma-GTP and AlP activities, and urea nitrogen in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Additionally, decreases in total and free cholesterol, and phospholipid for males and an increase of total cholesterol and a decrease of cholinesterase activity for females were detected. 6. At autopsy, atrophy of thymus and spleen was observed in rats given 50 mg/kg/day or more, but without histopathological correlation. Histopathological examinations revealed hypertrophy and fatty degeneration of hepatocytes, which were accompanied with increases of absolute and/or relative liver weight, in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Electron-microscopy showed proliferation of smooth endoplasmic reticulum in the same groups. In the kidney, eosinophilic and intranuclear inclusions in the tubular epithelium were detected, in which cytoplasm there were no toxic injuries, in males given 10 mg/kg/day or more and females given 50 mg/kg/day or more. 7. After 5 weeks recovery period, above-mentioned changes were generally disappeared, suggesting that these were reversible. 8. The non-effective dose levels and the toxic dose levels of P-4 were estimated to be 2 mg/kg/day for males and 10 mg/kg/day for females, and 50 mg/kg/day for males and 150 mg/kg/day for females, respectively.