Chronic toxicity of the anticonvulsant zonisamide in beagle dogs.
The chronic toxicity of the new anticonvulsant drug zonisamide (1,2-benzisoxazole-3-methanesulfonamide) was evaluated in a detailed 52-week study in which dose levels of 0, 10, 30 and 75 mg/kg/day were administered orally in gelatin capsules to groups of five Beagle dogs per sex. Potential toxicity was based on the effects of zonisamide on body weight and food consumption; clinical and ophthalmic examinations; electrocardiography and heart rates; clinical biochemistry, hematology and urinalysis determinations; organ weights and gross and histopathologic evaluations; electron microscopy of high dose and control male dogs; and plasma zonisamide concentrations. Zonisamide was relatively well tolerated during the study. In animals given 75 mg/kg/day, early body weight losses occurred and therefore, from Weeks 2 and 3 until study termination, for males and females respectively, the high dose was given as two equal portions (i.e., 37.5 mg/kg each) approximately 3-4 hr apart. Clinical laboratory analyses in the dogs given 75 mg/kg revealed a small but statistically significant decrease in plasma albumin concentration and a small increase in alkaline phosphatase activity. In animals given 75 mg/kg, liver weights were increased and a brownish discoloration of the liver was noted grossly at necropsy. No significant light microscopic changes were evident; however, electron microscopic evaluation of the liver tissue from the 5 male dogs given 75 mg/kg revealed the presence of concentric lamellae of paired smooth membranes which were not seen in control animals. At the 10 and 30 mg/kg dose levels, plasma zonisamide concentrations reached steady-state and were proportional to dose, but at 75 mg/kg, plasma levels were disproportionately higher and never achieved steady-state. The results of this study indicated that at the high dose level of 75 mg/kg, chronic administration of zonisamide had a mild effect on the liver, particularly the endoplasmic reticulum.
Walker
R M
RM
Parke-Davis Research Institute, Mississauga, Ontario, Canada.
DiFonzo
C J
CJ
Barsoum
N J
NJ
Smith
G S
GS
Macallum
G E
GE
D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004285:Dogs; D004435:Eating / Q000187:drug effects; D004562:Electrocardiography; D007555:Isoxazoles / Q000633:toxicity*; D008099:Liver / Q000473:pathology; D010080:Oxazoles / Q000633:toxicity*; D012709:Serum Albumin / Q000378:metabolism; D012737:Sex Factors; D013997:Time Factors; D000078305:Zonisamide
D000927:Anticonvulsants; D007555:Isoxazoles; D010080:Oxazoles; D012709:Serum Albumin; D000078305:Zonisamide