[A six-month intraperitoneal repeated dose toxicity study of tazobactam/piperacillin and tazobactam in rats].
Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor. Tazobactam/Piperacillin (TAZ/PIPC) is a formulation consisting of TAZ and PIPC in a ratio of 1:4. A six-month intraperitoneal repeated dose toxicity study of TAZ/PIPC and TAZ including a one-month recovery period were carried out using male and female rats. The doses were 200, 400 and 800 mg/kg/day for TAZ/PIPC, and 40, 80 and 160 mg/kg/day for TAZ. The results were as follows. 1. No test article-related deaths occurred during the study period. No effect on clinical finding of survival rats was evident. 2. There was no dose-related increases of food consumption in both the males and females given TAZ/PIPC and PIPC. Slight reductions in body weight gain occurred in males given 800 mg/kg/day of TAZ/PIPC. 3. Decreases in erythrocyte, hemoglobin and hematocrit, and increases in reticulocytes were seen only at study termination in the group given 800 mg/kg/day of TAZ/PIPC. Increases in reticulocytes were seen only at study termination in the females given 80 or 160 mg/kg/day of TAZ. 4. A decrease in triglyceride levels was observed in the males given 800 mg/kg/day of TAZ/PIPC or 160 mg/kg/day of TAZ. 5. The ophthalmoscopic examination or urinalysis show no test article-related changes. 6. Enlarged ceca in all groups of animals given TAZ/PIPC and in the females given 160 mg/kg/day of TAZ were observed. 7. An increase of relative organ weight in liver was noted in the males and females given 800 mg/kg/day of TAZ/PIPC, in the males given 80 or 160 mg/kg/day of TAZ and in the females given 160 mg/kg/day of TAZ. 8. In the hepatocytes, accumulation of PAS-positive materials which was identified histochemically and ultrastructurally as glycogen, was present in the males given 800 mg/kg/day of TAZ/PIPC and in the males given 80 or 160 mg/kg/day of TAZ. 9. After a one-month recovery period, the changes of liver had generally disappeared, suggesting that they were reversible. 10. From the histopathological changes of liver, the no-toxic dose level in both the males and females was 400 mg/kg/day and 40 mg/kg/day for TAZ/PIPC and TAZ, respectively.
Hayashi
T
T
Drug Safety Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Yada
H
H
Auletta
C S
CS
Daly
I W
IW
Knezevich
A L
AL
Cockrell
B Y
BY
D000818:Animals; D004359:Drug Therapy, Combination / Q000633:toxicity*; D005260:Female; D006003:Glycogen / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D010878:Piperacillin / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors
D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D006003:Glycogen; D000078142:Tazobactam; D010878:Piperacillin