[Reproductive and developmental toxicity studies of tazobactam/piperacillin or tazobactam (2)--Teratological study in rats with intravenously administration].
Tazobactam (TAZ) is a newly developed beta-lactamase inhibitor and piperacillin (PIPC) is an antibiotics which is used in clinical field widely. The combination of TAZ and PIPC (TAZ/PIPC), which is combined with TAZ and PIPC at rate of 1:4, has been developed because of PIPC is unstable to various beta-lactamases. Teratogenic potential were studied in rats given daily intravenous doses of TAZ/PIPC (625, 1250, 2500 or 3750 mg/kg/day) or TAZ (125, 500 or 3000 mg/kg/day). TAZ/PIPC or TAZ were given from day 7 to day 17 of pregnancy. Total daily doses were administered in two equally divided doses. The study includes postnatal evaluation of the growth and development and reproductive performance of the F1 generation. Maternal deaths occurred in all groups given TAZ/PIPC. The incidence (range of 3 to 6 animals/group) was not dose dependent. Maternal body weight was decreased in rats receiving 3000 mg/kg of TAZ and food consumption was reduced in all drug-treated groups. Slight decreases in fetal body weights were observed at some doses that caused maternal body-weight or food-consumption decreases (2500 or 3750 mg/kg of TAZ/PIPC, 3000 mg/kg of TAZ). But these depressions of fetal body weights were not significant from control data. There were no fetal malformations or variations attributable to the test articles. Postnatal growth and development, behavior and reproductive performance of the F1 generation were not affected by the administration of TAZ/PIPC or TAZ. In conclusion, TAZ/PIPC or TAZ was not teratogenic in the rats. It is seemed that non-observed effect dose levels (NOELs) of TAZ/PIPC and TAZ for dams is less than 625 and 125 mg/kg/day in general toxicity respectively, however, NOELs of TAZ/PIPC is 3750 mg/kg/day or more and that of TAZ is 300 mg/kg/day or more for their offspring under the condition of this study.
Sato
T
T
Drug Safety Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Lochry
E A
EA
Hoberman
A M
AM
Christian
M S
MS
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D000831:Animals, Newborn; D004359:Drug Therapy, Combination / Q000633:toxicity*; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D010878:Piperacillin / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects*; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors
D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D000078142:Tazobactam; D010878:Piperacillin