[Reproductive and developmental toxicity studies of tazobactam/piperacillin or tazobactam(1)--Fertility and general reproduction study in rats with intraperitoneal 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. Fertility and general reproductive performance were studied in rats given daily intraperitoneal doses of TAZ/PIPC (200, 800 or 1600 mg/kg/day) or TAZ (40, 160 or 640 mg/kg/day). TAZ/PIPC or TAZ were given during premating period (70 days in males and 15 days in females), the pairing period (in males and females) and the gestation and lactation periods (in females). Total daily doses were administered in two equally divided doses. The study includes evaluation of the F1 generation and the F2 generation through weaning. In the TAZ/PIPC, maternal toxicity (decreased food consumption) was observed at 200 mg/kg and above dosage groups. At maternotoxic doses of 800 and 1600 mg/kg groups, increased resorptions, decreased live litter size, and increased fetal variations (reversible changes in ribs) were observed. Reversible delays in ossification of caudal vertebrae were also observed at 1600 mg/kg group. In the TAZ, maternal toxicities were observed at 160 mg/kg group (decreased food consumption) and 640 mg/kg group (decreased body weight gain and food consumption). Furthermore, necropsy (raised and/or colored areas present in the cecum) revealed slight increases at 40 mg/kg and above dosage groups. Slight decreases in implantations and resultant slight decreases in live litter size, reversible delays in renal development, and increased stillbirths were observed at 640 mg/kg group. Postnatal growth and development, behavior and reproductive performance of the F1 generation were not affected by the administration of TAZ/PIPC or TAZ. There were no effects on any of the fetal or pup parameters evaluated in the F2 generation. In conclusion, mating behavior and fertility were not affected by TAZ/PIPC or TAZ in this study. TAZ/PIPC or TAZ caused adverse change in reproductive performance of the F0 generation only at doses that caused maternal toxicity. The F1 and F2 generation were not affected.(ABSTRACT TRUNCATED AT 400 WORDS)
Sato
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Drug Safety Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
Lochry
E A
EA
Hoberman
A M
AM
Christian
M S
MS
D000818:Animals; D004359:Drug Therapy, Combination / Q000633:toxicity*; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007274:Injections, Intraperitoneal; 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