[Single-dose toxicity study and twenty-eight-days intravenously repeated dose toxicity study of desethyl-piperacillin in rats].
Desethyl-piperacillin (desethyl-PIPC) is an active metabolite of PIPC which was newly found in clinical field. We carried out a single intravenous toxicity study at the dosage of 2000 mg/kg, and 28-days intravenous toxi-city study at the daily dosage of 400 mg/kg followed by 28-days recovery study using both sexes of rats. The following results were obtained. In the single dose toxicity study, no deaths occurred in rats injected 2000 mg/kg of desethyl-PIPC, therefore it is presumed that minimal lethal dose of desethyl-PIPC is over 2000 mg/kg in both sexes. As clinical signs, decrease in locomotor activity, deep breath and loose stool were observed. In the patho-logical study, dilatation of cecal lumen was observed macroscopically, but no significant changes were observed histologically. In the repeated dose toxicity study, loose stool, increase in water consumption, dilatation of cecal lumen and increase in its weight were noted. These abnormal findings were considered to be due to antimicrobial activity of desethyl-PIPC. In addition, decrease in the ratio of serum gamma-globulin and increase in the ratio of alpha 1-globulin were observed, but A/G ratio was not affected. After withdrawal of desethyl-PIPC administration, these abnormal findings tended to disappear. As mentioned above, the minimal lethal dose of desethyl-PIPC is over 2000 mg/kg in the single dose toxicity study and abnormal signs were slight in the repeated dose toxicity study at the dosage of 400 mg/kg of desethyl-PIPC for 28 days in rats. It is, therefore, concluded that desethyl-PIPC is a low toxic metabolite of PIPC.
Nakamura
S
S
Drug Safety Research Laboratory, Toyama Chemical Co., Ltd., Japan.
Sanzen
T
T
Nakagawa
S
S
Yoshida
K
K
Shibata
T
T
Kawamura
Y
Y
Kodama
T
T
D000510:Alpha-Globulins / Q000378:metabolism; D000818:Animals; D002432:Cecum / Q000187:drug effects / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D004108:Dilatation, Pathologic / Q000139:chemically induced; D004326:Drinking / Q000187:drug effects; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010878:Piperacillin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects; D005719:gamma-Globulins / Q000378:metabolism
D000510:Alpha-Globulins; D005719:gamma-Globulins; C068097:desethylpiperacillin; D010878:Piperacillin