title: [Convulsive liability of an oral carbapenem antibiotic, tebipenem pivoxil].
abstract: Tebipenem pivoxil (TBPM-PI), the first oral carbapenem antibiotic both in Japan and abroad, was examined on its convulsive liability. We used ICR male mice and Sprague-Dawley male rats to examine the pro-convulsive effect and anticonvulsive effect of TBPM-PI and its active metabolite, TBPM. (1) When mice were treated with TBPM-PI (30-1000 mg/kg, p.o.) or TBPM (10-300 mg/kg, i.v.), no convulsion was noted at any dose level. When rats were treated with TBPM (300 mg/kg, i.v.), no convulsant effects were noted in electroencephalography or behavioral observation. In intraventricular injection of TBPM in mice, clonic convulsion was observed in 7/10 animals at 100 microg but no effect at 30 microg. On the other hand, the administration of 10/10 microg imipenem/cilastatin (IPM/CS) resulted in clonic convulsion in all animals and tonic convulsion in 3/10 animals, and 4/10 animals died. The administration of 100 microg meropenem did not cause any effects. (2) When mice were co-administered with pentylenetetrazole (45 mg/kg: maximum dose level at which no convulsion is induced) and TBPM-PI (30-300 mg/kg, p.o.) or TBPM (300 mg/kg, i.v.), convulsion enhancing effect was not noted. On the other hand, the co-administration of pentylenetetrazole with IPM/CS (300/300 mg/kg, i.v.) enhanced a convulsive effect of pentylenetetrazole. (3) When mice were treated with TBPM-PI (30-300 mg/kg, p.o.) or TBPM (100 mg/kg, i.v.), inhibitory effect was not noted on convulsions induced by electrostimulation, pentylenetetrazole or strychinine. In conclusion, there were no pro-convulsive effects or anticonvulsive effect in the oral administration of TBPM-PI or intravenous administration of TBPM. Pro-convulsive effect was observed in the intraventricular injection of TBPM as in the case of other carbapenem antibiotics, but such action was weaker than that in IPM/CS administration. Accordingly, the risk of occurrence of convulsion related to TBPM-PI administration was low compared to IPM/CS administration, and TBPM-PI was considered to be less potential to induce convulsions in clinical use.
authors.affiliation: Applied Pharmacology Research Labs., Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yagi
authors.forename: Toru
authors.initials: T
authors.lastname: Nawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kurata
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shibasaki
authors.forename: Hisashi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Tohru
authors.initials: T
authors.lastname: Kurosawa
mesh_terms: D000284:Administration, Oral; D000818:Animals; D015780:Carbapenems / Q000008:administration & dosage / Q000009:adverse effects*; D015377:Cilastatin / Q000008:administration & dosage / Q000009:adverse effects; D000077728:Cilastatin, Imipenem Drug Combination; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004357:Drug Synergism; D015378:Imipenem / Q000008:administration & dosage / Q000009:adverse effects; D007262:Infusions, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D012640:Seizures / Q000139:chemically induced*
chemical_list: D015780:Carbapenems; D004338:Drug Combinations; D015377:Cilastatin; D015378:Imipenem; D000077728:Cilastatin, Imipenem Drug Combination; C500135:tebipenem; D010433:Pentylenetetrazole