Low convulsive activity of a new carbapenem antibiotic, DK-35C, as compared with existing congeners

Since carbapenems and cephalosporins have been suggested to induce convulsi ve side effects through an inhibitory action on the central gamma-aminobuty ric acid (GABA)-mediated inhibitory transmission, the present study evaluat ed the convulsive activity of a new carbapenem antibiotic (1R,5S,6S)-6[(R)- 1-hydroxyethyl]-2-[(3S,5S)-5(S-methyl-4-thiomorpholinylcarbonyl)pyrrolidin- 3-thio]-1-methylcarbapen-2-em-3-carboxylic acid (DK-35C) in in vitro and in vivo experiments, in comparison with cefazolin, imipenem and meropenem. In in vitro experiments, their abilities to inhibit [H-3]muscimol (5 nM) bind ing to GABA, receptors were measured using crude synaptic membranes prepare d from the rat cerebral cortex. The concentrations (mM) of the antibiotics which inhibit 50% of the specific binding, were 0.6 for imipenem, 1.8 for c efazolin, 15.4 for DK-35C and 27.6 for meropenem. In in vivo experiments, i ntracerebroventricular (i.c.v.) injections of cefazolin, imipenem and DK-35 C induced convulsions in a dose-dependent manner in rats. The doses (nmol/r at) of the antibiotics which induce convulsions in 50% of rats, were 57 for imipenem, 96 for cefazolin, 377 for DK-35C and > 3000 for meropenem. In th e mouse pentyienetetrazole (PTZ) convulsive model, intravenous pretreatment with cefazolin (800 mg/kg) or imipenem (200 mg/kg) shifted the dose-respon se curve of PTZ (i.p.) to the left, indicating enhancement of the convulsiv e activity of PTZ. However, pretreatment with cefazolin, meropenem or DK-35 C at a dose of 400 mg/kg did not produce any marked effects on the convulsi ve activity of PTZ compared with the saline vehicle-pretreated control. The results clearly demonstrate a good correlation between in vitro GABA(A) re ceptor binding assay and in vivo i.c.v. convulsive model using rats, and su ggest that DK-35C may possess a relatively weak convulsive activity mediate d through an interaction with GABA, receptors. (C) 1999 Elsevier Science Ir eland Ltd. All rights reserved.