Low convulsive activity of a new carbapenem antibiotic, DK-35C, as compared with existing congeners.
Since carbapenems and cephalosporins have been suggested to induce convulsive side effects through an inhibitory action on the central gamma-aminobutyric acid (GABA)-mediated inhibitory transmission, the present study evaluated the convulsive activity of a new carbapenem antibiotic (1R,5S,6S)-6[(R)-1-hydroxyethyl]-2-[(3S,5S)-5(S-methyl-4thiomorpholin  ylcarbonyl)pyrrolidin-3-thio]-l-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 [3H]muscimol (5 nM) binding to GABA(A) receptors were measured using crude synaptic membranes prepared 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 cefazolin, 15.4 for DK-35C and 27.6 for meropenem. In in vivo experiments, intracerebroventricular (i.c.v.) injections of cefazolin, imipenem and DK-35C induced convulsions in a dose-dependent manner in rats. The doses (nmol/rat) 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 the mouse pentylenetetrazole (PTZ) convulsive model, intravenous pretreatment with cefazolin (800 mg/kg) or imipenem (200 mg/kg) shifted the dose-response curve of PTZ (i.p.) to the left, indicating enhancement of the convulsive activity of PTZ. However, pretreatment with cefazolin, meropenem or DK-35C at a dose of 400 mg/kg did not produce any marked effects on the convulsive activity of PTZ compared with the saline vehicle-pretreated control. The results clearly demonstrate a good correlation between in vitro GABA(A) receptor binding assay and in vivo i.c.v. convulsive model using rats, and suggest that DK-35C may possess a relatively weak convulsive activity mediated through an interaction with GABA(A) receptors.
Jin
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C
Bioanalysis and Biotransformation Research Center, Korea Institute of Science and Technology, Seoul, South Korea. cbjin@kistmail.kist.re.kr
Jung
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I
Ku
H J
HJ
Yook
J
J
Kim
D H
DH
Kim
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M
Cho
J H
JH
Oh
C H
CH
D000818:Animals; D015780:Carbapenems / Q000378:metabolism / Q000633:toxicity*; D002437:Cefazolin / Q000633:toxicity; D002511:Cephalosporins / Q000633:toxicity; D018755:GABA Agonists / Q000378:metabolism; D015378:Imipenem / Q000633:toxicity; D007276:Injections, Intraventricular; D008297:Male; D000077731:Meropenem; D051379:Mice; D008813:Mice, Inbred ICR; D009118:Muscimol / Q000378:metabolism; D010433:Pentylenetetrazole; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced*; D013570:Synaptic Membranes / Q000187:drug effects; D013845:Thienamycins / Q000633:toxicity
D015780:Carbapenems; D002511:Cephalosporins; C401103:DK 35C; D018755:GABA Agonists; D011963:Receptors, GABA-A; D013845:Thienamycins; D009118:Muscimol; D015378:Imipenem; D000077731:Meropenem; D002437:Cefazolin; D010433:Pentylenetetrazole