title: Correlation between in vitro and in vivo models of proconvulsive activity with the carbapenem antibiotics, biapenem, imipenem/cilastatin and meropenem.
abstract: The present study evaluated the proconvulsant liability of biapenem, a novel carbapenem antibiotic, in in vitro and in vivo experiments, in comparison with the carbapenems, imipenem/cilastatin and meropenem. Imipenem/cilastatin is a carbapenem antibiotic with known proconvulsive liability in man and in animal experiments. In in vivo studies imipenem/cilastatin, at doses of 400/400 mg/kg i.v., significantly lowered the convulsive threshold of pentylenetetrazol (PTZ) in mice and shifted the dose-response curve of PTZ. The effects of biapenem (400 mg/kg i.v.) and another reference carbapenem, meropenem (400 mg/kg i.v.), in the mouse PTZ model were not significantly different from control. In in vitro experiments the carbapenems were tested for their ability to inhibit [3H]muscimol (1.3 mM) binding to rat brain homogenates at concentrations of 1-10 mM. Similar to in vivo results, when compared to imipenem/cilastatin, biapenem and meropenem did not inhibit [3H]muscimol binding to the GABAA receptor complex in brain homogenates while imipenem/cilastatin exhibited significant inhibition (IC50 = 4.6 mM). These results further confirm the correlation between in vitro GABAA binding and in vivo PTZ convulsive testing with carbapenem antibiotics, and suggest that biapenem possesses a low proconvulsive liability.
authors.affiliation: American Cyanamid Company, Pearl River, New York, USA.
authors.forename: I P
authors.initials: IP
authors.lastname: Day
authors.forename: J
authors.initials: J
authors.lastname: Goudie
authors.forename: K
authors.initials: K
authors.lastname: Nishiki
authors.forename: P D
authors.initials: PD
authors.lastname: Williams
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001667:Binding, Competitive; D015377:Cilastatin / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015378:Imipenem / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D007275:Injections, Intravenous; D008297:Male; D000077731:Meropenem; D051379:Mice; D009118:Muscimol / Q000378:metabolism; D010433:Pentylenetetrazole / Q000633:toxicity; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced*; D013845:Thienamycins / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D011963:Receptors, GABA-A; D013845:Thienamycins; D015377:Cilastatin; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D015378:Imipenem; D000077731:Meropenem; D010433:Pentylenetetrazole; C065257:biapenem