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Journal of Antimicrobial Chemotherapy (1994) 34, 737-746
© 1994 The British Society for Antimicrobial Chemotherapy

research-article

Quantitation of GABAA receptor inhibition required for quinolone-induced convulsions in mice

Y. Tsutomi, K. Matsubayashi and K. Akabane*

Exploratory Research Laboratories I. Daiichi Pharmaceutical Co. 1-16 13 Kitakasai, Edogawa, Tokyo 134, Japan

Received 1 February 1994; accepted 20 June 1994

*Corresponding author.

We quantified the amount of inhibition of {gamma}-aminobutyric acid (GABA)A receptor binding required for the onset of convulsions induced by ciprofloxacin in combination with biphenylacetic acid (BPAA) in mice. In fasting mice iv ciprofloxacin given 30 min after oral BPAA (50 mg/kg) induced convulsions at does of 40 mg/kg or above. In contrast, ofloxacin caused no convulsions even at 100 mg/kg, the highest dose tested. When mice received 40 mg/kg of ciprofloxacin or ofloxacin, maximal brain concentrations of each quinolone at 30 min were 0.37 or 1.97 µg/g, respectively. These brain concentrations of ciprofloxacin and ofloxacin were not affected by combination with BPAA. In the presence of ciprofloxacin and BPAA (at brain tissue concentrations which induced convulsions), the binding of 3H-muscimol to GABAA receptor sites was inhibited by approximately 30%. Using results from a similar binding study, an impracticable iv dose of ofloxacin (500 mg/kg) was estimated to be required to inhibit GABAA receptor binding by 30%, and therefore to induce similar convulsions to those seen with ciprofloxacin at a dose of 40 mg/kg. These results may indicate that epileptic convulsions occur when ciprofloxacin and BPAA interact with each other to antagonize at least 30% of GABAA receptor binding in mice, and provide evidence for a significant role of GABAA receptor inhibition in the occurrence of quinolone-induced convulsions.


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