Biphenylacetic acid enhances the antagonistic action of fluoroquinolones on the GABA(A)-mediated responses of the isolated guinea-pig ileum

This paper examines the effect of biphenylacetic acid on the antagonistic a ction of norfloxacin and enoxacin on the GABA(A)-mediated responses of the isolated guinea-pig ileum. GABA produced transient contractions followed by relaxation. The contractile effect of exogenously applied GABA was concent ration-dependent with EC50 = 9.8 x 10(-6) M. This contractile effect was no t significantly modified by biphenylacetic acid, and the EC50 value for GAB A in the presence of 10(-5) M biphenylacetic acid was 1.15 x 10(-5) M. The GABA contractile effect was inhibited, dose-dependently, by either norfloxa cin or enoxacin, but only at concentrations higher than 10(-5) M. The respo nse of the ileum to GABA (at EC50) was reduced to 35 and 36% by pretreatmen t with 10(-5) M norfloxacin or enoxacin, respectively. However, in the pres ence of 10(-5) M biphenylacetic acid, the response of the ileum to GABA was reduced to 2.2% by pretreatment with 10(-5) M enoxacin, while it was compl etely abolished by pretreatment with 10(-5) M norfloxacin and the IC50 valu es were 5.5 x 10(-7) and 1.5 x 10(-6) M for norfloxacin and enoxacin, respe ctively. These data show that biphenylacetic acid whilst having no effect a t the GABA(A)-mediated contractile response of the guinea-pig ileum, enhanc es the antagonistic effect of both enoxacin and norfloxacin. This suggests that combined administration of fluoroquinolones and biphenylacetic acid sy nergistically inhibits GABA(A)-receptors at the intestinal level. (C) 2001 Academic Press.