The effects of quinolones and NSAIDs upon GABA-evoked currents recorded from rat dorsal root ganglion neurones.
Recent animal studies have demonstrated a proconvulsant effect of certain quinolone and non-steroidal anti-inflammatory drug combinations. Radioligand binding experiments have indicated that these actions may be mediated by antagonism of the GABAA receptor. The present study has further investigated this hypothesis in a functional assay by examining the effects of the quinolones ciprofloxacin and ofloxacin alone and in combination with either fenbufen or biphenyl acetic acid (BPAA) upon GABA-evoked currents recorded from voltage-clamped rat dorsal root ganglion neurones (DRG) maintained in cell culture. GABA-evoked whole cell currents were weakly but dose-dependently (30 microM-1 mM) reduced in the presence of ciprofloxacin and ofloxacin. The IC50 for ciprofloxacin was 100 microM but greater than 1 mM for ofloxacin. Application of either fenbufen (100 microM) or BPAA (100 microM) alone produced little effect on the GABA-evoked currents. However, the inhibitory action of ciprofloxacin was enhanced in the presence of 100 microM fenbufen by approximately five-fold whereas the antagonism of GABA responses by ofloxacin was unaffected. In contrast, BPAA (100 microM) had a dramatic effect on the inhibitory actions of both antibiotics such that the IC50 for ciprofloxacin and ofloxacin was reduced to 0.03 and 0.3 microM respectively. The present results support earlier binding studies and extend them by demonstrating electrophysiologically a potent quinolone/NSAID drug interaction at the GABAA receptor. The mechanism(s) of this novel interaction remains to be determined. These results are commensurate with clinical observations of an increased risk of fits in patients prescribed certain quinolones together with certain NSAIDs.
Halliwell
R F
RF
Department of Pharmacology and Clinical Pharmacology, Ninewells Hospital and Medical School, Dundee, UK.
Davey
P G
PG
Lambert
J J
JJ
D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002478:Cells, Cultured / Q000187:drug effects; D002939:Ciprofloxacin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D005727:Ganglia, Spinal / Q000187:drug effects; D015242:Ofloxacin / Q000494:pharmacology*; D010648:Phenylacetates / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D051381:Rats
D000894:Anti-Inflammatory Agents, Non-Steroidal; D058787:GABA-A Receptor Antagonists; D010648:Phenylacetates; D010654:Phenylbutyrates; C012776:biphenylylacetic acid; D002939:Ciprofloxacin; C010725:fenbufen; D015242:Ofloxacin