In Vivo and In Vitro Toxicodynamic Analyses of New Quinolone-and Nonsteroidal Anti-Inflammatory Drug-Induced Effects on the Central Nervous System

Abstract

We investigated the correlation between an in vivo isobologram based on the concentrations of new quinolones (NQs) in brain tissue and the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) for the occurrence of convulsions in mice and an in vitro isobologram based on the concentrations of both drugs for changes in the γ-aminobutyric acid (GABA)-induced current response in Xenopus oocytes injected with mRNA from mouse brains in the presence of NQs and/or NSAIDs. After the administration of enoxacin (ENX) in the presence or absence of felbinac (FLB), ketoprofen (KTP), or flurbiprofen (FRP), a synergistic effect was observed in the isobologram based on the threshold concentration in brain tissue between mice with convulsions and those without convulsions. The three NSAIDs did not affect the pharmacokinetic behavior of ENX in the brain. However, the ENX-induced inhibition of the GABA response in the GABAA receptor expressed in Xenopus oocytes was enhanced in the presence of the three NSAIDs. The inhibition ratio profiles of the GABA responses for both drugs were analyzed with a newly developed toxicodynamic model. The inhibitory profiles for ENX in the presence of NSAIDs followed the order KTP (1.2 μM) > FRP (0.3 μM) > FLB (0.2 μM). These were 50- to 280-fold smaller than those observed in the absence of NSAIDs. The inhibition ratio (0.01 to 0.02) of the GABAA receptor in the presence of both drugs was well-fitted to the isobologram based on threshold concentrations of both drugs in brain tissue between mice with convulsions and those without convulsions, despite the presence of NSAIDs. In mice with convulsions, the inhibitory profiles of the threshold concentrations of both drugs in brain tissue of mice with convulsions and those without convulsions can be predicted quantitatively by using in vitro GABA response data and toxicodynamic model.

Quantitative Comparison of the Convulsive activity of Combinations of Twelve Fluoroquinolones with Five Nonsteroidal Antiinflammatory Agents

“…Pharmacodynamic model: To analyze the inhibitory effects of the combinations of the fluoroquinolones and NSAIDs on [ 3 H]muscimol binding to the GABAA receptor, the following model, previously developed by us, 6) was used with minor modification. With regard to the binding of fluoroquinolones and NSAIDs to GABAA receptor, three mass balance equations [1][2][3] may be written, as Ki?…”

“…We previously reported that the convulsive activity of at least some combinations of fluoroquinolones and NSAIDs is synergistic, as determined using isobolograms for the occurrence of convulsions and the concentrations of enoxacin (ENX) and three NSAIDs in mouse brain. 6) We have also shown that the convulsive activity of fluoroquinolones in vivo can be estimated from in vitro studies of receptor occupancy. 6,7) This study investigates the convulsive activity of twelve fluoroquinolones in the presence or absence of five NSAIDs, using GABAA receptor binding assay.…”

“…6) We have also shown that the convulsive activity of fluoroquinolones in vivo can be estimated from in vitro studies of receptor occupancy. 6,7) This study investigates the convulsive activity of twelve fluoroquinolones in the presence or absence of five NSAIDs, using GABAA receptor binding assay. For fenbufen, we investigated the effect of its metabolite, 4biphenylacetic acid (BPAA), which accounts for the potentiation of convulsive activity.…”

“…For fenbufen, we investigated the effect of its metabolite, 4biphenylacetic acid (BPAA), which accounts for the potentiation of convulsive activity. 6) We also estimated the risk of convulsion in a clinical setting using a pharmacodynamic model based on receptor occupancy.…”

Effects of Acute Renal Failure and Ganciclovir on the Pharmacodynamics of Levofloxacin-Induced Seizures in Rats

“…2) The convulsant activity of fluoroquinolones was related to the inhibition of the binding of gamma-aminobutyric acid (GABA) to its receptor in the central nervous system, 3,4) and this response was potentiated by non-steroidal anti-inflammatory drugs. [4][5][6] Seizures were also reported to occur in patients with renal insufficiency. 7) Kawakami et al 8) reported that renal failure can potentiate the neurotoxicity of enoxacin not only by a decreased capability for renal elimination of the drug but also by an increased sensitivity to convulsant activity of enoxacin in the central nervous system.…”