Pharmacokinetic‐pharmacodynamic modelling of the convulsant interaction between norfloxacin and biphenyl acetic acid in rats

Abstract

1 Fluoroquinolones (FQs) are associated with a low incidence of central nervous system (CNS) side eects, possibly leading to convulsions, especially when co-administered with nonsteroidal antiin¯ammatory drugs (NSAIDS). Although the in vivo pro-convulsant activity of NSAIDS is essentially unknown, the convulsant potential of FQs is traditionally evaluated by in vitro gaminobutyric acid (GABA) binding experiments in the presence of 4-biphenyl acetic acid (BPAA), the active metabolite of fenbufen. 2 The aim of this study was therefore to investigate the BPAA-nor¯oxacin convulsant interaction in vivo. 3 Male Sprague-Dawley rats (n=27) were given BPAA orally, at various doses 1 h before nor¯oxacin infusion, which was maintained until the onset of maximal seizures, when cerebrospinal uid (CSF) and plasma samples were collected for analysis. 4 An inhibitory E max eect model with a baseline eect parameter was ®tted to the nor¯oxacin versus BPAA concentrations in the CSF, previously shown to be part of the biophase. This model includes three parameters: the concentrations of nor¯oxacin in the absence of BPAA (C CSF0, Nor ), and when BPAA concentration tends toward in®nity (C CSFbase, Nor ), and the BPAA concentration for which half of the maximal eect is observed (C CSF50, BPAA ). The maximal proconvulsant eect of BPAA is given by the C CSF0, Nor / C CSFbase, Nor ratio, estimated to approximately 6 in this study. 5 Derived models were developed in plasma to account for the non-linear CSF diusion of nor¯oxacin and protein binding of BPAA. 6 In conclusion this study has shown that the convulsant interaction between nor¯oxacin and BPAA in rats, can be adequately characterized by modelling of the CSF concentrations of the two drugs at the onset of activity, following their administration in various proportions.

Convulsant and Subconvulsant Doses of Norfloxacin in the Presence and Absence of Biphenylacetic Acid Alter Extracellular Hippocampal Glutamate but Not Gamma-Aminobutyric Acid Levels in Conscious Rats

“…It is known that BPAA itself shows no binding affinity for GABA A receptors (2) and has no effect on GABA-activated currents (12). We observed earlier that even at oral doses as high as 300 mg/kg, BPAA alone does not induce seizures in rats (17). Accordingly, neither behavioral changes nor alterations in GABA and glutamate overflows in the hippocampus were observed in the animals treated with BPAA (100 mg/kg p.o.)…”

“…Therefore, the dose of norfloxacin in the presence of BPAA also had to be adjusted. Consistent with the fact that BPAA increases the convulsant effect of norfloxacin by about sixfold (17), it was decided to reduce the norfloxacin dose sixfold (from 300 to 50 mg/kg) in rats pretreated with BPAA. This adjustment turned out to be appropriate since in this group, too, about 50% of the rats exhibited severe seizures, allowing comparisons between animals treated with norfloxacin alone and animals treated with norfloxacin in the presence of BPAA.…”

“…infusions of norfloxacin in rats until the onset of maximal seizures (5,6,7,17). The dose of norfloxacin that induced convulsant activity varied with the infusion rate and therefore the duration (5) but was, on average, on the order of 2 mmol/kg, which is close to 600 mg/kg.…”

“…Dose adjustments in rats treated with both BPAA and norfloxacin were more challenging because two drugs were involved. We have shown earlier that the proconvulsant effect of BPAA tended toward a maximum when the administered dose increased, and in practice, an oral dose of 50 mg/kg would produce a proconvulsant effect close to the maximum (17). A dose of 100 mg/kg was therefore selected in order to avoid any absence of effects due to an insufficient dose of BPAA.…”

“…It was shown that both the central diffusion and the affinity for the receptors responsible for the epileptogenic activity vary considerably among FQs, from which it was concluded that these two factors must be considered for prediction of convulsant activity in vivo (7). The proconvulsant effect of BPAA on norfloxacin, selected as a representative FQ, was investigated by the same type of approach (17). The objective of the present study was to elucidate more about the mechanism of convulsant activity of norfloxacin in vivo, both in the absence and in the presence of BPAA, by intracerebral microdialysis in conscious, freely moving rats.…”