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

1 Fluoroquinolones (FQs) are associated with a low incidence of central ner vous system (CNS) side effects, possibly leading to convulsions, especially when co-administered with nonsteroidal antiinflammatory drugs (NSAIDS). Al though the in vha pro-convulsant activity of NSAIDS is essentially unknown, the convulsant potential of FQs is traditionally evaluated by in vitro gam ma-aminobutyric acid (GABA) binding experiments in the presence of 4-biphen yl acetic acid (BPAA), the active metabolite of fenbufen. 2 The aim of this study was therefore to investigate the BPAA-norfloxacin c onvulsant interaction in vivo. 3 Male Sprague-Dawley rats (n=27) were given BPAA orally, at various doses Ih before norfloxacin infusion, which was maintained until the onset of max imal seizures, when cerebrospinal fluid (CSF) and plasma samples were colle cted for analysis. 4 An inhibitory E-max effect model with a baseline effect parameter was fit ted to the norfloxacin versus BPAA concentrations in the CSF, previously sh own to be part of the biophase. This model includes three parameters: the c oncentrations of norfloxacin in the absence of BPAA (C-CSFO, (Nor)), and wh en BPAA concentration tends toward infinity (C-CSFbase, (Nor)), and the BPA A concentration for which half of the maximal effect is observed (C-CSF50, (BPAA)) The maximal proconvulsant effect of BPAA is given by the C-CSF0, (N or) / 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 diffusion of norfloxacin and protein binding of BPAA. 6 In conclusion this study has shown that the convulsant interaction betwee n norfloxacin and BPAA in rats, can be adequately characterized by modellin g of the CSF concentrations of the two drugs at the onset of activity, foll owing their administration in various proportions.