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Pharmacokinetic‐pharmacodynamic modelling of the convulsant interaction between norfloxacin and biphenyl acetic acid in rats
Author(s) -
Marchand Sandrine,
Pariat Claudine,
Bouquet Serge,
Courtois Philippe,
Couet William
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703260
Subject(s) - convulsant , norfloxacin , pharmacology , chemistry , metabolite , pharmacokinetics , in vivo , biochemistry , antibiotics , medicine , biology , receptor , microbiology and biotechnology , ciprofloxacin
Fluoroquinolones (FQs) are associated with a low incidence of central nervous system (CNS) side effects, possibly leading to convulsions, especially when co‐administered with nonsteroidal anti‐inflammatory 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 γ‐aminobutyric acid (GABA) binding experiments in the presence of 4‐biphenyl acetic acid (BPAA), the active metabolite of fenbufen. The aim of this study was therefore to investigate the BPAA‐norfloxacin convulsant interaction in vivo . Male Sprague‐Dawley rats ( n =27) were given BPAA orally, at various doses 1 h before norfloxacin infusion, which was maintained until the onset of maximal seizures, when cerebrospinal fluid (CSF) and plasma samples were collected for analysis. An inhibitory E max effect model with a baseline effect parameter was fitted to the norfloxacin versus BPAA concentrations in the CSF, previously shown to be part of the biophase. This model includes three parameters: the concentrations of norfloxacin in the absence of BPAA (C CSF0, Nor ), and when BPAA concentration tends toward infinity (C CSFbase, Nor ), and the BPAA 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, Nor / C CSFbase, Nor ratio, estimated to approximately 6 in this study. Derived models were developed in plasma to account for the non‐linear CSF diffusion of norfloxacin and protein binding of BPAA. In conclusion this study has shown that the convulsant interaction between norfloxacin 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.British Journal of Pharmacology (2000) 129 , 1609–1616; doi: 10.1038/sj.bjp.0703260