Parabolic equation relating free and total drug concentrations in cases of nonlinear plasma protein binding

Behm, Harriet L.; Wagner, John G.

doi:10.1002/jps.2600700725

Cited by 7 publications

(2 citation statements)

References 13 publications

(9 reference statements)

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“…However plasma protein binding of norfloxacin was linear (and actually almost negligible) but not that of BPAA. The Langmuir equation (Behm & Wagner, 1981; Benincosa & Morris, 1993; Kochak et al ., 1993) (), was successful in fitting BPAA bound (C B ) versus free plasma (C U ) concentrations: where C Bmax, BPAA is the maximal concentration of BPAA necessary to saturate 100% of binding sites, and C U50, BPAA is the unbound BPAA fraction which could saturate 50% of binding sites of BPAA. By re‐organization of the , one obtains unbound concentrations (C U, BPAA ) as a function of the total plasma concentration of BPAA (C P, BPAA ) (see ) where Norfloxacin unbound versus plasma total concentrations were linearly related and fitted according to the following equation (): where fu is the free fraction of norfloxacin in plasma.…”

Section: Methodsmentioning

confidence: 99%

“…The Langmuir equation (Behm & Wagner, 1981;Benincosa & Morris, 1993;Kochak et al, 1993) (Equation 5a), was successful in ®tting BPAA bound (C B ) versus free plasma (C U ) concentrations: Figure 1 Schematic representation of the convulsant interaction between nor¯oxacin and BPAA with distinction between the pharmacodynamic interaction of the two compounds in CSF (biophase) and the pharmacokinetic relationships characteristic of the CSF diusion and plasma protein binding of each compound.…”

Section: Csf Concentrations Modellingmentioning

confidence: 99%

See 1 more Smart Citation

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

Marchand

Pariat

Bouquet

et al. 2000

British J Pharmacology

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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.

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