Pharmacokinetic-pharmacodynamic modelling of tiagabine CNS effects upon chronic treatment in rats: lack of change in concentration-EEG effect relationship.
Eur J Pharm Sci
; 12(2): 141-50, 2000 Dec.
Article
em En
| MEDLINE
| ID: mdl-11102742
ABSTRACT
The pharmacodynamics of the gamma-aminobutyric acid (GABA) uptake inhibitor (R)-N-(4,4-di-(methylthien-2-yl)but-3-enyl) nipecotic acid (tiagabine) was quantified in rats following chronic (14 days) administration by an integrated pharmacokinetic-pharmacodynamic (PK/PD) modelling approach. The increase in beta activity (11.5-30 Hz) of the EEG as derived by fast Fourier transformation analysis was used as pharmacodynamic endpoint. Two groups of male Wistar rats were treated for 14 days with either tiagabine at a steady-state concentration of 198+/-10 ng ml(-1) or placebo. Chronic treatment with tiagabine resulted in an increase of the EEG effect parameter by 38+/-2 microV. In the PK/PD experiment the time course of the EEG effect was determined in conjunction with the decline of drug concentrations after an i.v. bolus administration of 10 mg kg(-1). The pharmacokinetics of tiagabine was most adequately described by a bi-exponential function. No influence of chronic treatment on the pharmacokinetics was observed. Hysteresis between plasma concentration and EEG effect was accounted for by incorporation of an 'effect-compartment' in the model. The observed relationship between tiagabine concentrations and EEG effect was non-linear and described on the basis of the Hill equation. Between the treatment groups no differences in the pharmacodynamic parameters were observed. The population means for the different pharmacodynamic parameters were maximum EEG effect 82 microV, EC(50) 486 ng ml(-1), Hill factor 2.0 and k(e0) 0.060 min(-1). In the in vitro [(3)H]GABA uptake assay no changes in affinity or functionality for the GABA uptake transporter were observed, consistent with the absence of adaptation. It is concluded that chronic treatment with tiagabine in an effective dose range for 14 days does not produce functional adaptation to tiagabine-induced GABA-ergic inhibition in vivo.
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Base de dados:
MEDLINE
Assunto principal:
Encéfalo
/
Eletroencefalografia
/
Ácido gama-Aminobutírico
/
Anticonvulsivantes
/
Ácidos Nipecóticos
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Eur J Pharm Sci
Assunto da revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2000
Tipo de documento:
Article
País de afiliação:
Holanda