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Application of a Combined “Effect Compartment/Indirect Response Model” to the Central Nervous System Effects of Tiagabine in the Rat

  • Adriaan Cleton
  • Henrik J. M. M. de Greef
  • Peter M. Edelbroek
  • Robert A. Voskuyl
  • Meindert DanhofEmail author
Article

Abstract

Pharmacological inhibition of GABA uptake transporters provides a mechanism for increasing GABAergic transmission, which may be useful in the treatment of various neurological disorders. The purpose of our investigations was to develop an integrated pharmacokinetic–pharmacodynamic (PK/PD) model for the characterization of the pharmacological effect of tiagabine, R-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl)nipecotic acid, in individual rats in vivo. The tiagabine-induced increase in the amplitude of the EEG 11.5–30 Hz frequency band (β), was used as pharmacodynamic endpoint. Chronically instrumented male Wistar rats were randomly allocated to four groups which received an infusion of 3, 10, or 30 mg kg−1\((\bar x \pm SE,{\text{ }}n = 23)\)\(96 \pm 9\)ml min-1 kg−1, 1.5ŷ0.1 L kg−1and 20ŷ0.2 min.A time delay was observed between the occurrence of maximum plasma drug concentrations and maximal response. A physiological PK/PD model has been used to account for this time delay, in which a biophase was postulated to account for tiagabine available to the GABA uptake carriers in the synaptic cleft and the increase in EEG effect was considered an indirect response due to inhibition of GABA uptake carriers. The population values for the pharmacodynamic parameters characterizing the delay in pharmacological response relative to plasma concentrations were keo=0.030 min−1and kout=81 min−1, respectively. Because of the large difference in these values the PK/PD model was simplified to the effect compartment model. Population estimates\((\bar x \pm SE)\)were E0=155 ŷ 6 μV, Emax=100 ŷ 5 μV, EC50=287 ŷ 7 ng ml−1, Hill factor=1.8 ŷ 0.2 and keo=0.030 ŷ 0.002 min−1. The results of this analysis show that for tiagabine the combined “effect compartment-indirect response” model can be simplified to the classical “effect compartment” model.

pharmacokinetics pharmacodynamics effect compartment model indirect response sigmoid Emax tiagabine GABA uptake inhibitor 

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Copyright information

© Plenum Publishing Corporation 1999

Authors and Affiliations

  • Adriaan Cleton
    • 1
  • Henrik J. M. M. de Greef
    • 1
  • Peter M. Edelbroek
    • 2
    • 3
  • Robert A. Voskuyl
    • 2
  • Meindert Danhof
    • 1
    Email author
  1. 1.Division of Pharmacology, Leiden/Amsterdam Center for Drug ResearchLeiden UniversityLeidenThe Netherlands
  2. 2.Stichting Epilepsie Instellingen NederlandHeemstede
  3. 3.Department of PhysiologyLeiden University Medical CenterLeidenThe Netherlands

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