title: Pharmacodynamic analysis of the interaction between tiagabine and midazolam with an allosteric model that incorporates signal transduction.
abstract: OBJECTIVE
  The objective of this study was to characterize quantitatively the pharmacodynamic interaction between midazolam (MDL), an allosteric modulator of the gamma-aminobutyric acid subtype A (GABAA) receptor, and tiagabine (TGB), an inhibitor of synaptic GABA uptake.
  
  
  METHODS
  The in vivo concentration-response relation of TGB was determined through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Rats received a single intravenous dose of 10 mg/kg TGB in the absence and the presence of a steady-state plasma concentration of MDL. The EEG response in the 11.5- to 30-Hz frequency band was used as the pharmacodynamic end point.
  
  
  RESULTS
  Infusion of MDL resulted in a mean steady-state plasma concentration of 66 +/- 3 ng/ml. A significant pharmacokinetic interaction with TGB was observed. MDL inhibited TGB clearance by 20 +/- 7 ml/min/kg from the original value of 89 +/- 6 ml/min/kg. However, no changes in plasma protein binding of both drugs were observed. The concentration-EEG relation of TGB was described by the sigmoid-Emax model. The pharmacodynamic parameter estimates of TGB were: Emax = 327 +/- 10 microV, EC50 = 392 +/- 20 ng/ml, and nH = 3.1 +/- 0.3. These values were not significantly different in the presence of MDL. Factors that may explain the lack of synergism were identified by a mechanism-based interaction model that separates the receptor activation from the signal-transduction process. High efficiency of signal transduction and the presence of a baseline response were shown to diminish the degree of synergism.
  
  
  CONCLUSIONS
  We conclude that the in vivo pharmacodynamic interaction between MDL and TGB is additive rather than synergistic. This strongly suggests that allosteric modulation of the antiseizure activity of a GAT-1 inhibitor by a benzodiazepine does not offer a therapeutic advantage.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorlaeus Laboratory, Leiden, The Netherlands.
authors.forename: Daniël M
authors.initials: DM
authors.lastname: Jonker
authors.forename: Dick A C
authors.initials: DA
authors.lastname: Vermeij
authors.forename: Peter M
authors.initials: PM
authors.lastname: Edelbroek
authors.forename: Rob A
authors.initials: RA
authors.lastname: Voskuyl
authors.forename: Vladimir K
authors.initials: VK
authors.lastname: Piotrovsky
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004569:Electroencephalography / Q000187:drug effects*; D004827:Epilepsy / Q000188:drug therapy; D018757:GABA Modulators / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008433:Mathematics; D008874:Midazolam / Q000493:pharmacokinetics / Q000494:pharmacology*; D008954:Models, Biological; D014179:Neurotransmitter Uptake Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D009557:Nipecotic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000078308:Tiagabine
chemical_list: D000927:Anticonvulsants; D018757:GABA Modulators; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D011963:Receptors, GABA-A; D008874:Midazolam; D000078308:Tiagabine