An investigation into the pharmacokinetics of 3-mercaptopropionic acid and development of a steady-state chemical seizure model using in vivo microdialysis and electrophysiological monitoring

OBJECTIVES: The goal of the present study was to develop a chemical seizure model using the convulsant, 3-mercaptopropionic acid (3-MPA). A pharmacodynamics approach was taken, combining in vivo microdialysis sampling with electrophysiological methods to simultaneously monitor, in real-time, the 3-MPA concentration in the brain and the corresponding electrocorticographic (ECoG) activity. METHODS: The 3-MPA was administered in two doses (50 and 100 mg/kg) in order to study its pharmacokinetics. Microdialysis samples were collected from the striatum, hippocampus, and jugular vein every 5 min. The microdialysates were analyzed using high-performance liquid chromatography with electrochemical detection (HPLC-EC). The ECoG activity was monitored via screws placed onto the cortex. Noncompartmental pharmacokinetics analysis was performed to obtain the elimination constants (K(e)), the maximum concentration (C(max)), the time to achieve maximum concentration (T(max)), and the area under the concentration-time curves (AUC(inf)). RESULTS: The average brain K(e) for the 50 and the 100mg/kg doses were 0.060 and 0.018 min(-1), respectively. The brain AUC(inf) for the 50 and 100mg/kg doses were 353 and 2168 mg min(-1)mL(-1), respectively. This led to a 67-fold increase in the observed number of seizures in the higher dose with the average seizure intensity double that of the smaller dose. These data led to the dosing scheme for the chemical seizure model of administering a 3-MPA loading dose of 60 mg/kg followed by a constant infusion of 50 mg/(kg min(-1)). CONCLUSIONS: This study describes, to our knowledge, the first successful attempt to combine in vivo microdialysis with electrophysiology to monitor in real-time, the concentration and effects of 3-MPA in the brain. This led to the development of a steady-state chemical seizure model.