THE KINETICS OF TIAGABINE IN BLOOD AND EXTRACELLULAR FLUID FRONTAL CORTEX AND HIPPOCAMPUS: A MICRODIALYSIS STUDY
Abstract number :
2.266
Submission category :
Year :
2002
Submission ID :
3374
Source :
www.aesnet.org
Presentation date :
12/7/2002 12:00:00 AM
Published date :
Dec 1, 2002, 06:00 AM
Authors :
Neville Ratnaraj, Xiaolan Wang, Philip N. Patsalos. Clinical and Experimental Epilepsy, Institute of Neurology, London, United Kingdom
RATIONALE: Previously we investigated the kinetic inter-relationship of tiagabine (TGB) in cerebrospinal fluid (CSF) and showed that TGB appeared rapidly in the CSF compartment and that blood concentrations reflected CSF values (Ratnaraj et al., 2000). In this study, we have further investigated the kinetics of TGB by monitoring extracellular fluid (ECF) concentrations in the frontal cortex and hippocampus of freely behaving rats using microdialysis.
METHODS: Sprague-Dawley rats weighing 300-350 g (n=5) were used. Under halothane anaesthesia, a catheter was placed in the internal jugular vein for blood sampling and microdialysis probes were implanted stereotactically into the hippocampus and frontal cortex for monitoring of the ECF. Two days later, TGB (40 mg/kg) was administered ip. Blood samples (100 [mu]L) were collected at 15 minutes intervals for the first hour and at 30 minutes intervals for a further 6 hours. Microdialysate samples (flow rate (2 [mu]L/min) were collected at 10 minutes intervals for 2 hours. Blood and ECF TGB content were determined by HPLC.
RESULTS: TGB serum concentrations rose rapidly after ip TGB administration (Tmax, 16 [plusminus] 0.3 mins) with Cmax values of 27754 [plusminus] 2000 nmol/L. In contrast Tmax values for ECF frontal cortex and hippocampus were 41 [plusminus] 5 and 34 [plusminus] 3 nmol/L, respectively. Recovery corrected Cmax values for frontal cortex were 266 [plusminus] 10 nmol/L and for the hippocampus they were 291 [plusminus] 11 nmol/L. TGB half-life values in serum, ECF frontal cortex and hippocampus were 50 [plusminus] 2.6, 174 [plusminus] 32 and 133 [plusminus] 9 mins respectively.
CONCLUSIONS: TGB rapidly enters brain ECF with concentrations peaking somewhat later than that in serum. As TGB ECF concentrations are similar in both the frontal cortex and the hippocampus, the brain distribution of TGB does not appear to be region specific. However, ECF half-life values in both the frontal cortex and the hippocampus are three fold greater then that of serum and this may be an important consideration in the therapeutics of TGB.
References:
Ratnaraj N, Wang X, Patsalos PN. Blood and cerebrospinal fluid kinetics of tiagabine in rats. Epilepsia 2000; 41 (Suppl. 6): 150.
[Supported by: The work was supported in part by the National Society for Epilepsy.]