Document Detail

The pharmacokinetic inter-relationship of tiagabine in blood, cerebrospinal fluid and brain extracellular fluid (frontal cortex and hippocampus).
MedLine Citation:
PMID:  15519917     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Tiagabine is a unique antiepileptic drug with a novel mechanism of action. Whilst some limited data are available as to the peripheral blood pharmacokinetics of tiagabine, data regarding the kinetics of tiagabine in the central brain compartment are very limited. We therefore sought to investigate serum, cerebrospinal fluid (CSF) and frontal cortex and hippocampal extracellular fluid (ECF) kinetic inter-relationship of tiagabine in a freely moving rat model.
METHODS: Adult male rats were implanted with either a jugular vein catheter and a cisterna magna catheter for blood and CSF sampling, respectively, or a blood catheter and a microdialysis probe in the hippocampus and frontal cortex (for ECF sampling). Tiagabine was administered intraperitoneal (i.p.) at 20 or 40 mg/kg and blood, CSF and ECF were collected at timed intervals for the measurement of tiagabine concentrations by high performance liquid chromatography.
RESULTS: Tiagabine concentrations in blood and CSF rose linearly and dose-dependently and time to maximum concentration (Tmax) was 15 and 29 min, respectively. Mean CSF/serum tiagabine concentration ratios (range, 0.008-0.01) were much smaller than the mean free/total tiagabine concentration ratios in serum (0.045 +/- 0.003). Entry of tiagabine into brain ECF (frontal cortex and hippocampus) was rapid with Tmax values of 31-46 min. Distribution of tiagabine in brain was not brain region specific with values in the frontal cortex and hippocampus being indistinguishable. Whilst elimination from CSF was comparable to that of serum, half-life (t(1/2)) values in ECF were three times longer.
CONCLUSIONS: Tiagabine is associated with linear kinetic characteristics and with rapid brain penetration. However, CSF concentrations are not reflective of free non-protein-bound concentrations in serum. The observation that tiagabine elimination from the brain is threefold slower than that seen in blood, may explain as to the relatively long duration of action of tiagabine.
Xiaolan Wang; Neville Ratnaraj; Philip N Patsalos
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Seizure     Volume:  13     ISSN:  1059-1311     ISO Abbreviation:  Seizure     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-11-02     Completed Date:  2005-01-24     Revised Date:  2014-10-21    
Medline Journal Info:
Nlm Unique ID:  9306979     Medline TA:  Seizure     Country:  England    
Other Details:
Languages:  eng     Pagination:  574-81     Citation Subset:  IM    
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MeSH Terms
Anticonvulsants* / blood,  cerebrospinal fluid,  pharmacokinetics,  therapeutic use
Epilepsy / drug therapy*
Extracellular Fluid / metabolism*
Frontal Lobe / metabolism*
Hippocampus / metabolism*
Nipecotic Acids* / blood,  cerebrospinal fluid,  pharmacokinetics,  therapeutic use
Rats, Sprague-Dawley
Reg. No./Substance:
0/Anticonvulsants; 0/Nipecotic Acids; Z80I64HMNP/tiagabine

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