Tiagabina (Estudio En Sangre Y Líquido Clr)

Seizure (2004) 13, 574—581

The pharmacokinetic inter-relationship of tiagabine in blood, cerebrospinal fluid and brain extracellular fluid (frontal cortex and hippocampus)
Xiaolan Wang, Neville Ratnaraj, Philip N. Patsalos*
Pharmacology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London WC1N 3BG, UK

KEYWORDS
Tiagabine;Pharmacokinetics; Blood; Cerebrospinal fluid; extracellular fluid; Hippocampus; Frontal cortex

Summary 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 toinvestigate 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 frontalcortex (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 beingindistinguishable. Whilst elimination from CSF was comparable to that of serum, half-life (t1/2 ) 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 isthreefold slower than that seen in blood, may explain as to the relatively long duration of action of tiagabine. © 2004 BEA Trading Ltd. Published by Elsevier Ltd. All rights reserved.

*Corresponding author. Tel.: +44-20-7837-3611x3830; fax: +44-20-7278-5616. E-mail address: P.Patsalos@ion.ucl.ac.uk (P.N. Patsalos). 1059-1311/$30 — see front matter © 2004 BEA Trading Ltd. Published by Elsevier Ltd.All rights reserved. doi:10.1016/j.seizure.2004.01.007

The pharmacokinetic of tiagabine

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Introduction
Tiagabine ([R-(−)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid] hydrochloride) is a unique antiepileptic drug (AED) with a novel mechanism of action in that it selectively and specifically inhibits the uptake of -aminobutyric acid (GABA) into astrocytes and neurones, bythe transporter GAT-1, and thus increases the extracellular concentration of GABA in the brain. Tiagabine is effective in the management of partial seizures with or without secondary generalisation, and is licensed for use as adjunctive therapy in patients refractory to available first-line AEDs.1—4 Tiagabine is effective in a variety of seizure models including amygdala-kindled seizures,5audiogenic seizures6 and convulsions associated with status epilepticus induced in cobalt-lesioned rats by the administration of homocysteine thiolactone.7 The latter observation raises the possibility that it may be useful in the management of status epilepticus in patients. However, from a pharmacokinetic aspect, drugs used in the management of status epilepticus need to be able to rapidly and...