Visual Field Constriction with GABAergic Antiepileptic Drugs; a Pre-Clinical Pharmacokinetic / Pharmacodynamic Investigation
Abstract number :
1.123
Submission category :
Year :
2000
Submission ID :
2625
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Graeme J Sills, Sarah Santangeli, Philip N Patsalos, Elaine Butler, Gerard Forrest, Neville Ratnaraj, Martin J Brodie, Univ of Glasgow, Glasgow, United Kingdom; Institute of Neurology, London, United Kingdom.
RATIONALE: Long-term vigabatrin (VGB) treatment is associated with the development of concentric visual field constriction. Anecdotal reports have suggested that this may be a class effect of all drugs with ?-aminobutyric acid (GABA)-related mechanisms of action. The following study was designed to investigate the pharmacokinetic and pharmacodynamic profiles of a range of GABAergic drugs in specific regions of rat brain and eye. METHODS: Adult male Sprague Dawley rats (n=12) were administered control (0.9% saline), VGB (250, 500 or 1000 mg/kg), tiagabine (TGB; 5, 10 or 20 mg/kg), topiramate (TPM; 12.5, 25, 50 or 100 mg/kg) or gabapentin (GBP; 50, 100 or 200 mg/kg). At one hour (TGB) and two hours (VGB, TPM, GBP) post-dosing, animals were sacrificed, a truncal blood sample obtained, their brains dissected into eight specific regions and the retina and vitreous humour isolated from each eye. Samples were analysed for GABA concentrations and the activities of glutamic acid decarboxylase (GAD) and GABA-transaminase (GABA-T). Plasma and tissue drug concentrations were also determined. RESULTS: VGB treatment was associated with a dose-related decrease in the activities of GAD (?71% of control) and GABA-T (?37% of control) and a rise in GABA concentrations (?159% of control). This effect was most pronounced in the retina. VGB levels were also dose-related but were found to be significantly higher (?509%) in the retina than in any other tissue investigated. TGB, TPM and GBP were without effect on GABA concentrations and the activities of GAD and GABA-T in all tissues. TGB, TPM and GBP levels were also dose-related, with TGB levels slightly lowered in the retina (?78%) and TPM (?199%) and GBP (?174%) levels marginally raised, when compared to brain tissue. CONCLUSIONS: Accumulation of VGB in the retina, with or without the associated increase in GABA levels, may be responsible for the visual field constriction reported clinically. In contrast, TGB, TPM and GBP had no effect on the GABA system and did not accumulate significantly in the retina. These results suggest that TGB, TPM and GBP are unlikely to cause visual field constriction in man.