A microdialysis study of the novel antiepileptic drug levetiracetam: extracellular pharmacokinetics and effect on taurine in rat brain

Abstract

1 Using a rat model which allows serial blood sampling and concurrent brain microdialysis sampling, we have investigated the temporal kinetic inter-relationship of levetiracetam in serum and brain extracellular¯uid (frontal cortex and hippocampus) following systemic administration of levetiracetam, a new antiepileptic drug. Concurrent extracellular amino acid concentrations were also determined. 2 After administration (40 or 80 mg kg 71 ), levetiracetam rapidly appeared in both serum (T max , 0.4 ± 0.7 h) and extracellular¯uid (T max , 2.0 ± 2.5 h) and concentrations rose linearly and dosedependently, suggesting that transport across the blood-brain barrier is rapid and not rate-limiting. The serum free fraction (free/total serum concentration ratio; mean+s.e.mean range 0.93 ± 1.05) was independent of concentration and con®rms that levetiracetam is not bound to blood proteins. 3 The kinetic pro®les for the hippocampus and frontal cortex were indistinguishable suggesting that levetiracetam distribution in the brain is not brain region speci®c. However, t 1/2 values were signi®cantly larger than those for serum (mean range, 3.0 ± 3.3 h vs 2.1 ± 2.3 h) and concentrations did not attain equilibrium with respect to serum. 4 Levetiracetam (80 mg kg 71 ) was associated with a signi®cant reduction in taurine in the hippocampus and frontal cortex. Other amino acids were una ected by levetiracetam. 5 Levetiracetam readily and rapidly enters the brain without regional speci®city. Its prolonged e ux from and slow equilibration within the brain may explain, in part, its long duration of action. The concurrent changes in taurine may contribute to its mechanism of action.

Levetiracetam Inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture

“…Our results supplement the current literature aimed at elucidating the mechanism of action of LEV [30], [40], [34]. Currently, little is known regarding the mechanism behind the antiepileptic properties of LEV.…”

“…Studies have demonstrated that while LEV does not exhibit any direct action on GABAergic transmission and does not show affinity for GABAergic or glutamatergic receptors, it does induce a change in GABA turnover in the striatum [27], [23], [9]. Other studies have focused on biochemical alterations induced by LEV and have found that it decreases levels of the amino acid taurine, a low affinity agonist for GABA A receptors, in the hippocampus but does not elicit changes in other amino acids [34].…”

The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam

“…Determining the effect of LEV on SV2A function is complicated by both the absence of proven SV2A functions, and also by the unusual pharmacology of LEV, which lacks effects on the electrophysiology of normal brain tissue and neurons (4,27), and on standard amino acid neurotransmitter release as studied by microdialysis in normal brain (28). The apparent lack of effect on normal electrophysiology has implications for any hypothesis of LEV's effects on the function(s) of SV2A.…”

Newer Antiepileptic Drugs in Status Epilepticus: Prescription Trends and Outcomes in Comparison with Traditional Agents

“…This may reflect a suboptimal SE treatment approach with insufficient doses of newer AEDs, or their prescriptions without or with underdosed benzodiazepines as first line treatment (34). However, in animal studies levetiracetam has shown a relatively slow penetration into the central nervous system, with latencies of more than 1 hour to achieve maximum concentrations in the cerebrospinal or in the brain extra-cerebral fluid (35)(36)(37). Animal studies with phenytoin, on the other side, shows maximum concentrations in cerebrospinal and brain extra-cerebral fluids within 9-13minutes and 39-34minutes, respectively (38).…”