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

X Tong, P N Patsalos, X Tong, P N Patsalos

Abstract

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 fluid (frontal cortex and hippocampus) following systemic administration of levetiracetam, a new antiepileptic drug. Concurrent extracellular amino acid concentrations were also determined. After administration (40 or 80 mg kg(-1)), levetiracetam rapidly appeared in both serum (T(max), 0.4 - 0.7 h) and extracellular fluid (T(max), 2.0 - 2.5 h) and concentrations rose linearly and dose-dependently, 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 confirms that levetiracetam is not bound to blood proteins. The kinetic profiles for the hippocampus and frontal cortex were indistinguishable suggesting that levetiracetam distribution in the brain is not brain region specific. However, t(1/2) values were significantly 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. Levetiracetam (80 mg kg(-1)) was associated with a significant reduction in taurine in the hippocampus and frontal cortex. Other amino acids were unaffected by levetiracetam. Levetiracetam readily and rapidly enters the brain without regional specificity. Its prolonged efflux 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.

Figures

Figure 1
Figure 1
Serum and frontal cortex and hippocampal microdialysate concentration versus time profiles for levetiracetam following intraperitoneal administration of 40 mg kg−1 levetiracetam. Data are mean±s.e.mean of six rats.
Figure 2
Figure 2
Serum and frontal cortex and hippocampal microdialysate concentration versus time profiles for levetiracetam following intraperitoneal administration of 80 mg kg−1 levetiracetam. Data are mean±s.e.mean of six rats.
Figure 3
Figure 3
Serum free fraction (free/total concentration ratio) versus time profile for levetiracetam. Dotted line indicates mean value of ratio.
Figure 4
Figure 4
Levetiracetam hippocampal extracellular fluid/serum concentration versus time profiles after 40 mg kg−1 and 80 mg kg−1 levetiracetam. Data are mean±s.e.mean of six rats.
Figure 5
Figure 5
Dialysate taurine in the frontal cortex (a) and hippocampus (b) before and after the administration of levetiracetam (80 mg kg−1) or 0.9% saline (control). Values are mean of four rats and are expressed as percentage of baseline; vertical bars show s.e.mean.

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