The pharmacokinetics and neuropharmacological action of the new antiepileptic drugs vigabatrin and levetiracetam

• Main Author: Tong, Xin
• Published: University College London (University of London) 2007
• Subjects: 616.853061
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444576

Epilepsy affects approximately 1% of the world population and is the most serious neurological conditions. In the UK, 30-35,000 new cases of epilepsy are diagnosed each year, resulting in a prevalence of 300,000 nationwide. There is significant need for new drug treatments. Yet we have a poor understanding of how many of these drugs mediate their antiepileptic effect, and how and where they are distributed within the brain. This thesis sought to investigate the pharmacokinetic and neuropharmacokinetic inter-relationship and the neuropharmacology of two new antiepileptic drugs, vigabatrin and levetiracetam two drugs with distinct mechanisms of action. Firstly, a freely moving and freely behaving rat model was used to determine the pharmacokinetics of vigabatrin and levetiracetam simultaneously in serum, cerebrospinal fluid (CSF) and brain frontal cortex and hippocampal extracellular fluid (ECF). Secondly, amino acid neurotransmitter concentrations were monitored in CSF (by direct CSF sampling) and brain ECF (by microdialysis) after vigabatrin and levetiracetam administration. Thirdly, the effects of vigabatrin and levetiracetam on paired-pulse inhibition recorded in the dentate gyrus evoked by perforant path stimulation were established. Vigabatrin rapidly entered the blood (serum), CSF and ECF (frontal cortex and hippocampus) compartments with concentrations increasing linearly and dose- dependently. Time to maximum concentration (rmax) was achieved at a mean value of 0.4 0.06 minutes in the blood compartment, 0.9 0.1 minutes in the CSF compartment and 0.8 0.1 minutes in both the frontal cortex and hippocampal ECF compartments. Although the CSF kinetics of vigabatrin paralleled that seen in serum, CSF vigabatrin concentrations represented only 2% of serum vigabatrin concentrations and did not reflect free drug concentrations in serum. Vigabatrin was not protein bound in serum. Furthermore, the efflux of vigabatrin from the CSF compartment was significantly slower (mean terminal half life {1/2} values, 2.2-3.3 h) than that suggested by serum values (mean tm values, 1.1-1.4 h). Distribution in the brain ECF was brain region specific vigabatrin concentrations achieved in the frontal cortex were 2-fold greater than concentrations achieved in the hippocampus. However, the efflux of vigabatrin from the two brain regions was essentially identical (mean t a values, 2.4-3.6 h) and indeed was similar to values seen in the CSF compartment. The findings are consistent with an active uptake and elimination of vigabatrin from the CSF and ECF. Levetiracetam rapidly entered the blood (serum) and ECF (frontal cortex and hippocampus) compartments with concentrations increasing linearly and dose- dependently. Mean rmax values were 0.4 - 0.7 minutes in the blood compartment and 1.8 - 2.5 minutes in both the frontal cortex and hippocampal ECF compartments. Levetiracetam was not protein bound in serum. In contrast to vigabatrin, levetiracetam did not exhibit brain region specificity in that its neuropharmacokinetic profiles in frontal cortex and hippocampal ECF were essentially identical. However, the efflux of levetiracetam from the two brain regions was slower (mean t a values, 3.1 - 3.3 h) compared to that which occurred in the blood compartment (mean tm values, 2.2 h). In the CSF compartment, vigabatrin administration was associated with changes in 5 of the 16 amino acid neurotransmitter concentrations measured over time. Thus whilst arginine and tyrosine concentrations decreased, homocarnosine, glycine and taurine concentrations increased. Although gamma-aminobutyric acid (GABA) was not measured in CSF, the fact that homocarnosine (a GABA conjugate) concentrations increased is consistent with a GABAergic action for vigabatrin. In the frontal cortex and hippocampal ECF compartments, vigabatrin administration was associated with significant changes in various amino acid concentrations but the changes did not parallel those seen in CSF. The most profound change was that with GABA. However, whilst ECF GABA concentrations increased 6-fold in the frontal cortex, concentrations in the hippocampus were unaffected. These GABA changes did not parallel the concentration versus time profile of ECF vigabatrin nevertheless vigabatrin concentrations in the frontal cortex were 2-fold higher than those achieved in the hippocampus. These findings indicate that CSF amino acid measurements may be a poor reflection of ECF amino acid changes and that changes in ECF amino acids is regionally specific. That vigabatrin reduced paired pulse inhibition in the dentate gyrus evoked by perforant path stimulation at 20 ms interpulse interval but not at 50 ms and 100 ms intervals would suggest that vigabatrin by increasing extracellular GABA may either desensistise synaptic GABAA receptors or inhibit GABA release through an action on GABAB receptors. In the brain ECF compartment, levetiracetam administration was associated with changes in only two (taurine and glutamate) of the 20 amino acid neurotransmitter concentrations measured over time. The significance of these changes in relation to the mechanism of action of levetiracetam is unknown.