The results of preclinical investigations suggest that vigabatrin and tiagabine are pharmacologically distinct compounds with different anticonvulsant, neurotoxicity, and pharmacokinetic profiles. It is possible that they will ultimately prove to have different clinical efficacies and spectra of activity. The molecular formula of tiagabine is C20 H25 NO2 S2 HCl.
Pharmacodynamics. The precise mechanism of the antiseizure effect of tiagabine is unknown, although it is believed to be related to its ability to enhance the activity of GABA, the major inhibitory neurotransmitter in the CNS. Tiagabine binds to recognition sites associated with the GABA uptake carrier and blocks GABA uptake into presynaptic neurons, permitting more GABA to be available for receptor binding on the surfaces of postsynaptic cells. Inhibition of GABA uptake has been shown for synaptosomes, neuronal cell cultures, and glial cell cultures. Tiagabine increases the amount of GABA available in the extracellular space of the globus pallidus and substantia nigra.
Neuroimaging study using 18F fluorodeoxyglucose-PET has shown that following tiagabine treatment, regional cerebral metabolic rate of glucose uptake in ventral medial prefrontal cortex increased significantly in patients with generalized social anxiety disorder. These findings suggest that therapeutic effects of tiagabine in this disorder may be mediated via GABAergic modulation of ventral medial prefrontal cortex. Following administration of tiagabine in healthy male volunteers, acute increases in endogenous synaptic GABA were detectable in the living human brain using [11C]Ro15-4513, an inverse agonist GABA-benzodiazepine receptor PET tracer (12). Reductions in synaptic [11C]Ro15-4513 binding were significant in the hippocampus, parahippocampal region, amygdala, and anterior cingulate cortex.
Experimental studies have shown neuroprotective effect of tiagabine pretreatment on the nigrostriatal axis by attenuation of microglial activation in a neurotoxin-induced mouse model of Parkinson disease (09). This finding indicates a potential application of tiagabine for treatment of Parkinson disease. Theoretically, GABA transporter blockade by drugs such as tiagabine offers an indirect approach to increase GABA inhibition to lower the excitation threshold of neurons following cerebral ischemia for neuroprotective effect. A study of several drugs on a mouse model of cerebral ischemia showed that low dose tiagabine improved motor recovery, but higher doses induced seizures, and none of the drugs reduced infarct volume (08). These findings indicate that tiagabine should be used with caution in cases of cerebral ischemia.
Pharmacokinetics. Features of pharmacokinetics of tiagabine are:
| • Tiagabine is rapidly and almost completely absorbed after oral administration. |
| • Peak plasma concentrations are reached at approximately 45 minutes following an oral dose. |
| • With therapeutic dose, serum levels are between 20 and 100 microg/L. |
| • Tiagabine is 96% bound to human plasma proteins, mainly to serum albumin. |
| • The pharmacokinetics of tiagabine is linear over the single dose range of 2 to 24 mg. Following multiple dosing, steady state is achieved within 2 days. |
| • The elimination half-life is 7 to 9 hours in normal volunteers, but it is only 4 to 7 hours in patients receiving hepatic enzyme-inducing drugs such as carbamazepine, phenytoin, primidone, and phenobarbital. |
| • Cerebrospinal fluid concentrations of tiagabine do not reflect free non-protein-bound concentrations in serum. The duration of action of tiagabine is relatively long because its elimination from the brain is 3-fold slower than that seen in blood. |
| • Two metabolic pathways for tiagabine have been identified in humans: (1) thiophene ring oxidation leading to the formation of 5-oxo-tiagabine; and (2) glucuronidation. |
| • Approximately 2% of an oral dose of tiagabine is excreted unchanged, with 25% and 63% of the remaining dose excreted into the urine and feces, respectively. |
The pharmacokinetics of total and unbound tiagabine are unaffected in subjects with renal failure requiring hemodialysis.
