Tiagabine

TIAGABINE

Tiagabine is a derivative of nipecotic acid and was “rationally designed” as an inhibitor of GABA uptake (as opposed to discov-ery through random screening).

Mechanism of Action

Tiagabine is an inhibitor of GABA uptake in both neurons and glia. It preferentially inhibits the transporter isoform 1 (GAT-1) rather than GAT-2 or GAT-3 and increases extracellular GABA levels in the forebrain and hippocampus where GAT-1 is prefer-entially expressed. It prolongs the inhibitory action of synapti-cally released GABA, but its most significant effect may be potentiation of tonic inhibition. In rodents, it is potent against kindled seizures but weak against the maximal electroshock model, consistent with its predominant action in the forebrain and hippocampus.

Clinical Uses

Tiagabine is indicated for the adjunctive treatment of partial sei-zures and is effective in doses ranging from 16 to 56 mg/d. Divided doses as often as four times daily are sometimes required. Minor adverse events are dose related and include nervousness, dizziness, tremor, difficulty in concentrating, and depression. Excessive confusion, somnolence, or ataxia may require discon-tinuation. Psychosis occurs rarely. The drug can cause seizures in some patients, notably those taking the drug for other indications. Rash is an uncommon idiosyncratic adverse effect.

Pharmacokinetics

Tiagabine is 90–100% bioavailable, has linear kinetics, and is highly protein bound. The half-life is 5–8 hours and decreases in the presence of enzyme-inducing drugs. Food decreases the peak plasma concentration but not the area under the concentration curve . Hepatic impairment causes a slight decrease in clearance and may necessitate a lower dose. The drug is oxidized in the liver by CYP3A. Elimination is primarily in the feces (60–65%) and urine (25%).