Gabapentin and pregabalin are not metabolized and do not induce hepatic enzymes; they are eliminated unchanged in the urine. Both drugs are absorbed by the l-amino acid transport system, which is found only in the upper small intestine. The oral bioavailability of gabapentin decreases with increasing dose because of saturation of this transport system. In contrast, pregabalin exhibits linear absorption within the therapeutic dose range. This is explained, in part, by the fact that pregabalin is used at much lower doses than gabapentin so it does not saturate the transport system. Also, pregabalin may be absorbed by mechanisms other than the l-amino acid transport system. Because of dependence on the transport system, absorption of gabapentin shows patient-to-patient variability and dosing requires individualization. Pregabalin bioavailability exceeds 90% and is independent of dose so that it may produce a more predictable patient response. Gabapentinoids are not bound to plasma proteins. Drug-drug interactions are negligible. The half-life of both drugs is relatively short (ranging from 5 to 8 hours for gabapentin and 4.5 to 7.0 hours for pregabalin); they are typically administered two or three times per day. Sustained-release, once-a-day preparations of gabapentin are available. The gabapentin prodrug gabapentin enacarbil is also available in an extended-release formulation. This prodrug is actively absorbed by high-capacity nutrient transporters, which are abundant throughout the intestinal tract, and then converted to gabapentin presumably within the intestine, so there is dose-proportional systemic gabapentin exposure over a wide dose range.
Tiagabine, a selective inhibitor of the GAT-1 GABA transporter, is a second-line treatment for focal seizures. It is contraindicated in generalized onset epilepsies.
Mechanism of Action
Tiagabine is a lipophilic, blood-brain barrier-permeant analog of nipecotic acid, a GABA uptake inhibitor that is not active systemically. The chemical structure of tiagabine consists of the active moiety—nipecotic acid—and a lipophilic anchor that allows the molecule to cross the blood-brain barrier. Tiagabine is highly selective for the GAT-1 GABA transporter isoform, the most abundant GABA transporter expressed in brain, and has little or no activity on the other sodiumand chloride-dependent GABA transporters, GAT-2, GAT-3, or BGT-1. The action of the GABA that is released by inhibitory neurons is normally terminated by reuptake into the neuron and surrounding glia by these transporters. Tiagabine inhibits the movement of GABA from the extracellular space—where the GABA can act on neuronal receptors—to the intracellular compartment, where it is inactive. This action of tiagabine causes prolongation of GABA-mediated inhibitory synaptic responses and potentiation of tonic inhibition; the latter is caused by the action of GABA on extrasynaptic GABA receptors. Tiagabine is considered a “rationally designed” antiseizure drug because it was developed with the understanding that potentiation of GABA action in the brain is a possible antiseizure mechanism.