LEV is a single enantiomer (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide with a molecular weight of 170.21 (1,2). The structural formula of the agent is shown in Figure 63.1. The drug is a white to off-white crystalline powder with a faint odor and bitter taste. It is very soluble in water (104.0 g/100 mL), freely soluble in chloroform and in methanol, and soluble in ethanol. It is much less soluble to insoluble in acetonitrile and n-hexane. Keppra^* (the only brand name of this compound) tablets contain LEV and the inactive ingredients silicon dioxide, cornstarch, methylcellulose, magnesium stearate, polyethylene glycol 4000, and coloring agents. LEV is supplied as 250-mg (blue), 500-mg (yellow), and 750-mg (orange) tablets (2). Currently, an oral suspension is undergoing clinical investigation for approval in the United States.

Prior to undergoing standardized AED testing by the National Institutes of Health, LEV was found to have antiepileptic properties. In contrast to all approved AEDs, LEV lacked conventional modulation of the acute seizure model (maximum electroshock seizure [MES] test and pentylenetetrazol [PTZ]), suggesting a novel mechanism of action (3, 4, 5). Moreover, LEV displays unique potent protection against kindled seizures in both mice and rats during kindling models (3,4). In comparative tests with established AEDs in a number of animal models of epileptic seizures, LEV displays potent protection in a broad range of animal models of chronic epilepsy, including partial and primary generalized seizures (5).

The precise mechanism by which LEV exerts its AED effect is unknown. It does not appear to derive its function from known mechanisms involved in inhibitory and excitatory neurotransmission, but it may be active at a brain-specific binding site (6). A stereoselective binding site for LEV has been shown to exist exclusively in membranes from cells in the central nervous system (CNS), but not in peripheral tissue (3,6). There is no significant displacement (≤10 mM) of ligands specific for 55 different binding sites. Established AEDs, such as carbamazepine, phenytoin, valproate, phenobarbital, and clonazepam, do not possess an affinity for this binding site (6).

In studies performed to demonstrate the cellular pharmacodynamics of LEV, the agent reduces calcium current through neuron-specific, high-voltage-activated N-type calcium channels, thus reducing seizure potential (7). It does not modulate neuronal voltage-gated sodium, T-type calcium currents, or glutamate receptor-mediated neurotransmission in the spinal cord, nor does it have any conventional effects at the gamma-aminobutyric acid (GABA)a receptors (7). However, LEV does promote inhibitory neurotransmission by reducing negative allosteric effects of zinc and the beta-carbolines on GABAa and glycine receptors (8). In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that LEV inhibits burst firing without affecting normal neuronal excitability, suggesting selective suppression of hypersynchronization
of epileptiform burst firing and propagation of seizure activity (9). The only certainty regarding the mechanism of action is that further investigation is warranted to elucidate the ways in which LEV exerts its selective effects.