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A study has been carried out of binary solid systems made up of the antiepileptic drug levetiracetam, LEV, and a nonsteroidal anti-inflammatory drug, NSAID, capable of managing the inflammation that accompanies epileptic activity. One aim of this research was to identify eutectic mixtures and co-crystals, which are able to impact positively on their biopharmaceutical properties. The NSAIDs studied are (S)- and (R,S)-ibuprofen, (S)- and (R,S)-naproxen, (R,S)-ketoprofen and (R,S)-flurbiprofen, all class II in the Biopharmaceutical Classification System. A green mechanochemical methodology has been used to prepare binary mixtures with different molar ratios, and the binary solid-liquid phase diagrams established. For LEV+(S)-ibuprofen, formation of a single (1:1) co-crystal was confirmed; this was found to melt incongruently. The co-crystal was found to be stable in accelerated stability tests. For the other systems, interesting eutectic mixtures were identified, which showed enhanced dissolution rates of the NSAID relative to the pure drug. For LEV+(R,S)-ibuprofen, LEV+(S)-naproxen and LEV+(R,S)-naproxen, the eutectic mixture compositions have the effective doses of both components. All the NSAIDs investigated are chiral, and their racemates are racemic compounds. Levetiracetam, the (S)-enantiomer of etiracetam, was not efficient in enantiomer discrimination, as all the racemic compound structures are present as the prepared solid mixtures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A simple, fast and cost-effective method was developed and validated for the determination of levetiracetam (LEV) in plasma/serum of patients using high performance liquid chromatography (HPLC) with ultraviolet detection. The stability of LEV plasma/serum samples over time and in different blood collection tubes was evaluated. Serum/plasma samples were deproteinized by methanol spiked with the internal standard, gabapentin. HPLC was carried out on a Venusil XBP C 18 , 250 × 4.6 mm, 5 μm column, at a flow rate of 1.0 mL/min and with mobile phase consisting of 50 mm potassium dihydrogen phosphate-acetonitrile at a pH of 5.5. The UV detector was set at 205 nm and 10 μL was injected. Total runtime was 15 min. Calibration curves were linear (correlation coefficient = 0.999) over a concentration range of 1-60 μg/mL. Relative standard deviation values for both the inter-day and intra-day precision and accuracy were <5% for the concentration range. The influence of different collection tubes and the effect of time on the stability of LEV was investigated. These factors may cause inaccuracies owing to drug-protein binding and interference in the matrix. This method is simple, fast, cost-effective, reliable and accurate with minimal sample preparation for daily routine use in therapeutic drug monitoring., (Copyright © 2017 John Wiley & Sons, Ltd.)

In the last few years there has been a huge progress in a development of printing techniques and their application in pharmaceutical sciences and particularly in the pharmaceutical technology. The variety of printing methods makes it necessary to systemize them, explain the principles of operation, and specify the possibilities of their use in pharmaceutical technology. This paper aims to review the printing techniques used in a drug development process. The growing interest in 2D and 3D printing methods results in continuously increasing number of scientific papers. Introduction of the first printed drug Spritam@ to the market seems to be a milestone of the 3D printing development. Thus, a particular aim of this review is to show the latest achievements of the researchers in the field of the printing medicines.

Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [ 3 H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM. Subsequent concentration-inhibition curves revealed the antihistaminic prodrug loratadine (K i  = 1.16 μM) and the antimalarial drug quinine (K i  = 2.03 μM) to be the most potent SV2A protein ligands of the investigated drug library. Both compounds were similarly potent as LEV (K i  = 1.74 μM), providing structurally novel scaffolds for SV2A ligands. A pharmacophore model was established, which indicated steric and electronic conformities of brivaracetam with the new SV2A ligands, and preliminary structure-activity relationships were determined. The anti-convulsive effects of the natural product quinine may - at least in part - be explained by interaction with SV2A. Loratadine and quinine represent new lead structures for anti-epileptic drug development., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hypromellose matrices exhibit extended burst effect immediately after contact with aqueous medium, especially when a water-soluble drug is incorporated. The objective of this study was to reduce burst effect and maintain complete dissolution of a very soluble levetiracetam over 12 h period from hypromellose K4M matrices to obtain zero-order kinetics. Desired changes were achieved by applying water dispersions of insoluble Eudragits ® (NE, NM, RL, RS) as a granulation liquid to the drug/microcrystalline cellulose mixture during high-shear granulation (non-thermal treated set) and consequently by thermally treating granules or final tablets (TT), respectively. Applying Eudragit ® water dispersions to the drug/microcrystalline cellulose mixture was recognized as an effective method of significantly reducing the burst release (25.4-33.7%) of levetiracetam in comparison with a reference sample without Eudragit ® . Multivariate data analysis showed that the addition of Eudragit ® reduced burst effect, increased fitting with zero-order kinetics, and supported matrix erosion as the supplementary mechanism to predominant diffusion. Moreover, resulting PCA sub-model revealed the addition of Eudragit ® RL and thermal treatment of tablets to be the most suitable method of all. For a 12 h dissolution profile, characterized by low burst effect and drug release close to 100% at the 12th hour, sample RL&#95;TT was the most suitable.

Background: Parenteral antiepileptic drugs are frequently used in critically ill patients for seizure control therapy or prevention. Many of these patients require additional parenteral nutrition (PN). Therefore, a parallel infusion of the frequently used antiepileptic drug levetiracetam (LEV) is interesting in terms of the restricted i.v. lines (e.g., neonates). The potential interactions of the complex PN admixture with the drug product and the appropriate admixing of a drug at effective dosages require physicochemical lab assessments to obtain specific and reliable pharmaceutical documentation for the intended admixing., Aim: To assess the of compatibility and stability of LEV, a neutral and hydrophilic drug, in commercial all-in-one (AiO) PN admixtures using simple validated tests to provide necessary data in a timely manner and to allow convenient, documented and safe treatment with PN as the drug vehicle., Methods: Different concentrations of LEV were injected into two different AiO PN admixtures with no further additives. Stability and compatibility tests for the drug and the PN admixtures were performed over seven days at +4°C, +23±1°C and +37°C without light protection. Stability and sample characteristics were observed by visual inspection and the validated light microscope method. Moreover, the pH level of the admixture was checked, as were the concentrations of LEV over time in the PN admixtures, using an established LC-MS/MS method., Results: The stability controls of LEV at different temperatures were within absolute ±20% of the theoretical value in a concentration range of 98.91-117.84% of the initial value. No changes in pH occurred (5.55±0.04) and no microscopic out of specification data or visual changes were observed. The mean value of the largest lipid droplet in each visual field over seven days was 2.4±0.08μm, comparable to that of the drug-free AiO admixture. Samples stored at +37°C showed yellowish discolorations after 96h of storage., Conclusion: LEV showed compatibility and stability over seven days in the selected PN admixtures, and the described methods represented a valuable and timely approach to determine the stability and compatibility of the highly hydrophilic, not dissociated LEV in AiO admixtures under conditions of use. Further studies with clinically relevant and representative examples of physicochemically different drug classes are needed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Since the 1970s, racetams have been in use as cognitive enhancers. Levetiracetam was discovered to have antiseizure activity in animal models and was then found to bind to SV2A in synaptic and endocrine vesicles. Brivaracetam, an analog of levetiracetam, was identified in a medicinal chemistry campaign with the objective of discovering analogs with higher affinity at racetam-binding sites and greater antiseizure potency., (Copyright © 2016. Published by Elsevier Inc.)

In present work, nanocrystals of zeolites were employed as sensing interface for augmented electrochemical sensing of antiepileptic drug, that is, leviteracetum (LEV). Electrochemical sensing method was developed by depositing nanocrystals of zeolites and horseradish peroxidase (nanocrys zeolites-HRP) onto indium tin oxide (ITO)-coated glass surface for LEV detection. Various stages of biosensor fabrication were characterized by Transmission electron microscopy, X-ray diffraction, scanning electron microscopy, and electrochemical impedance spectroscopy. The fabricated nanocrys zeolites-HRP-modified sensor exhibited wide linear range (10-500 μM) and a low detection limit of 0.01 μM. The biosensor also showed a short response time (within 2 s). In addition, the biosensor exhibited high reproducibility, good storage stability, and anti-interference ability. The applicability of the nanocrys zeolites-HRP-modified sensor is to determine LEV level in spiked serum samples., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Fluorescence spectroscopy in combination with circular dichroism (CD) and ultraviolet-visible (UV-vis) absorption spectroscopy were employed to investigate the binding of a new platinum(II) complex containing an antiepileptic drug "Levetiracetam" to bovine serum albumin (BSA) under the physiological conditions. In the mechanism discussion, it was proved that the fluorescence quenching of BSA by Pt(II) complex is a result of the formation of Pt(II) complex-BSA complex. The thermodynamic parameters ΔG, ΔH, and ΔS at different temperatures (283, 298, and 310 K) were calculated, and the negative value for ΔH and ΔS indicate that the hydrogen bonds and van der Waals interactions play major roles in Pt(II) complex-BSA association. Binding studies concerning the number of binding sites (n~1) and apparent binding constant K b were performed by fluorescence quenching method. The site marker competitive experiments indicated that the binding of Pt(II) complex to BSA primarily took place in site II. Based on the Förster's theory, the average binding distance between Pt(II) complex and BSA was obtained (r = 5.29 nm). Furthermore, UV-vis, CD, and synchronous fluorescence spectrum were used to investigate the structural change of BSA molecules with addition of Pt(II) complex. These results indicate that the binding of Pt(II) complex to BSA causes apparent change in the secondary structure of BSA and do affect the microenvironment around the tryptophan residue.

The nature of the pharmacodynamic interactions of drugs is influenced by the drugs׳ mechanisms of action. It has been hypothesized that drugs with different mechanisms are likely to interact synergistically, whereas those with similar mechanisms seem to produce additive interactions. In this review, we describe an extensive investigation of the published literature on drug combinations of anticonvulsants, the nature of the interaction of which has been evaluated by type I and II isobolographic analyses and the subthreshold method. The molecular targets of antiepileptic drugs (AEDs) include Na(+) and Ca(2+) channels, GABA type-A receptor, and glutamate receptors such as NMDA and AMPA/kainate receptors. The results of this review indicate that the nature of interactions evaluated by type I isobolographic analyses but not by the two other methods seems to be consistent with the above hypothesis. Type I isobolographic analyses may be used not only for evaluating drug combinations but also for predicting the targets of new drugs., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The water-soluble platinum(II) complex, [Pt(LV)(dmso)Cl]Cl (LV is Levetiracetam an anti-epileptic drug belonging to the pyrrolidine family) was synthesized and characterized using physico-chemical, spectroscopic and computational methods. Multi-spectroscopic methods used to study the interaction of Pt(II) complex with calf thymus (ct-DNA) in Tris-HCl buffer solution (pH 7.4). The Pt(II) complex was found to be a minor groove binder with a preference for the A-T region compared to the G-C region. This was substantiated by displacement studies with Hoechst 33258, a known minor groove binder. The mean binding constant obtained from the spectroscopic techniques was 7 × 10(4) M(-1). In comparison with the previous study, the binding constant of Pt(II) complex is 15 times greater than the corresponding value of levetiracetam. These results indicate that the binding affinity of Pt(II) complex is stronger than levetiracetam.

Purpose: The long-term stability of levetiracetam solution in oral syringes was investigated in order to define a suitable beyond-use date and demonstrate the feasibility of storing prepared syringes for extended periods as an alternative to commercial levetiracetam unit dose cups., Methods: Levetiracetam oral solution (100 mg/mL) was drawn into 1- and 10-mL amber polypropylene oral syringes. Triplicate samples of the syringe preparations were stored at refrigeration (2-8 °C) or room temperature (20-25 °C) and evaluated at monthly intervals for up to six months. At each time point, the samples were visually inspected and levetiracetam stability was assessed via pH measurement and high-performance liquid chromatography (HPLC). A short-term forced degradation study was conducted to confirm that the HPLC assay method was stability indicating., Results: Over the six-month storage period, there was no significant change in either the visual appearance or pH of any of the levetiracetam samples. The results of serial HPLC assessment indicated that at least 97% of the initial levetiracetam concentration was retained in all samples of 1- and 10-mL oral syringes at both refrigeration and room temperature. Although this study was conducted using a generic product, the stability data obtained may be applied in repackaging decisions regarding other generic formulations of levetiracetam with similar excipient compositions., Conclusion: Commercial levetiracetam 100-mg/mL oral solution was stable for up to six months in amber polypropylene oral syringes stored at both refrigeration and room temperature conditions.

LEV (levetiracetam), an antiepileptic drug which possesses a unique profile in animal models of seizure and epilepsy, has as its unique binding site in brain, SV2A (synaptic vesicle protein 2A). Previous studies have used a chimaeric and site-specific mutagenesis approach to identify three residues in the putative tenth transmembrane helix of SV2A that, when mutated, alter binding of LEV and related racetam derivatives to SV2A. In the present paper, we report a combined modelling and mutagenesis study that successfully identifies another 11 residues in SV2A that appear to be involved in ligand binding. Sequence analysis and modelling of SV2A suggested residues equivalent to critical functional residues of other MFS (major facilitator superfamily) transporters. Alanine scanning of these and other SV2A residues resulted in the identification of residues affecting racetam binding, including Ile273 which differentiated between racetam analogues, when mutated to alanine. Integrating mutagenesis results with docking analysis led to the construction of a mutant in which six SV2A residues were replaced with corresponding SV2B residues. This mutant showed racetam ligand-binding affinity intermediate to the affinities observed for SV2A and SV2B.

Introduction: Gabapentin (Neurontin) and levetiracetam (Keppra) are anticonvulsants with novel structures and suggested therapeutic ranges of 2-10 mg/L and 6-20 mg/L, respectively. Gabapentin is also used extensively to manage neuropathic pain, and for this indication, wherein higher doses are prescribed, plasma concentrations of 15-30 mg/L are typical., Objective: Here, we describe a simple rapid assay to support therapeutic drug monitoring of gabapentin and levetiracetam in plasma by ultra-pressure liquid chromatography couples to tandem mass spectrometry (UPLC-MS/MS) detection., Methods: After the addition of internal standard and protein precipitation of patient plasma with methanol:acetonitrile in a 50:50 ratio, 1 μL of supernatant sample is injected onto an Acquity UPLC HSS T3, 1.8 μm, 2.1 × 50 mm (Waters) column. Elution occurs using a linear gradient of acetonitrile and water, each having 0.1% formic acid added. The column is eluted into a Waters Acquity UPLC TQD, operating in a positive mode to detect gabapentin at transition 172.18 > 154.11, levetiracetam at 171.11 > 126, and internal standard (3-amino-2-naphthoic acid) at 188.06 > 170. Secondary transitions for each analyte are also monitored for gabapentin at 172.18 > 137.06, levetiracetam at 171.11 > 154, and internal standard at 188.06 > 115. Runtime is 1.5 minutes per injection with baseline resolved chromatographic separation., Results: The analytical measurement ranges were 1-150 mg/L for gabapentin and for levetiracetam. Intra-assay imprecision by the coefficient of variance (CV) was less than 8% and interassay CV was less than 5% for both analytes, at 4 different concentrations. Results obtained from patient samples were compared with results generated by established high-performance liquid chromatography-UV methods with the following regression statistics: y = 1.12x - 0.77, r = 0.996, Sy, x = 0.89, and n = 29 for gabapentin and y = 0.991x + 0.70, r = 0.997, Sy, x = 2.24, and n = 30 for levetiracetam. No analytical interferences were identified., Conclusion: : In summary, a simple reliable UPLC-MS/MS method was developed and validated for routine clinical monitoring of gabapentin and levetiracetam.

The novel antiepileptic drug levetiracetam ((2S-(2-oxo-1-pyrrolidinyl)butanamide, KEPPRA possesses a specific binding site in brain, which has very recently been identified as the synaptic vesicle protein SV 2 A. The aim of this study was to evaluate the presence of a levetiracetam binding site in the spinal cord and compare its properties to that in rat brain. We used [(3)H]ucb 30889 ((2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide), a levetiracetam analogue, to perform binding assays, photoaffinity labelling and autoradiography experiments, and revealed the presence of SV 2 A by Western-blot analysis. [(3)H]ucb 30889 binding kinetics at 4 degrees C were biphasic and saturation binding curves were compatible with the labelling of a homogenous population of binding sites with a K(d) similar to that in brain. Competition curves with ligands known to interact with levetiracetam binding sites and photolabelling experiments indicated that [(3)H]ucb 30889 labels the same 90 kDa protein in both spinal cord and brain. Levetiracetam binding site was localised in the grey matter of the spinal cord and its expression was not modified in a model of neuropathic pain. This study demonstrates the presence of a specific levetiracetam binding site in the rat spinal cord, which is similar to that found in rat brain.

A large number of new antiepileptic drugs (AEDs) have become available over the last 10 years. Results from placebo-controlled clinical trials and community-based practice have demonstrated that levetiracetam has a broad spectrum of activity in suppressing seizures as add-on treatment and monotherapy and that it is safe and well-tolerated. Levetiracetam also has a favourable pharmacokinetic profile characterised by rapid and nearly complete absorption, very low potential for drug interactions and a prolonged pharmacodynamic effect that permits twice-daily dosing. Although, the mechanism of action of levetiracetam is not completely understood, preclinical studies suggest that it may have antiepileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression.

Levetiracetam (2S-(2-oxo-1-pyrrolidinyl)butanamide, KEPPRA, a novel antiepileptic drug, has been shown to bind to a specific binding site located in brain (levetiracetam binding site [Eur. J. Pharmacol. 286 (1995) 137]). However, [3H]levetiracetam displayed only micromolar affinity for these sites making it an unsuitable probe for further characterization. The present study describes the binding properties of an analogue of levetiracetam: [3H]ucb 30889, (2S)-2-[4-(3-azidophenyl)-2-oxopyrrolidin-1-yl]butanamide. [3H]ucb 30889 binds reversibly to specific binding sites in rat brain. Kinetics at 4 degrees C were biphasic with half-times of association and dissociation of, respectively, 3 and 4 min for the fast component and 47 and 61 min for the slow component. [3H]ucb 30889 saturation binding curves were compatible with the labelling of a homogenous population of binding sites having a B(max) of 4496+/-790 fmol/mg protein (mean+/-S.D., n=5) and a K(d) of 62+/-20 nM (mean+/-S.D., n=5), a 20-fold increase in affinity compared to [3H]levetiracetam. Competition binding curves with ligands known to interact with levetiracetam binding sites and tissue distribution restricted to the brain indicated that [3H]ucb 30889 and [3H]levetiracetam bind to the same site. Although levetiracetam binding sites and GABA(A) (gamma-aminobutyric acid) receptors share some ligands such as pentobarbital and pentylenetetrazol, experiments performed with [35S]TBPS (tert-butyl-bicyclo[2.2.2]phosporothionate), a probe for the GABA(A) Cl(-) channel do not support the hypothesis that levetiracetam binding sites are part of the GABA(A) receptor complex. Preliminary autoradiography studies in rat brain revealed that [3H]ucb 30889 labels specific sites in all brain regions and that this binding is concentration-dependently displaced by levetiracetam.

Microemulsion electrokinetic chromatography was applied for the separation of levetiracetam from other antiepileptic drugs (primidone, phenobarbital, phenytoin, lamotrigine and carbamazepine) that are potentially coadministered in therapy of patients. The influence of the composition of the microemulsion system (with sodium dodecyl sulfate as charged surfactant) was investigated, modifying the kind of cosurfactant (lower alcohols from C3 to C5), the pH (and salinity) of the aqueous background electrolyte, and the ratio of aqueous phase to organic constituents forming the microdroplets of the oil-in-water emulsion. Separation selectivity was depending on all these parameters, resulting even in changes of the migration sequence of the analytes. Only moderate correlation was observed for the microemulsion system compared with a micellar system, both consisting of the aqueous borate buffer (pH 9.2) and SDS as micelle former (linear correlation coefficient for analyte mobilities is 0.974). The sample solvent plays an important role on the shape of the resulting chromatograms: methanol at concentrations higher than 35% impairs peak shape and separation efficiency. The microemulsion method (with 93.76% aqueous borate buffer (pH 9.2, 10 mM), 0.48% n-octane, 1.80% SDS, 3.96% 1-butanol, all w/w) is suitable for the determination of levetiracetam in human plasma (combined with a sample pretreatment based on solid-phase extraction).

Levetiracetam is a new antiepileptic drug with a chemical structure similar to piracetam, but different pharmacological properties. The pharmacokinetic profile of levetiracetam closely approximates the ideal characteristics expected of an antiepileptic drug: good bioavailability, linear kinetics, rapid achievement of steady-state concentrations, minimal protein binding and minimal metabolism. It has been approved as add-on therapy for the treatment of partial-onset seizures in adults. Its efficacy has been proved through four pivotal double-blind, aleatorized, placebo-controlled trials. Levetiracetam is well-tolerated and the incidence of adverse events is similar to placebo. There is no evidence of any specific interactions between levetiracetam and digoxin, warfarin, probenecid or other antiepileptic drugs. Preclinical studies have shown potential efficacy against generalized seizures. Antidystonic and antimyoclonic effects have been also suggested. There are few data of its efficacy on monotherapy and pediatric population.

Levetiracetam is a new antiepileptic drug, structurally and mechanistically dissimilar to other marketed antiepileptic drugs. It is effective in reducing partial seizures in patients with epilepsy, both as adjunctive treatment and as monotherapy. Levetiracetam has many therapeutic advantages for patients with epilepsy. It has favorable pharmacokinetic characteristics (good bioavailability, linear pharmacokinetics, insignificant protein binding, lack of hepatic metabolism, and rapid achievement of steady-state concentrations) and a low potential for drug interactions. Recommended starting dosages are considered to be clinically effective; therefore, patients can have some protection from seizures soon after they begin levetiracetam. The most common adverse effects observed with levetiracetam are mild and include somnolence, asthenia, and dizziness. Clinical experience and data from meta-analyses indicate that levetiracetam is well tolerated, with efficacy comparable or slightly better than that observed with other new antiepileptic drugs. Levetiracetam may be particularly useful in patients who are unresponsive to other antiepileptic drugs, patients receiving drugs with increased potential for drug interactions, or those with hepatic impairment.

Purpose: The new antiepileptic drug, levetiracetam (LEV, ucb LO59), is a chiral molecule with one asymmetric carbon atom whose anticonvulsant activity is highly enantioselective. The purpose of this study was to evaluate and compare the pharmacokinetics (PK) of LEV [(S)-alpha-ethyl-2-oxo-pyrrolidine acetamide] and its enantiomer (R)-alpha-ethyl-2-oxo-pyrrolidine acetamide (REV) after i.v. administration to dogs. This is the first time that the pharmacokinetics of both enantiomers has been evaluated., Methods: Optically pure LEV and REV were synthesized, and 20 mg/kg of individual enantiomers was administered intravenously to six dogs. Plasma and urine samples were collected until 24 h, and the concentrations of LEV and REV were determined by an enantioselective assay. The levels of 2-pyrrolidone-N-butyric acid, an acid metabolite of LEV and REV, were determined by high-performance liquid chromatography (HPLC). The data were used for PK analysis of LEV and REV., Results: LEV and REV had similar mean +/- SD values for clearance; 1.5 +/- 0.3 ml/min/kg and volume of distribution; 0.5 +/- 0.1 L/kg. The half-life (t1/2) and mean residence time (MRT) of REV (t1/2, 4.3 +/- 0.8 h, and MRT, 6.0 +/- 1.1 h) were, however, significantly longer than those of LEV (t1/2, 3.6 +/- 0.8 h, and MRT, 5.0 +/- 1.2 h). The renal clearance and fraction excreted unchanged for LEV and REV were significantly different., Conclusions: In addition to the enantioselective pharmacodynamics, alpha-ethyl-2-oxo-pyrrolidine acetamide has enantioselective PK. The enantioselectivity was observed in renal clearance. Because REV has more favorable PK in dogs than LEV, the higher antiepileptic potency of LEV is more likely due to intrinsic pharmacodynamic activity rather than to enantioselective PK.