Abstract
<p>Levetiracetam (LEV), an antiepileptic drug (AED) with favorable pharmacokinetic profile, is increasingly being used in clinical practice, although information on its metabolism and disposition are still being generated. Therefore a simple, robust and fast liquid-liquid extraction (LLE) followed by high-performance liquid chromatography method is described that could be used for both pharmacokinetic and therapeutic drug monitoring (TDM) purposes. Moreover, recovery rates of LEV in plasma were compared among LLE, stir bar-sorptive extraction (SBSE), and solid-phase extraction (SPE). Solvent extraction with dichloromethane yielded a plasma residue free from usual interferences such as commonly co-prescribed AEDs, and recoveries around 90% (LLE), 60% (SPE) and 10% (SBSE). Separation was obtained using reverse phase Select B column with ultraviolet detection (235 nm). Mobile phase consisted of methanol:sodium acetate buffer 0.125 M pH 4.4 (20:80, v/v). The method was linear over a range of 2.8-220.0 µg mL<sup>-1</sup>. The intra- and inter-assay precision and accuracy were studied at three concentrations; relative standard deviation was less than 10%. The limit of quantification was 2.8 µg mL<sup>-1</sup>. This robust method was successfully applied to analyze plasma samples from patients with epilepsy and therefore might be used for pharmacokinetic and TDM purposes.</p>
Highlights
Levetiracetam (LEV; α-ethyl-2-oxo-1-pyrrolidine acetamide; Figure 1) is an antiepileptic drug (AED) approved by the Food and Drug Administration to be prescribed in polytherapy for management of partial onset seizures with or without secondary generalization in adults and children with refractory epilepsy, and as monotherapy for treatment of partial onset seizures in patients with newly diagnosed epilepsy (Mbizvo et al.,2012; Patsalos, 2004).Its innovative mechanism of action based on the selective binding to a synaptic vesicle protein (SV2A) involved in neurotransmitter release (Macdonald; Rogawski, 2008) and the favorable pharmacokinetic profile makes LEV a promising AED in terms of efficacy and tolerability
Considering that analytical procedures allowing rapid and robust quantifications of LEV concentrations in biologic fluids are of great interest both for therapeutic drug monitoring (TDM) and pharmacokinetic applications, this work aimed to present a study of a reliable analytical method based on comparisons of recovery rates from liquid-liquid extraction (LLE), stir bar-sorptive extraction (SBSE) and solid-phase extraction (SPE) cleanup procedures followed by high-performance liquid chromatography (HPLC) analysis for determination of LEV concentrations in plasma samples
This paper presents a simple, robust and fast method for determination of LEV in human plasma using reverse-phase HPLC combined with UV detection
Summary
Levetiracetam (LEV; α-ethyl-2-oxo-1-pyrrolidine acetamide; Figure 1) is an antiepileptic drug (AED) approved by the Food and Drug Administration to be prescribed in polytherapy for management of partial onset seizures with or without secondary generalization in adults and children with refractory epilepsy, and as monotherapy for treatment of partial onset seizures in patients with newly diagnosed epilepsy (Mbizvo et al.,2012; Patsalos, 2004).Its innovative mechanism of action based on the selective binding to a synaptic vesicle protein (SV2A) involved in neurotransmitter release (Macdonald; Rogawski, 2008) and the favorable pharmacokinetic profile makes LEV a promising AED in terms of efficacy and tolerability. Levetiracetam (LEV; α-ethyl-2-oxo-1-pyrrolidine acetamide; Figure 1) is an antiepileptic drug (AED) approved by the Food and Drug Administration to be prescribed in polytherapy for management of partial onset seizures with or without secondary generalization in adults and children with refractory epilepsy, and as monotherapy for treatment of partial onset seizures in patients with newly diagnosed epilepsy (Mbizvo et al.,2012; Patsalos, 2004). In contrast to most other AEDs, LEV elimination is not significantly dependent on the cytochrome P450 enzymatic system; about 66% of an oral dose are excreted unchanged in urine, and 24% undergo hydrolysis in blood to the inactive metabolite ucb L057 (Patsalos, 2004). As a relatively new AED, LEV pharmacokinetics is still under investigation, especially regarding its disposition and elimination in situations such as pregnancy and extremes of ages (Italiano, Perucca, 2013; Tomson, Landmark, Battino, 2013)
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