Serum protein binding of 25 antiepileptic drugs in a routine clinical setting: A comparison of free non–protein‐bound concentrations

Abstract

SummaryObjectiveGiven that only the free non–protein‐bound concentration of an antiepileptic drug (AED) crosses the blood–brain barrier, entering the brain and producing an antiepileptic effect, knowledge and measurement of the free drug fraction is important. Such data are sparse, particularly for newerAEDs, and have arisen from the use of disparate methodologies and settings over the past six decades. We report on the protein binding of 25AEDs that are available for clinical use, along with two pharmacologically active metabolites (carbamazepine‐epoxide andN‐desmethyl clobazam), using standardized methodology and under set conditions.MethodsThe protein binding of the variousAEDs was undertaken in sera of 278 patients with epilepsy. Separation of the free non–protein‐bound component was achieved by using ultracentrifugation (Amicon Centrifree Micropartition System) under set conditions: 500 μl serum volume; centrifugation at 1,000gfor 15 min, and at 25°C. Free and totalAEDconcentrations were measured by use of fully validated liquid chromatography/mass spectroscopy (LC/MS) techniques.ResultsGabapentin and pregabalin are non–protein‐bound, whereas highly boundAEDs (≥88%) include clobazam, clonazepam, perampanel, retigabine, stiripentol, tiagabine, and valproic acid as well as theN‐desmethyl‐clobazam (89%) metabolite. The minimally bound drugs (<22%) include ethosuximide (21.8%), lacosamide (14.0%), levetiracetam (3.4%), topiramate, (19.5%) and vigabatrin (17.1%). Ten of the 25AEDs exhibit moderate protein binding (mean range 27.7–74.8%).SignificanceThese data provide a comprehensive comparison of serum protein binding of all availableAEDs including the metabolites, carbamazepine‐epoxide andN‐desmethyl‐clobazam. Knowledge of the free fraction of theseAEDs can be used to optimize epilepsy treatment.