title: Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats.
abstract: Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox-Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1 mg/kg body weight (bw), 5 mg/kg bw, and 20 mg/kg bw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450 g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography-mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13 h, depending on route of administration--intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01 ± 3.80 ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52 ± 39.45 ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1 mg/kg bw and 5 mg/kg bw was 0.89 ± 0.09 μg/ml and 3.188 ± 0.71 μg/ml, respectively. The median (range) time to reach maximum plasma concentration (t(max)) was 4 (2-8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514 ± 0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC(0-t)) of 0.441 ± 0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio.
authors.affiliation: University of Medicine and Pharmacy of Tirgu Mures, Faculty of Medicine, Department of Physiology, Doctoral School, Romania; University of Medicine and Pharmacy of Tirgu Mures, Faculty of Pharmacy, Department of Pharmacology and Clinical Pharmacy, Romania.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Gáll
authors.affiliation: University of Medicine and Pharmacy of Tirgu Mures, Faculty of Pharmacy, Department of Physical Chemistry, Romania. Electronic address: vancea.szende@umftgm.ro.
authors.forename: Szende
authors.initials: S
authors.lastname: Vancea
authors.affiliation: University of Medicine and Pharmacy of Tirgu Mures, Faculty of Medicine, Department of Physiology, Doctoral School, Romania; University of Medicine and Pharmacy of Tirgu Mures, Faculty of Medicine, Department of Physiology, Romania.
authors.forename: Tibor
authors.initials: T
authors.lastname: Szilágyi
authors.affiliation: University of Medicine and Pharmacy of Tirgu Mures, Faculty of Medicine, Department of Physiology, Romania.
authors.forename: Orsolya
authors.initials: O
authors.lastname: Gáll
authors.affiliation: University of Medicine and Pharmacy of Tirgu Mures, Faculty of Pharmacy, Department of Pharmacology and Clinical Pharmacy, Romania.
authors.forename: Melinda
authors.initials: M
authors.lastname: Kolcsár
mesh_terms: D061605:Administration, Intravenous; D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D004285:Dogs; D006801:Humans; D008297:Male; D017208:Rats, Wistar; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D014230:Triazoles; C079703:rufinamide
keywords: 2-hydroxyethylcellulose (PubChem CID: 24846132); Brain-to-plasma ratio; Dimethyl Sulfoxide (PubChem CID: 679); Pharmacokinetics; Plasma concentration; Rat; Rufinamide; Rufinamide (PubChem CID: 129228)