title: Analysis of oxcarbazepine and the 10-hydroxycarbazepine enantiomers in plasma by LC-MS/MS: application in a pharmacokinetic study.
abstract: Oxcarbazepine is a second-generation antiepileptic drug indicated as monotherapy or adjunctive therapy in the treatment of partial seizures or generalized tonic-clonic seizures in adults and children. It undergoes rapid presystemic reduction with formation of the active metabolite 10-hydroxycarbazepine (MHD), which has a chiral center at position 10, with the enantiomers (S)-(+)- and R-(-)-MHD showing similar antiepileptic effects. This study presents the development and validation of a method of sequential analysis of oxcarbazepine and MHD enantiomers in plasma using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Aliquots of 100 μL of plasma were extracted with a mixture of methyl tert-butyl ether: dichloromethane (2:1). The separation of oxcarbazepine and the MHD enantiomers was obtained on a chiral phase Chiralcel OD-H column, using a mixture of hexane:ethanol:isopropanol (80:15:5, v/v/v) as mobile phase at a flow rate of 1.3 mL/min with a split ratio of 1:5, and quantification was performed by LC-MS/MS. The limit of quantification was 12.5 ng oxcarbazepine and 31.25 ng of each MHD enantiomer/mL of plasma. The method was applied in the study of kinetic disposition of oxcarbazepine and the MHD enantiomers in the steady state after oral administration of 300 mg/12 h oxcarbazepine in a healthy volunteer. The maximum plasma concentration of oxcarbazepine was 1.2 µg/mL at 0.75 h. The kinetic disposition of MHD is enantioselective, with a higher proportion of the S-(+)-MHD enantiomer compared to R-(-)-MHD and an AUC(0-12) S-(+)/R-(-) ratio of 5.44.
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Natalicia
authors.initials: N
authors.lastname: de Jesus Antunes
authors.forename: Lauro
authors.initials: L
authors.lastname: Wichert-Ana
authors.forename: Eduardo Barbosa
authors.initials: EB
authors.lastname: Coelho
authors.forename: Oscar
authors.initials: O
authors.lastname: Della Pasqua
authors.forename: Veriano
authors.initials: V
authors.lastname: Alexandre
authors.forename: Osvaldo Massaiti
authors.initials: OM
authors.lastname: Takayanagui
authors.forename: Eduardo
authors.initials: E
authors.lastname: Tozatto
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000284:Administration, Oral; D001774:Blood Chemical Analysis / Q000379:methods*; D002220:Carbamazepine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002853:Chromatography, Liquid; D006801:Humans; D057230:Limit of Detection; D000078330:Oxcarbazepine; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry
chemical_list: C039775:10,11-dihydro-10-hydroxycarbamazepine; D002220:Carbamazepine; D000078330:Oxcarbazepine
keywords: 10-hydroxycarbazepine; LC-MS/MS; enantiomers; oxcarbazepine; pharmacokinetics