title: Stereoselective determination of metoprolol and its metabolite α-hydroxymetoprolol in plasma by LC-MS/MS: application to pharmacokinetics during pregnancy.
abstract: Metoprolol is available for clinical use as a racemic mixture. The S-(-)-metoprolol enantiomer is the one expressing higher activity in the blockade of the β(1)-adrenergic receptor. The α-hydroxymetoprolol metabolite also has activity in the blockade of the β(1)-adrenergic receptor. The present study describes the development and validation of a stereoselective method for sequential analysis of metoprolol and of α-hydroxymetoprolol in plasma using high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). 1-ml aliquots of plasma were extracted with dichloromethane : diisopropyl ether (1:1, v/v). Metoprolol enantiomers and α-hydroxymetoprolol isomers were separated on a Chiralpak AD column (Daicel Chemical Industries, New York, NY, USA) and quantitated by LC-MS/MS. The limit of quantitation obtained was 0.2 ng of each metoprolol enantiomer/ml plasma and 0.1 ng/ml of each α-hydroxymetoprolol isomer/ml plasma. The method was applied to the study of kinetic disposition of metoprolol in plasma samples collected up to 24 h after the administration of a single oral dose of 100-mg metoprolol tartrate to a hypertensive parturient with a gestational age of 42 weeks. The clinical study showed that the metoprolol pharmakokinetics is enantioselective, with the observation of higher area under the curve (AUC)(0-∞) values for S-(-)-metoprolol (AUC(S-(-)) /AUC(R-(+))  = 1.81) and the favoring of the formation of the new chiral center 1'R of α-hydroxymetoprolol (AUC(0-∞) (1'R/1'S)  = 2.78).
authors.affiliation: Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Natalícia De Jesus
authors.initials: Nde J
authors.lastname: Antunes
authors.forename: Ricardo Carvalho
authors.initials: RC
authors.lastname: Cavalli
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Marques
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000097:blood*; D000328:Adult; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D005260:Female; D006801:Humans; D008790:Metoprolol / Q000031:analogs & derivatives* / Q000097:blood*; D011247:Pregnancy; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; C029504:alpha-hydroxymetoprolol; D008790:Metoprolol