Stereoselective Determination of Metoprolol and its Metabolite α‐Hydroxymetoprolol in Plasma by LC‐MS/MS: Application to Pharmacokinetics during Pregnancy |
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Authors: | Natalícia De Jesus Antunes Ricardo Carvalho Cavalli Maria Paula Marques Vera Lucia Lanchote |
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Affiliation: | 1. Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeir?o Preto, Universidade de S?o Paulo, , Ribeir?o Preto, S?o Paulo, Brazil;2. Departamento de Ginecologia e Obstetrícia, Faculdade de Medicina de Ribeir?o Preto, Universidade de S?o Paulo, , Ribeir?o Preto, S?o Paulo, Brazil |
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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 β1‐adrenergic receptor. The α‐hydroxymetoprolol metabolite also has activity in the blockade of the β1‐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 (AUCS‐(?)/AUCR‐(+) = 1.81) and the favoring of the formation of the new chiral center 1′R of α‐hydroxymetoprolol (AUC0?∞1′R/1′S = 2.78). Chirality, 25:1–7, 2013. © 2012 Wiley Periodicals, Inc. |
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Keywords: | metoprolol enantiomers LC‐MS/MS pharmacokinetics parturient arterial hypertension |
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