Stereoselective Determination of Metoprolol and its Metabolite a-Hydroxymetoprolol in Plasma by LC-MS/MS: Application to Pharmacokinetics during Pregnancy

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 beta 1-adrenergic receptor. The a-hydroxymetoprolol metabolite also has activity in the blockade of the beta 1-adrenergic receptor. The present study describes the development and validation of a stereoselective method for sequential analysis of metoprolol and of a-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 a-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 a-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)0-8 values for S-(-)-metoprolol (AUCS-(-)/AUCR-(+)?=?1.81) and the favoring of the formation of the new chiral center 1'R of a-hydroxymetoprolol (AUC0-81'R/1'S?=?2.78). Chirality, 25:17, 2013. (c) 2012 Wiley Periodicals, Inc.