Stereoselective Determination of Metoprolol and its Metabolite α‐Hydroxymetoprolol in Plasma by LC‐MS/MS: Application to Pharmacokinetics during Pregnancy. Issue 1 (24th October 2012)

• Record Type: Journal Article
• Authors: Antunes, Natalícia De Jesus; Cavalli, Ricardo Carvalho; Marques, Maria Paula; Lanchote, Vera Lucia
• Is Part Of: Chirality. Volume 25:Issue 1(2013:Jan.)
• Page Start: 1
• Page End: 7
• Publication Date: 2012-10-24
• Subjects: Chirality -- Periodicals; Pharmaceutical chemistry -- Periodicals; 541.22
• DOI: 10.1002/chir.22102
• Languages: English
• ISSNs: 0899-0042

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>Metoprolol is available for clinical use as a racemic mixture. The <italic>S</italic>‐(−)‐metoprolol enantiomer is the one expressing higher activity in the blockade of the β<sub>1</sub>‐adrenergic receptor. The α‐hydroxymetoprolol metabolite also has activity in the blockade of the β<sub>1</sub>‐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)<sup>0−∞</sup> values for <italic>S</italic>‐(−)‐metoprolol (AUC<sub><italic>S</italic>‐(−)</sub>/AUC<sub><italic>R</italic>‐(+)</sub> = 1.81) and the favoring of the formation of the new chiral center 1′<italic>R</italic> of α‐hydroxymetoprolol (AUC<sup>0−∞</sup><sub>1′<italic>R</italic>/1′<italic>S</italic></sub> = 2.78). <italic>Chirality, 25:1–7, 2013.</italic> © 2012 Wiley Periodicals, Inc.</p> </abstract>