Background Metoprolol, a widely used β-blocker, is administered as a racemic mixture, with (S)-metoprolol being more pharmacologically active. Its metabolism by CYP2D6 exhibits significant inter-individual variability due to genetic polymorphisms. While enantioselective pharmacokinetics have been studied in single-dose trials, data on long-term therapy in hypertensive patients is limited. This study examines urinary enantiomer profiles to assess variability in metabolism and excretion. Objectives This study investigates the enantiomeric profile of metoprolol in urine samples collected from hypertensive patients receiving long-term racemic metoprolol therapy. The research aims to improve the analytical performance of the method to explore the enantioselective metabolism and excretion of the drug, focusing on the variation in enantiomer ratios among patients and the potential implications for clinical practice. Methods Urine samples were collected from 30 hypertensive patients treated with racemic metoprolol. The samples were analyzed using capillary electrophoresis (CE) with clarithromycin as a chiral selector. Prior to CE analysis, liquid-liquid extraction was performed to isolate metoprolol from urine. The CE method employed an online preconcentration method and had a detection limit of 0.015 µg mL−1 for each enantiomer, a linear range of 0.05 to 2.0 µg mL−1, and demonstrated intra-day and inter-day precision below 6.3%, with accuracy within 5.6%. Results Metoprolol enantiomers were quantified in patients’ urine samples, with enantiomer ratios varying among individuals. The enantiomer ratio (S/R) exceeded 1 in most patients, reflecting higher (S)-metoprolol concentrations. However, in approximately 40% of patients, the ratio was less than 1, suggesting possible enantioselective renal excretion. Conclusion The study confirms that there is substantial inter-individual variability in the enantioselective metabolism and excretion of metoprolol among hypertensive patients. The findings emphasize the need to consider enantioselective pharmacokinetics in clinical practice, especially for chiral drugs like metoprolol. The results also suggest that the duration of treatment may affect the metabolism and excretion of enantiomers, warranting further investigation into the effects of long-term drug administration on enantiomeric ratios. Graphical abstract

Profiling metoprolol enantiomers in urine of hypertensive patients

期刊论文
发表日期：

2025年7月3日

查看全文

Behrouz Seyfinejad,
Kimiya Jouyban,
Jalil Houshyar,
Amirreza Jabbaripour Sarmadian,
Abolghasem Jouyban

摘要

Background

Metoprolol, a widely used β-blocker, is administered as a racemic mixture, with (S)-metoprolol being more pharmacologically active. Its metabolism by CYP2D6 exhibits significant inter-individual variability due to genetic polymorphisms. While enantioselective pharmacokinetics have been studied in single-dose trials, data on long-term therapy in hypertensive patients is limited. This study examines urinary enantiomer profiles to assess variability in metabolism and excretion.

Objectives

This study investigates the enantiomeric profile of metoprolol in urine samples collected from hypertensive patients receiving long-term racemic metoprolol therapy. The research aims to improve the analytical performance of the method to explore the enantioselective metabolism and excretion of the drug, focusing on the variation in enantiomer ratios among patients and the potential implications for clinical practice.

Methods

Urine samples were collected from 30 hypertensive patients treated with racemic metoprolol. The samples were analyzed using capillary electrophoresis (CE) with clarithromycin as a chiral selector. Prior to CE analysis, liquid-liquid extraction was performed to isolate metoprolol from urine. The CE method employed an online preconcentration method and had a detection limit of 0.015 µg mL⁻¹ for each enantiomer, a linear range of 0.05 to 2.0 µg mL⁻¹, and demonstrated intra-day and inter-day precision below 6.3%, with accuracy within 5.6%.

Results

Metoprolol enantiomers were quantified in patients’ urine samples, with enantiomer ratios varying among individuals. The enantiomer ratio (S/R) exceeded 1 in most patients, reflecting higher (S)-metoprolol concentrations. However, in approximately 40% of patients, the ratio was less than 1, suggesting possible enantioselective renal excretion.

Conclusion

The study confirms that there is substantial inter-individual variability in the enantioselective metabolism and excretion of metoprolol among hypertensive patients. The findings emphasize the need to consider enantioselective pharmacokinetics in clinical practice, especially for chiral drugs like metoprolol. The results also suggest that the duration of treatment may affect the metabolism and excretion of enantiomers, warranting further investigation into the effects of long-term drug administration on enantiomeric ratios.

Graphical abstract