A cross-sectional study on metoprolol concentrations in various biological samples and their inter-correlations

Houshyar et al. BMC Pharmacology and Toxicology https://doi.org/10.1186/s40360-024-00773-3 (2024) 25:45 BMC Pharmacology and Toxicology Open Access RESEARCH A cross-sectional study on metoprolol concentrations in various biological samples and their inter-correlations Jalil Houshyar1,2†, Nastaran Hashemzadeh3†, Maryam Khoubnasabjafari4,5, Amirreza Jabbaripour Sarmadian6, Vahid Jouyban-Gharamaleki7,8, Mohammad Reza Afshar Mogaddam9, Elnaz Marzi Khosrowshahi9 and Abolghasem Jouyban10* Abstract Background Concentrations of metoprolol in exhaled breath condensate (EBC) have not been investigated. Herein, we aim to determine the metoprolol levels in EBC, plasma, and urine samples. Methods Biological samples were collected from 39 patients receiving metoprolol. Metoprolol was determined using liquid chromatography mass spectrometery. The obtained metoprolol levels in biological fluids were investigated for possible inter-correlations. Results Acceptable linearity was obtained with coefficient of determinations equal to 0.9998, 0.9941, and 0.9963 for EBC, plasma, and urine samples, respectively. The calibration curves were linear in the ranges of 0.6–500, 0.4–500, and 0.7–10,000 µg·L− 1 regarding EBC, plasma, and urine samples, respectively. The detection and quantification limits were (0.18, 0.12, and 0.21 µg·L− 1) and (0.60, 0.40, and 0.70 µg·L− 1) for EBC, plasma, and urine samples, respectively. The relative standard deviations for the intra- and inter-day replications were obtained between 5.2 and 6.1 and 3.3–4.6%, respectively. The obtained mean metoprolol levels in EBC, plasma, and urine samples of 39 patients were 5.35, 70.76, and 1943.1 µg·L− 1. There were correlations between daily dose and plasma and urinary concentrations of metoprolol in the investigated samples, whereas no significant correlation was observed for daily dose and EBC levels. The correlation among plasma-urine levels was significant, however, the non-significant correlation was obtained between plasma and EBC concentrations. Conclusion Metoprolol levels varied widely due to the metabolic pattern of the Azeri population, different dosages received by the patients, formulation effects, age, sex, and interactions with the co-administered drugs. A poor correlation of EBC-plasma concentrations and a significant correlation of plasma-urine concentrations were observed. Further investigations are required to provide the updated services to personalized medicine departments. † Jalil Houshyar and Nastaran Hashemzadeh contributed equally to this work. *Correspondence: Abolghasem Jouyban Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/. Houshyar et al. BMC Pharmacology and Toxicology (2024) 25:45 Page 2 of 11 Keywords Drug monitoring, Metoprolol, Preconcentration, HPLC, Exhaled breath condensate, Plasma, Urine, Correlations Background Metoprolol, a selective blocker of β1-adrenergic receptors, is one of the most widely used drugs in clinical practice [1, 2]. The β1 receptors are mainly found in the heart and affect cardiac function. Therefore, metoprolol is mainly prescribed to manage cardiovascular disorders, including hypertension, heart failure, angina, cardiac arrhythmias, and myocardial infarction [1, 3, 4]. In addition to therapeutic applications, metoprolol is used as a doping agent in sports to enhance the shooting of amateur sportsmen [5]. Considering the clinical importance and high prevalence of cardiovascular disorders and the widespread use and misuse of metoprolol, measuring the therapeutic level of metoprolol is particularly critical. A therapeutic regimen can be easily managed by determining drug levels in biological fluids. Therefore, therapeutic drug monitoring (TDM) of beta-blockers using liquid chromatography-mass spectrometry, which is a relatively expensive process and requires highly skilled personnel, [6] is performed in some hospitals. Metoprolol distributes very rapidly between the blood and various extravascular sites, and only 1 to 2% of the total amount of the drug in the body is localized in the blood at an apparent distribution equilibrium [7]. The blood/plasma concentration of metoprolol is in the range of 5–80 µg·L− 1 (mean 33 µg·L− 1) after the 20 mg dose administration, and 14–212 µg·L− 1 (mean 111 µg·L− 1) after the 50 mg dose [8]. Drug levels in the blood or blood-derived fluids such as serum and plasma reflect systemic drug exposure, widely accepted in biomedicine, and are currently the most widely used biological samples in clinical analysis. However, these samples have disadvantages such as invasive sampling, the need for a skilled person for sampling, very high matrix effect, and low compliance of the patients [9]. In addition, sample preparation methods are necessary for the analysis of these samples, because the blood concentration range is below the limit of detection (LOD) of direct analysis in most analytical tools. Furthermore, direct analysis is not feasible due to the matrix interferences in these samples [10]. Therefore, alternative biological fluids, including exhaled breath condensate (EBC) and urine may be considered. The EBC sample consists of water vapor present in the breath and very small liquid droplets of the fluid covering the surface of the lung, which are condensed by a cooling collection device [11]. The main advantages of using the EBC samples include non-invasive sampling, a simple matrix (compared to other biological fluids), the possibility of repeating sampling as often as needed, and the feasibility of direct sample injection to the analytical tools [12]. The EBC can be considered as a possible alternative sample for drug concentration monitoring [13– 16], early diagnosis of diseases by checking the level of appropriate biomarkers, and response to drug treatment [12, 17]. Several analytical techniques for the determination of metoprolol in pharmaceutical and biological samples have (...truncated)