Simultaneous LC-ESI-MS/MS Quantification of Levosimendan and Its Metabolites for Therapeutic Drug Monitoring of Cardiac Surgery Patients

Abstract

Levosimendan is used in severe chronic cardiac insufficiency, also within the peri-operative setting. Real-life pharmacokinetic data in surgical patients is lacking, making therapeutic drug monitoring (TDM) of levosimendan, its pharmacologically active metabolite OR-1896, and its intermediate OR-1855 important. A simultaneous highly sensitive quantification of levosimendan and its metabolites in small-volume samples has not yet been described. Here, levosimendan (LLOQ 0.450 nM), OR-1896, and OR-1855 (LLOQ both 1.0 nM) were successfully quantified by LC-ESI-MS/MS after liquid-liquid extraction in 300 µL of blood. A short C8 column under reversed-phase conditions enabled simultaneous and fast quantification of levosimendan in the negative and the metabolites in the positive ionization mode in a single run within 2 min. Interestingly and unexpectedly, constitutional isomers of levosimendan metabolites with identical mass transitions and similar retention times were observed in surgical patients’ samples, which we identified as the metamizole metabolites 4-aminoantipyrine and 4-acetamidoantipyrine. A longer C8 column and a modified mobile phase enabled selective quantification of all analytes in a single run within 7 min. We developed, validated, and applied highly sensitive LC-ESI-MS/MS methods for simultaneous quantification of levosimendan and its metabolites, enabling efficient TDM of cardiac surgery patients even with additional metamizole administration.

Levosimendan’s Effects on Length-Dependent Activation in Murine Fast-Twitch Skeletal Muscle

“…In addition, 100 µM levosimendan represents the top end of externally applied concentrations to skeletal muscle in the literature [ 14 ]. In patients with heart failure, levosimendan is usually administered in doses up to 0.2 µg/kg/min, translating to roughly 0.4 nM [ 53 ] in the blood serum. Whether concentrations in the µM range are factually present in patient’s muscle tissue remains to be investigated and must be related to experiments where levosimendan is diluted, e.g., in glucose solution to avoid an underestimation of its effects and thus define a dosage at which effects can be expected in the body.…”

Silver/graphene–polypyrrole composite for levosimendan detection

“…[7,8] Several methods have been proposed for determining levosimendan concentrations. [9][10][11] For example, high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), [9] HPLC-capillary electrophoresis (HPLC-CE), [10] and fluorescence [11] techniques have been used for detecting levosimendan concentrations. Electrochemical detection is an outstanding candidate for detecting levosimendan owing to its excellent sensitivity, high selectivity, fast response, simple operation, and cost-effectiveness.…”