Electromembrane extraction (EME) of the polar zwitterionic drugs, anthracyclines (ANT, doxorubicin, daunorubicin and its metabolite daunorubicinol), from rabbit plasma was investigated. The optimized EME was compared to conventional sample pretreatment techniques such as protein precipitation (PP) and liquid-liquid extraction (LLE), mainly in terms of extraction reliability, recovery and matrix effect. In addition, phospholipids profile in the individual extracts was evaluated. The extracted samples were analyzed using UHPLC-MS/MS with electrospray ionization in positive ion mode. The method was validated within the concentration range of 0.25-1000 ng/mL for all tested ANT. Compared with PP and LLE, the EME provided high extraction recovery (more than 80% for all ANT) and excellent sample clean-up (matrix effect were 100 ± 10% with RSD values lower than 4% for all ANT). Furthermore, only negligible amounts of phospholipids were detected in the EME samples. Finally, practical applicability of EME was proved by analysis of plasma samples taken from a pilot in vivo study in rabbits. Consistent results were obtained when using both EME and LLE to extract the plasma prior to the analysis, which further confirmed high reliability of EME. This study clearly showed that EME is a simple, rapid, repeatable technique for extraction of ANT from plasma and it is an up to date alternative to routine conventional extraction techniques.

Department of Pharmacy University of Oslo P O Box 1068 Blindern 0316 Oslo Norway; Department of Pharmacy Faculty of Health and Medical Sciences University of Copenhagen Universitetsparken 2 2100 Copenhagen Denmark

Department of Pharmacy University of Oslo P O Box 1068 Blindern 0316 Oslo Norway; Oslo University Hospital Division of Laboratory Medicine Department of Forensic Sciences P O Box 4459 Nydalen 0424 Oslo Norway

Faculty of Pharmacy in Hradec Králové Charles University Akademika Heyrovského 1203 500 05 Hradec Králové Czech Republic

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Daunorubicin and its hydroxy metabolite in cardiomyocytes: insights into cellular kinetics, toxicity, DNA damage, and dexrazoxane-induced cardioprotection