Liquid Chromatography–Tandem Mass Spectrometry for the Simultaneous Determination of Doxorubicin and its Metabolites Doxorubicinol, Doxorubicinone, Doxorubicinolone, and 7-Deoxydoxorubicinone in Mouse Plasma

Abstract

Doxorubicin, an anthracycline antitumor antibiotic, acts as a cancer treatment by interfering with the function of DNA. Herein, liquid chromatography-tandem mass spectrometry was for the first time developed and validated for the simultaneous determination of doxorubicin and its major metabolites doxorubicinol, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone in mouse plasma. The liquid–liquid extraction of a 10 μL mouse plasma sample with chloroform:methanol (4:1, v/v) and use of the selected reaction monitoring mode led to less matrix effect and better sensitivity. The lower limits of quantification levels were 0.5 ng/mL for doxorubicin, 0.1 ng/mL for doxorubicinol, and 0.01 ng/mL for doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone. The standard curves were linear over the range of 0.5–200 ng/mL for doxorubicin; 0.1–200 ng/mL for doxorubicinol; and 0.01–50 ng/mL for doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone in mouse plasma. The intra and inter-day relative standard deviation and relative errors for doxorubicin and its four metabolites at four quality control concentrations were 0.9–13.6% and –13.0% to 14.9%, respectively. This method was successfully applied to the pharmacokinetic study of doxorubicin and its metabolites after intravenous administration of doxorubicin at a dose of 1.3 mg/kg to female BALB/c nude mice.

Doxorubicin Anticancer Drug Monitoring by ds-DNA-Based Electrochemical Biosensor in Clinical Samples

“…Therefore, its continuous measurement in biological environments following treatment is crucial and required [ 11 , 12 , 13 , 14 , 15 ]. Numerous methods have been used for this purpose, such as high-performance liquid chromatography (HPLC), spectroscopic methods, and electrochemical sensors [ 11 , 16 , 17 , 18 , 19 ].…”

UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies

“…Various published extraction methods, including protein precipitation using methanol [ 10 , 11 , 12 ], acetonitrile precipitation combined with sonication [ 13 ], liquid–liquid extraction [ 14 , 15 , 16 ], solid-phase extraction [ 17 , 18 , 19 ], and electromembrane extraction [ 20 ] have been employed for the extraction of Leu-DOX and its metabolized products or DOX and its metabolites from diverse matrices such as plasma, urine, and tissues. In this specific study, we examined the viability of a direct protein precipitation technique for the concurrent identification of Leu-DOX and DOX.…”

A review of the pathophysiological mechanisms of doxorubicin-induced cardiotoxicity and aging

“…In human blood, the concentration after doxorubicin administration is typically between 0.025 and 0.250 µmol/L 24 – 28 , whereas in vitro experiments often apply doses of 1 µmol/L or higher. Additionally, mice can tolerate much higher doxorubicin concentrations, with tolerable blood concentrations reaching 0.7–2.1 µmol/L (10–30 mg/kg) 29 , 30 . Doxorubicin treatment has shown different pharmacological effects at different concentrations: At sub-micromolar concentrations, the primary mechanism of action is on DSB formation, while this shifts to free radical toxicity at 2–4 µmol/L 19 .…”