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.
Highlights
Doxorubicin (Adriamycin) is an anthracycline glycoside antitumor antibiotic used as a first-line drug in combination with other chemotherapy drugs for various types of cancers, including breast cancer, bladder cancer, soft tissue and bone sarcomas, malignant lymphoma, and acute lymphocytic leukemia [1]
For the first time, a sensitive and rapid LC with mass spectrometry (LC-MS)/MS method for the simultaneous determination of doxorubicin and its major four metabolites, i.e., doxorubicinol, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinone, using the least mouse plasma volume (10 μL) to evaluate the pharmacokinetics of doxorubicin and metabolites in formulation development and drug–drug interaction studies of doxorubicin
The Luna Omega C18 column exhibited better separation, an excellent peak shape, and good sensitivity for the analytes using a gradient elution of 0.1% formic acid in 95% methanol and 0.1% formic acid in
Summary
Doxorubicin (Adriamycin) is an anthracycline glycoside antitumor antibiotic used as a first-line drug in combination with other chemotherapy drugs for various types of cancers, including breast cancer, bladder cancer, soft tissue and bone sarcomas, malignant lymphoma, and acute lymphocytic leukemia [1]. It has serious adverse effects: dose-dependent cardiotoxicity and myelosuppression [2,3]. Several nanotechnology-based doxorubicin preparations have been developed since the 1990s [3,4,5]. Doxorubicin is metabolized to doxorubicinol, doxorubicinone, doxorubicinolone, 7deoxydoxorubicinone, 7-deoxydoxorubicinolone, 4-O-demethyl-7-deoxydoxorubicinolone, 4-demethyl7-deoxydoxorubicinolone sulfate, and 4-demethyl-7-deoxydoxorubicinolone glucuronide by carbonyl reduction, deglycosylation, O-demethylation, O-sulfation, and O-glucuronidation (Figure 1) [6,7,8,9,10].
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