Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Aug 25:14:3469-3475.
doi: 10.2147/DDDT.S251144. eCollection 2020.

Analysis of the Doxorubicin and Doxorubicinol in the Plasma of Breast Cancer Patients for Monitoring the Toxicity of Doxorubicin

Yahdiana Harahap  1 , Puspitasari Ardiningsih  1 , Agatha Corintias Winarti  1 , Denni Joko Purwanto  2
Affiliations

Analysis of the Doxorubicin and Doxorubicinol in the Plasma of Breast Cancer Patients for Monitoring the Toxicity of Doxorubicin

Yahdiana Harahap et al. Drug Des Devel Ther. .

Abstract

Introduction: Doxorubicin is an anthracycline antibiotic used as an anticancer agent. Long-term use of this anticancer agent could accumulate its metabolite, doxorubicinol, and cause cardiomyopathy, due to its cardiotoxicity. This cardiotoxic effect depends on the amount of doxorubicin and doxorubicinol accumulated in the body. This study aimed to analyze doxorubicin and doxorubicinol levels in the blood plasma of breast cancer patients.

Methods: Participants of this study were 30 breast cancer patients who had received doxorubicin in their therapy regimen. The samples were analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), with the Acquity UPLC BEH C18 Waters chromatography column (2.1 x 100 mm : 1.7 μm). Plasma (250 μL) samples were prepared by protein precipitation, using methanol. The mobile phase consisted of 0.1% acetic acid (eluent A) and acetonitrile (eluent B), with gradient elution; the flow rate was 0.15 mL/min and runtime, 7 min.

Results and discussion: This method was linear in the range of 1-1000 ng/mL for doxorubicin and 0.5-500 ng/mL for doxorubicinol. This method was successfully used to analyze doxorubicin and doxorubicinol, simultaneously, using hexamethylphosphoramide as the internal standard, in the plasma of breast cancer patients. Results showed that the measured concentrations of doxorubicin and doxorubicinol ranged between 12.54-620.01 ng/mL and 1.10-27.00 ng/mL, respectively. The measured cumulative doses of doxorubicin ranged between 48.76 and 319.01 mg/m2; thus, the risk of cardiomyopathy in the surveyed patients was under 4%, according to literature.

Keywords: LC-MS/MS; analysis; breast cancer; cardiotoxic; doxorubicin; doxorubicinol; partial validation; plasma.

PubMed Disclaimer

Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Chromatogram of blank plasma.
Figure 2
Figure 2
Chromatogram of LLOQ.
Figure 3
Figure 3
Graphic of Doxorubicin and Doxorubicinol measurement.
Figure 4
Figure 4
Cumulative doses of patients.
See this image and copyright information in PMC

References

    1. Mitry MA, Edwards JG. Doxorubicin induced heart failure: phenotype and molecular mechanisms. IJC Hear Vasc. 2016;10:17–24. doi: 10.1016/j.ijcha.2015.11.004 - DOI - PMC - PubMed
    1. Barpe DR, Rosa DD, Froehlich PE. Pharmacokinetic evaluation of doxorubicin plasma levels in normal and overweight patients with breast cancer and simulation of dose adjustment by different indexes of body mass. Eur J Pharm Sci. 2010;41(3–4):458–463. doi: 10.1016/j.ejps.2010.07.015 - DOI - PubMed
    1. Schaupp CM, White CC, Merrill GF, Kavanagh TJ. Metabolism of doxorubicin to the cardiotoxic metabolite doxorubicinol is increased in a mouse model of chronic glutathione deficiency: a potential role for carbonyl reductase 3. Chem Biol Interact. 2015;234:154–161. doi: 10.1016/j.cbi.2014.11.010 - DOI - PMC - PubMed
    1. Katzung BG, Masters SB, Trevor AJ. Basic & Clinical Pharmacology. 12th ed. McGraw Hill; 2012.
    1. Tao JJ, Visvanathan K, Wolff AC. Long term side effects of adjuvant chemotherapy in patients with early breast cancer. The Breast. 2015;24:S149–53. doi: 10.1016/j.breast.2015.07.035 - DOI - PMC - PubMed