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Quantitative liquid chromatographic analysis of anthracyclines in biological fluids

Kristof Maudens UGent (2009)
abstract
The optimization, validation and application of a liquid chromatographic method with fluorescence detection for the simultaneous determination of the four most important anthracyclines (doxorubicin, epirubicin, daunorubicin and idarubicin) and their toxicologically relevant metabolites in plasma and saliva is described. The thesis also explored the possibilities of liquid chromatography coupled to fluorescence detection for trace analysis of anthracyclines in urine. In Chapter I anthracyclines were introduced. They are widely used in clinical oncology. Current dosing, based on body surface area, leads to marked interindividual variations in efficacy and toxicity. Chapter II gave a literature overview of chromatographic methods for determination of anthracyclines in biological fluids. Chapter III summarized the objectives. The main goal was to develop an analytical method, that can be applied in routine laboratories to gain insight into individual pharmacokinetics of patients treated with anthracyclines. In Chapter IV the synthesis of some commercially unavailable metabolites was described. The optimization of a liquid chromatographic separation was the subject of Chapter V. Inclusion of epidaunorubicin in the assay allows internal standardization of applications. In Chapter VI the extraction of anthracyclines from biological fluids was studied. The first part discussed the extraction of plasma and saliva samples. The second part focused on the extraction for trace-analysis in urine. Chapter VII highlighted the importance of additives to stabilize chloroform, when chloroform is applied for extraction of anthracyclines. In Chapter VIII the developed method for the determination in plasma and saliva was validated according to selectivity, sensitivity, linearity, precision, accuracy, recovery and stability criteria. The methodology was applied to samples from patients receiving FEC-chemotherapy in Chapter IX. As expected, dosage based on body surface area could lead to interindividual variations in plasma concentrations. For these patients, this could be linked to haematological toxicity. Salivary epirubicinol concentrations could not be detected shortly after infusion, and always remained very low. Based on this method, it was impossible to detect an equilibrium between plasma and saliva concentrations for epirubicin within the first hours after dosing. A direct predictive power of saliva concentrations towards mucositis could not be assessed, since none of the patients developed such side effects.
Please use this url to cite or link to this publication:
author
promoter
UGent
organization
year
type
dissertation (monograph)
subject
keyword
Anthracyclines, doxorubicin, epirubicin, daunorubicin, idarubicin, epidaunorubicin, doxorubicinol, epirubicinol, daunorubicinol, idarubicinol, plasma, saliva, urine, HPLC, liquid chromatography, fluorescence detection, liquid-liquid extraction, method validation, LLE, solid phase extraction, SPE, TDM, clinical oncology, analytical chemistry, toxicology
pages
XIV, 191 pages
publisher
Ghent University. Faculty of Pharmaceutical Sciences
place of publication
Ghent, Belgium
defense location
Gent : Farmaceutisch Instituut (auditorium II)
defense date
2009-11-30 18:00
language
English
UGent publication?
yes
classification
D1
additional info
dissertation in part contains copyrighted material
copyright statement
I have transferred the copyright for this publication to the publisher
id
817123
handle
http://hdl.handle.net/1854/LU-817123
alternative location
http://lib.ugent.be/fulltxt/RUG01/001/376/255/RUG01-001376255_2010_0001_AC.pdf
date created
2010-01-03 17:14:31
date last changed
2010-01-29 14:12:54
@phdthesis{817123,
  abstract     = {The optimization, validation and application of a liquid chromatographic method with fluorescence detection for the simultaneous determination of the four most important anthracyclines (doxorubicin, epirubicin, daunorubicin and idarubicin) and their toxicologically relevant metabolites in plasma and saliva is described. The thesis also explored the possibilities of liquid chromatography coupled to fluorescence detection for trace analysis of anthracyclines in urine.
In Chapter I anthracyclines were introduced. They are widely used in clinical oncology. Current dosing, based on body surface area, leads to marked interindividual variations in efficacy and toxicity. Chapter II gave a literature overview of chromatographic methods for determination of anthracyclines in biological fluids. Chapter III summarized the objectives. The main goal was to develop an analytical method, that can be applied in routine laboratories to gain insight into individual pharmacokinetics of patients treated with anthracyclines.
In Chapter IV the synthesis of some commercially unavailable metabolites was described. The optimization of a liquid chromatographic separation was the subject of Chapter V. Inclusion of epidaunorubicin in the assay allows internal standardization of applications. In Chapter VI the extraction of anthracyclines from biological fluids was studied. The first part discussed the extraction of plasma and saliva samples. The second part focused on the extraction for trace-analysis in urine. Chapter VII highlighted the importance of additives to stabilize chloroform, when chloroform is applied for extraction of anthracyclines. In Chapter VIII the developed method for the determination in plasma and saliva was validated according to selectivity, sensitivity, linearity, precision, accuracy, recovery and stability criteria.
The methodology was applied to samples from patients receiving FEC-chemotherapy in Chapter IX. As expected, dosage based on body surface area could lead to interindividual variations in plasma concentrations. For these patients, this could be linked to haematological toxicity. Salivary epirubicinol concentrations could not be detected shortly after infusion, and always remained very low. Based on this method, it was impossible to detect an equilibrium between plasma and saliva concentrations for epirubicin within the first hours after dosing. A direct predictive power of saliva concentrations towards mucositis could not be assessed, since none of the patients developed such side effects.},
  author       = {Maudens, Kristof},
  keyword      = {Anthracyclines,doxorubicin,epirubicin,daunorubicin,idarubicin,epidaunorubicin,doxorubicinol,epirubicinol,daunorubicinol,idarubicinol,plasma,saliva,urine,HPLC,liquid chromatography,fluorescence detection,liquid-liquid extraction,method validation,LLE,solid phase extraction,SPE,TDM,clinical oncology,analytical chemistry,toxicology},
  language     = {eng},
  pages        = {XIV, 191},
  publisher    = {Ghent University. Faculty of Pharmaceutical Sciences},
  school       = {Ghent University},
  title        = {Quantitative liquid chromatographic analysis of anthracyclines in biological fluids},
  url          = {http://lib.ugent.be/fulltxt/RUG01/001/376/255/RUG01-001376255\_2010\_0001\_AC.pdf},
  year         = {2009},
}

Chicago
Maudens, Kristof. 2009. “Quantitative Liquid Chromatographic Analysis of Anthracyclines in Biological Fluids”. Ghent, Belgium: Ghent University. Faculty of Pharmaceutical Sciences.
APA
Maudens, K. (2009). Quantitative liquid chromatographic analysis of anthracyclines in biological fluids. Ghent University. Faculty of Pharmaceutical Sciences, Ghent, Belgium.
Vancouver
1.
Maudens K. Quantitative liquid chromatographic analysis of anthracyclines in biological fluids. [Ghent, Belgium]: Ghent University. Faculty of Pharmaceutical Sciences; 2009.
MLA
Maudens, Kristof. “Quantitative Liquid Chromatographic Analysis of Anthracyclines in Biological Fluids.” 2009 : n. pag. Print.