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Received on July 8, 2003
Accepted on October 13, 2003
Drug Monitoring and Toxicology |
1 Department of Clinical Chemistry, George-August University Gottingen, D-37075 Gottingen, Germany
2 Central Institute for Clinical Chemistry and Laboratory Medicine, Klinikum Stuttgart, Stuttgart, Germany
* To whom correspondence should be addressed. E-mail: varmstro{at}med.uni-goettingen.de.
Background: Because mycophenolic acid (MPA) is highly protein bound and because the free fraction is the pharmacologically active portion, a rapid, reliable, and sensitive procedure is required to study the relationship between free MPA and treatment efficacy/toxicity. Liquid chromatography-tandem mass spectrometry is ideally suited for such a method.
Methods: Free MPA was isolated from plasma by ultrafiltration. An online extraction cartridge with a column-switching technique, analytical liquid chromatography over an Aqua Perfect C$1 column, and electrospray tandem mass spectrometry was used to quantify free and total MPA. To investigate ion suppression, a continuous infusion of MPA was introduced into the effluent from the HPLC column, and different ultrafiltrates and extracted plasma samples were injected on the column.
Results: A chromatographic run time of 4 min separated MPA from metabolites and internal standard, thereby avoiding interference from in-source fragmentation. Ion suppression occurred well before elution of MPA and internal standard. The lower limit of quantification for free MPA was 0.5 µg/L, and the method was linear to 1000 µg/L. Interassay imprecision (CV) was <10% for free MPA (0.5-333 µg/L). Agreement was good for free MPA (n = 52) and total MPA (n = 106) between the propose method and a validated HPLC method with ultraviolet detection. The Passing-Bablok regression line was: y = 0.95x + 0.27 µg/L for free MPA and y = 0.98x + 0.03 µg/L for total MPA.
Conclusions: The presented method allows the accurate, precise, and rapid determination of free and total MPA in plasma over a wide analytical range covering the concentrations relevant to pharmacokinetic studies and routine monitoring of this drug.© 2004 American Association for Clinical Chemistry
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