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Clinical Chemistry 50: 152-159, 2004. First published November 18, 2003; 10.1373/clinchem.2003.024323
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(Clinical Chemistry. 2004;50:152-159.)
© 2004 American Association for Clinical Chemistry, Inc.

Drug Monitoring and Toxicology

Validation of a Rapid and Sensitive Liquid Chromatography–Tandem Mass Spectrometry Method for Free and Total Mycophenolic Acid

Frank Streit1, Maria Shipkova2, Victor William Armstrong1,a and Michael Oellerich1

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.

aAddress correspondence to this author at: Abteilung Klinische Chemie, Zentrum Innere Medizin, Georg-August-Universität Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany. Fax 49-551-398551; 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 C18 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 proposed 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 mg/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.




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