Universität zu Köln

Weissbarth, Gero, Wiesen, Martin H. J., Fietz, Cornelia, Streichert, Thomas, Ehren, Rasmus, Weber, Lutz T. and Mueller, Carsten (2020). Pharmacodynamic Monitoring of Mycophenolic Acid Therapy: Improved Liquid Chromatography-Tandem Mass Spectrometry Method for Measuring Inosin-5 '-Monophosphate Dehydrogenase Activity. Ther. Drug Monit., 42 (2). S. 282 - 289. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1536-3694

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Abstract

Background: Mycophenolic acid (MPA), a powerful inhibitor of lymphocyte proliferation, is widely used in transplantation medicine and as a glucocorticoid-sparing agent in rheumatic and inflammatory diseases. As inosine-5 '-monophosphate dehydrogenase (IMPDH), the target enzyme of MPA, shows high interindividual variability in its basal activity, the assessment of IMPDH activity in addition to pharmacokinetic monitoring has emerged as a strategy to individualize MPA pharmacotherapy. Methods: A liquid chromatography-tandem mass spectrometry method was developed to measure IMPDH activity in peripheral blood mononuclear cells from lithium-heparinized blood. Stable isotope-labeled analogs of analytes were used as internal standards for the quantitative analyses of xanthosine-5 '-monophosphate (XMP) and adenosine-5 '-monophosphate (AMP). IMPDH activity was expressed as enzymatic production of XMP per time normalized to the AMP concentration. Validation and evaluation of the new method were performed by using blood samples from healthy volunteers (n = 10). Results: Linearity was demonstrated over the concentration ranges of 0.25-80 mu M for XMP and 4-80 mu M for AMP (R-2 > 0.99). Between-day and within-day assay precisions and accuracies were within the acceptance criterion of +/- 15%. Matrix effects were fully compensated by the coelution of internal standards. Specific and linear XMP production (R-2 > 0.99) and the inhibition of IMPDH activity by MPA at clinically relevant doses were demonstrated. Conclusions: In this study, a liquid chromatography-tandem mass spectrometry method to measure IMPDH activity was established and fully evaluated for matrix and ion suppression effects. The method enabled precise quantification of IMPDH activity for the improvement of pharmacokinetic/pharmacodynamic therapeutic drug monitoring approaches to optimize immunosuppressive treatment with MPA.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Weissbarth, Gero UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiesen, Martin H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fietz, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Streichert, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Ehren, Rasmus UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Lutz T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Carsten UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-339259
DOI:	10.1097/FTD.0000000000000688
Journal or Publication Title:	Ther. Drug Monit.
Volume:	42
Number:	2
Page Range:	S. 282 - 289
Date:	2020
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1536-3694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NEPHROTIC SYNDROME; NONRADIOACTIVE DETERMINATION; IMPDH ACTIVITY; MOFETIL; BIOMARKER; CHILDREN; ASSAY Multiple languages Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33925