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Clinical Chemistry 45: 1047-1050, 1999;
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(Clinical Chemistry. 1999;45:1047-1050.)
© 1999 American Association for Clinical Chemistry, Inc.

Articles

The Apparent Inhibition of Inosine Monophosphate Dehydrogenase by Mycophenolic Acid Glucuronide Is Attributable to the Presence of Trace Quantities of Mycophenolic Acid

Magdalena Korecka1, Dejan Nikolic2, Richard B. van Breemen2 and Leslie M. Shaw1,a

1 Departments of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA 19104.

2 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, IL 60612.
a Author for correspondence. Fax 215-662-7529; e-mail shawlmj{at}mail.med.upenn.edu

Background: Mycophenolic acid glucuronide, the primary metabolite of the immunosuppressive agent mycophenolic acid, affords weak inhibition of proliferating and resting lymphocytes and recombinant human inosine monophosphate dehydrogenase in comparison to the active drug. We evaluated the hypothesis that mycophenolic acid is a trace contaminant of the glucuronide metabolite preparation and that this accounts for the observed effects of mycophenolic acid glucuronide on human inosine monophosphate dehydrogenase catalytic activity both in lymphocytes and the pure enzyme.

Methods: We used negative ion electrospray HPLC-mass spectrometry (HPLC-MS) and HPLC-tandem MS (HPLC-MS-MS) to identify mycophenolic acid as a contaminant of mycophenolic acid glucuronide. Quantification of the mycophenolic acid contaminant was achieved using a negative ion electrospray HPLC-MS method in the selected-ion monitoring mode.

Results: Trace amounts of mycophenolic acid were detected and definitively identified in the mycophenolic acid glucuronide preparation by the HPLC-MS-MS analysis. In addition to having identical HPLC retention times, pure mycophenolic acid and the contaminant produced the following major fragments upon HPLC-MS-MS analysis: deprotonated molecular ion, m/z 319; and fragment ions, m/z 275, 243, 205, and 191 (the most abundant fragment ion). Using the negative ion electrospray HPLC-MS procedure in the selected-ion monitoring mode, the quantity of the contaminant mycophenolic acid was determined to be 0.312% ± 0.0184% on a molar basis.

Conclusion: These data provide strong support for the proposal that the apparent inhibition of the target enzyme inosine monophosphate dehydrogenase by mycophenolic acid glucuronide is attributable to the presence of trace amounts of contaminant mycophenolic acid.© 1999 American Association for Clinical Chemistry




The following articles in journals at HighWire Press have cited this article:


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O. Gensburger, N. Picard, and P. Marquet
Effect of Mycophenolate Acyl-Glucuronide on Human Recombinant Type 2 Inosine Monophosphate Dehydrogenase
Clin. Chem., May 1, 2009; 55(5): 986 - 993.
[Abstract] [Full Text] [PDF]

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 Clin. Chem.Home page
F. Streit, M. Shipkova, V. W. Armstrong, and M. Oellerich
Validation of a Rapid and Sensitive Liquid Chromatography-Tandem Mass Spectrometry Method for Free and Total Mycophenolic Acid
Clin. Chem., January 1, 2004; 50(1): 152 - 159.
[Abstract] [Full Text] [PDF]

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T. Pawinski, M. Hale, M. Korecka, W. E. Fitzsimmons, and L. M. Shaw
Limited Sampling Strategy for the Estimation of Mycophenolic Acid Area under the Curve in Adult Renal Transplant Patients Treated with Concomitant Tacrolimus
Clin. Chem., September 1, 2002; 48(9): 1497 - 1504.
[Abstract] [Full Text] [PDF]


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