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Technical Briefs |
a address correspondence to this author at: Abteilung Klinische Chemie, Zentrum Innere Medizin, Georg-August-Universität, Robert Koch Strasse 40, D-37075 Göttingen, Germany
Mycophenolic acid (MPA), the active moiety of mycophenolate mofetil (MMF), is an antiproliferative agent that acts by inhibition of inosine monophosphate dehydrogenase type II (IMPDH-II), a key enzyme in the de novo purine biosynthetic pathway (1)(2). Several studies have documented that MMF is effective in the treatment of refractory rejection in renal, heart, and liver transplant recipients (2). The major pathway for elimination of MPA involves glucuronidation (3) at the phenolic hydroxyl group to form mycophenolate 7-O-glucuronide (7-O-MPAG). Modification of this phenolic hydroxy residue leads to a loss of pharmacological activity toward IMPDH-II (4)(5).
Most studies on the pharmacokinetics of MPA have utilized HPLC
procedures (6)(7) to measure both MPA and MPAG. Recently,
the first immunoassay became available for the quantification of MPA
(Emit-MPA, Dade Behring). 7-O- MPAG does not cross-react with this
assay. Comparison of plasma MPA concentrations from clinical samples
determined with HPLC showed an overestimation in relation to those
obtained with the Emit of up to 100%, with an average of 35% in a
group of 37 kidney recipients, which accounts for a mean overestimation
of 20% for the calculated areas under the concentration-time curve
(8). Through a modification of our HPLC procedure
(7), we were able to identify two putative MPA metabolites,
M-1 and M-2, from the plasma of transplant recipients, of which M-2 was
found to cross-react in the immunoassay (8). Recently, we
showed that in clinical samples from heart, kidney, and liver
recipients, the relative amounts of M-2 correlate with the bias between
MPA values determined with HPLC and the immunoassay (9). In
pharmacokinetic studies, it was shown that the areas under the
concentration-time curve for both M-1
Acknowledgments
Footnotes
References
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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 N. M. Davies, J. Grinyo, R. Heading, B. Maes, H.-U. Meier-Kriesche, and M. Oellerich Gastrointestinal side effects of mycophenolic acid in renal transplant patients: a reappraisal Nephrol. Dial. Transplant., September 1, 2007; 22(9): 2440 - 2448. [Abstract] [Full Text] [PDF]
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 P. Jacobson, K. Green, J. Rogosheske, C. Brunstein, B. Ebeling, T. DeFor, P. McGlave, and D. Weisdorf Highly Variable Mycophenolate Mofetil Bioavailability Following Nonmyeloablative Hematopoietic Cell Transplantation J. Clin. Pharmacol., January 1, 2007; 47(1): 6 - 12. [Abstract] [Full Text] [PDF]
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 O. Bernard, J. Tojcic, K. Journault, L. Perusse, and C. Guillemette Influence of Nonsynonymous Polymorphisms of UGT1A8 and UGT2B7 Metabolizing Enzymes on the Formation of Phenolic and Acyl Glucuronides of Mycophenolic Acid Drug Metab. Dispos., September 1, 2006; 34(9): 1539 - 1545. [Abstract] [Full Text] [PDF]
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 L. S. Ting, N. Partovi, R. D Levy, K W. Riggs, and M. H. Ensom Pharmacokinetics of Mycophenolic Acid and Its Glucuronidated Metabolites in Stable Lung Transplant Recipients Ann. Pharmacother., September 1, 2006; 40(9): 1509 - 1515. [Abstract] [Full Text] [PDF]
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I. S. Westley, L. R. Brogan, R. G. Morris, A. M. Evans, and B. C. Sallustio ROLE OF MRP2 IN THE HEPATIC DISPOSITION OF MYCOPHENOLIC ACID AND ITS GLUCURONIDE METABOLITES: EFFECT OF CYCLOSPORINE Drug Metab. Dispos., February 1, 2006; 34(2): 261 - 266. [Abstract] [Full Text] [PDF]
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 G. R. Ingle and T. Shah Enteric-coated mycophenolate sodium for transplant immunosuppression Am. J. Health Syst. Pharm., November 1, 2005; 62(21): 2252 - 2259. [Abstract] [Full Text] [PDF]
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N. Picard, D. Ratanasavanh, A. Premaud, Y. Le Meur, and P. Marquet IDENTIFICATION OF THE UDP-GLUCURONOSYLTRANSFERASE ISOFORMS INVOLVED IN MYCOPHENOLIC ACID PHASE II METABOLISM Drug Metab. Dispos., January 1, 2005; 33(1): 139 - 146. [Abstract] [Full Text] [PDF]
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R. G Morris Immunosuppressant Drug Monitoring: Is the Laboratory Meeting Clinical Expectations? Ann. Pharmacother., January 1, 2005; 39(1): 119 - 127. [Abstract] [Full Text] [PDF]
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N. K. Basu, L. Kole, S. Kubota, and I. S. Owens HUMAN UDP-GLUCURONOSYLTRANSFERASES SHOW ATYPICAL METABOLISM OF MYCOPHENOLIC ACID AND INHIBITION BY CURCUMIN Drug Metab. Dispos., July 1, 2004; 32(7): 768 - 773. [Abstract] [Full Text] [PDF]
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 I. Neumann, M. Haidinger, H. Jager, H. Grutzmacher, A. Griesmacher, M. M. Muller, P. M. Bayer, and F. Thomas Meisl Pharmacokinetics of Mycophenolate Mofetil in Patients with Autoimmune Diseases Compared Renal Transplant Recipients J. Am. Soc. Nephrol., March 1, 2003; 14(3): 721 - 727. [Abstract] [Full Text] [PDF]
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L. T. Weber, M. Shipkova, V. W. Armstrong, N. Wagner, E. Schutz, O. Mehls, L. B. Zimmerhackl, M. Oellerich, and B. Tonshoff Comparison of the Emit Immunoassay with HPLC for Therapeutic Drug Monitoring of Mycophenolic Acid in Pediatric Renal-Transplant Recipients on Mycophenolate Mofetil Therapy Clin. Chem., March 1, 2002; 48(3): 517 - 525. [Abstract] [Full Text] [PDF]
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L. T. Weber, M. Shipkova, V. W. Armstrong, N. Wagner, E. Schuutz, O. Mehls, L. B. Zimmerhackl, M. Oellerich, and B. Tonshoff The Pharmacokinetic-Pharmacodynamic Relationship for Total and Free Mycophenolic Acid in Pediatric Renal Transplant Recipients: A Report of the German Study Group on Mycophenolate Mofetil Therapy J. Am. Soc. Nephrol., March 1, 2002; 13(3): 759 - 768. [Abstract] [Full Text] [PDF]
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M. Mourad, J. Malaise, D. Chaib Eddour, M. De Meyer, J. Konig, R. Schepers, J. P. Squifflet, and P. Wallemacq Pharmacokinetic Basis for the Efficient and Safe Use of Low-Dose Mycophenolate Mofetil in Combination with Tacrolimus in Kidney Transplantation Clin. Chem., July 1, 2001; 47(7): 1241 - 1248. [Abstract] [Full Text] [PDF]
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M. Oellerich and V. W. Armstrong Prodrug Metabolites: Implications for Therapeutic Drug Monitoring Clin. Chem., May 1, 2001; 47(5): 805 - 806. [Full Text] [PDF]
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T. M. Annesley, S. Kurzyniec, G. D. Nordblom, N. Buchanan, W. Pool, M. Reily, R. Talaat, and W. L. Roberts Glucuronidation of Prodrug Reactive Site: Isolation and Characterization of Oxymethylglucuronide Metabolite of Fosphenytoin Clin. Chem., May 1, 2001; 47(5): 910 - 918. [Abstract] [Full Text] [PDF]
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M. Mourad, J. Malaise, D. Chaib Eddour, M. De Meyer, J. Konig, R. Schepers, J. P. Squifflet, and P. Wallemacq Correlation of Mycophenolic Acid Pharmacokinetic Parameters with Side Effects in Kidney Transplant Patients Treated with Mycophenolate Mofetil Clin. Chem., January 1, 2001; 47(1): 88 - 94. [Abstract] [Full Text] [PDF]
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O. Millan, F. Oppenheimer, M. Brunet, J. Vilardell, I. Rojo, J. Vives, and J. Martorell Assessment of Mycophenolic Acid-induced Immunosuppression: A New Approach Clin. Chem., September 1, 2000; 46(9): 1376 - 1383. [Abstract] [Full Text] [PDF]
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P. Morissette, M. Beaulieu, and B. Vinet A Specific Artificial Antibody toward Mycophenolic Acid Prepared by Molecular Imprinting Clin. Chem., September 1, 2000; 46(9): 1516 - 1518. [Full Text] [PDF]
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M. Shipkova, E. Schutz, V. W. Armstrong, P. D. Niedmann, M. Oellerich, and E. Wieland Determination of the Acyl Glucuronide Metabolite of Mycophenolic Acid in Human Plasma by HPLC and Emit Clin. Chem., March 1, 2000; 46(3): 365 - 372. [Abstract] [Full Text] [PDF]
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