Purpose of this study was to examine wether the long term exposure for mycophenolate mofetil (MMF) or enteric coated form (EC-MPS) is leading to an enzyme induction for IMPDH, thus decreasing MPA immunosuppressive properties.
Patients and Methods: By application of an IMPDH assay, which is based on HPLC analysis, enzyme activity was investigated in whole blood for the substrate xanthine monophosphate (XMP, pmol/min/ml) and for xanthine (X, mmolX/ mgProt.) in isolated lymphocytes from stable renal transplant patients. Dosage was comparable in each group. Gr.I (MMF-medication; n=23, gender: 10f/13m, age:48±12,6; MMF medication: 91 months, ± 32 mos); Gr.II (n=31, gender 11f /20m, age:47±11,9, EC-MPS medication 93 ± 29 months immediately prior to the morning dose of MMF/EC-MPS as well as kinetics at timepoints: predose, 30 and 60 min, 2 and 4 hrs. Measurements of basic IMPDH activity were performed in 60 healthy volunteers (XMP n=24, mean:318 pmol/min/ml; X n=36, mean:5,68 mmol X/mg Prot.(range 2,1-16,8). Follow up at week 1,2,3,4 and month 3,6,12,24,36,60,120.
Results: A multiple-regression-analysis was performed including age, MPA drug level, IMPDH activity and duration of MMF/EC-MPS therapy. There was an increase for the IMPDH activity (high variability) of nearly 8 fold between the untreated controls and the stable renal transplanted patients (controls: mean 318, patients: 1881±863 pmol/min/ml) in whole blood. In isolated lymphocytes we found an increase up to 330%, furthermore a decrease of IMPDH inhibition. Increase was higher in patients with rejection episodes and was found till month 41 (mean). There was a positive significant correlation only between dosage vs. activity (r2: 0,2685) but not for MPA-plasma concentration vs. dose and activity vs. MPA plasma concentration. Furthermore, we found a correlation (not linear) between duration of therapy and IMPDH activity supporting the theory that with a steady dosage the activity is decreasing with duration of therapy.
Conclusion: Results confirming the data of an increase of IMPDH activity in whole blood as well as in isolated lymphocytes through MMF/EC-MPS medication. A decreasing was found after an individual time due to a yet unknown mechanism. The therapeutical potential of MMF/ EC-MPS may be optimized by therapeutic drug monitoring especially under the aspects of CNI free immunosuppressive regimens. Drug minimization might be hazardous to the patients.
To cite this abstract in AMA style:Abendroth D, Marzinzig M, Stangl M. Variability of IMPDH-Activity in Long-Term MPA Mediated Immunosuppression [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/variability-of-impdh-activity-in-long-term-mpa-mediated-immunosuppression/. Accessed October 30, 2020.
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