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.

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