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Publications (4)7.61 Total impact

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    ABSTRACT: Mycophenolate mofetil (MMF) is routinely used as an immunosuppressant in a fixed daily dose regimen although it shows marked fluctuations in pharmacokinetics, and despite the fact that in regard to the active metabolite, mycophenolic acid (MPA), there is a well-known association between the pharmacokinetic parameters and clinical outcome. In order to determine the time course and the variability in cellular target of MPA after renal transplantation, we investigated the pharmacodynamic response in 8 patients receiving 1 g MMF for the first time prior to renal transplantation and in 8 stable renal transplant patients maintained on long-term MMF therapy (1 g b.i.d.) for more than 1 year. The pharmacodynamic response was measured using inosine 5'-monophosphate dehydrogenase (IMPDH) activity in peripheral mononuclear cells. MPA plasma concentrations were measured in parallel, IMPDH activity in 89 healthy blood donors was used as a control. We observed a high interindividual variability in IMPDH activity in the 89 untreated healthy volunteers (4.0 - 32.9 nmol/h/mg protein), in 8 patients on dialysis (5.3 - 18.9 nmol/h/mg protein) and in 8 renal transplant patients under long-term MMF treatment (2.3 - 14.4 nmol/h/mg protein). The mean AUC0-12h for mycophenolic acid was 2-fold higher in patients receiving long-term treatment with MMF (62.2 +/- 16.6 mg x h/ml) compared to dialysis patients receiving 1 g MMF for the first time (31.5 +/- 15.6 mg x h/ml). Despite this pharmacokinetic difference there were no statistically significant differences in the cellular pharmacodynamic response. Minimal IMPDH activity (1.62 +/- 1.23 vs. 1.77 +/- 1.49 nmol/h/mg protein) and maximal IMPDH inhibition (87.5 +/- 0.08 vs. 77.4 +/- 18.8%) during the dosing interval were similar. The considerable interindividual variability in the pharmacokinetics of MMF as well as in the drug target support the use of pharmacodynamic drug monitoring to optimize MMF dosing and to reduce the risk of graft rejection and side effects.
    International journal of clinical pharmacology and therapeutics 11/2003; 41(10):470-6. · 1.20 Impact Factor
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    ABSTRACT: The immunosuppressive activity of mycophenolate mofetil (MMF) is based on the reversible inhibition of inosine 5'-monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). It was the aim of this study to develop a nonradioactive method for specific measurement of IMPDH activity in isolated peripheral mononuclear cells (MNC). The procedure is based on the incubation of lysed MNC with inosine 5'-monophosphate (IMP) followed by direct chromatographic determination of produced xanthosine 5'-monophosphate (XMP). IMPDH activity was measured in MNC of MMF-treated patients and nontreated volunteers. The within-run (n = 10) and between-run (n = 20) coefficients of variation (CV) for IMPDH activity were < 8% and < 10%, respectively. IMPDH activity in 60 healthy volunteers (19-63 yr) ranged from 4.72 to 32.92 nmol/h/mg protein (mean = 18.39 +/- 6.24). The IC(50) for in vitro inhibition of IMPDH activity was about 2 to 3 microg/L. Application of a single dose of 1 g MMF in dialysis patients resulted in a significant inhibition (by 47-95%; p < 0.05) of IMPDH activity in lysed MNC. The proposed assay specifically and reliably measures IMPDH activity in MNC. The procedure is applicable to evaluate pharmacodynamic activity in MMF-treated patients. The observed interindividual variability of IMPDH activity may reflect pharmacodynamic differences in MMF-treated patients.
    Clinical Biochemistry 10/2001; 34(7):543-9. · 2.45 Impact Factor
  • Transplantation Proceedings 01/2001; 33(7-8):3313-5. · 0.95 Impact Factor
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    ABSTRACT: The immunosuppressive activity of Mycophenolate Mofetil (MMF) is based on the reversible inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) by mycophenolic acid. Pharmacodynamic monitoring by measurement of IMPDH activity reflects directly the biological response to MMF. For measurement of IMPDH activity in peripheral mononuclear cells we established a modified non-radioactive procedure, based on the incubation of cell lysates with inosine-5'-monophosphate and the chromatographic quantification of produced xanthosine-5'-monophosphate by isocratic ion-pair reversed phase HPLC. The between-run precision and within-run precision were 7% and 5%, respectively. We determined the time course of IMPDH activity in five patients after 1 g MMF and in five healthy subjects without administration of MMF. Additionally, IMPDH activity was determined in a population study of 40 healthy volunteers. In healthy volunteers, we observed a wide range of IMPDH activity (4.7-32.9 nmol/h/mg) with only weak diurnal variation. All patients receiving MMF had a significant reduction of IMPDH activity (65-100%) after administration of the drug. Inhibition persisted for up to 6 hours, and after 11 hours IMPDH activity returned to predose activities. The interindividual variability of IMPDH activity may account for pharmacodynamic differences in MMF-treated patients. Based on pharmacodynamic monitoring better dosing strategies for MMF-treated patients may evolve.
    Clinical Chemistry and Laboratory Medicine 12/2000; 38(11):1213-6. · 3.01 Impact Factor