Abstract
107 The dose regimen of CellCept™ (mycophenolate mofetil, MMF) is based on the pharmacokinetics of the active metabolite mycophenolic acid (MPA) and on empirically obtained efficacy data rather than on the kinetics of the immunosuppressive activity. This activity is based on the inhibition of inosine 5′-monophosphate dehydrogenase (IMPDH), a pivotal enzyme in the biosynthesis of guanine nucleotides. PK-PD relationships based on monitoring of MPA plasma concentrations and on the inhibition of IMPDH in whole blood cell fractions have been determined in animals following single dosing of MMF. However, this strategy has not yet been applied to transplant patients. By application of an IMPDH assay which is based on HPLC analysis of the substrate xanthine monophosphate (XMP), enzyme activity was investigated in blood from stable renal transplant patients obtained immediately prior to and 2 h after the morning dose of CellCept™. IMPDH activity was determined in whole blood cells as well as in isolated erythrocytes and the mononuclear cell fraction. By comparison with data from blood samples obtained from healthy subjects, the following results were seen: In healthy subjects, IMPDH activity in whole blood cells can be mainly attributed to the activity in the mononuclear cell fraction; In renal transplant patients, substantially (10-30 fold) elevated levels of IMPDH-activities were observed when compared with healthy controls. This marked increase of baseline IMPDH activity could be attributed to an enzyme induction which appears to be restricted to erythrocytes. 2 hours after drug administration enzyme activity decreased by approximately 70% in whole blood cells as well as in erythrocytes and mononuclear cells. The results imply that in renal transplant patients IMPDH-monitoring is not possible using whole blood preparations, but should be performed only in isolated mononuclear cell fractions. This could result in improved individualization of dose regimens.
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