Pharmacodynamic monitoring of mycophenolate mofetil

The immunosuppressive activity of Mycophenolate Mofetil (MMF) is based on t he reversible inhibition of inosine-5'-monophosphate dehydrogenase (IMPDH) by mycophenolic acid. Pharmacodynamic monitoring by measurement of IMPDH ac tivity reflects directly the biological response to MMF. For measurement of IMPDH activity in peripheral mononuclear cells we established a modified n on-radioactive procedure, based on the incubation of cell lysates with inos ine-5'-monophosphate and the chromatographic quantification of produced xan thosine-5'-monophosphate by isocratic ion-pair reversed phase HPLC. The bet ween-run precision and within-run precision were 7% and 5%, respectively. W e determined the time course of IMPDH activity in five patients after 1g MM F and in five healthy subjects without administration of MMF. Additionally, IMPDH activity was determined in a population study of 40 healthy voluntee rs. 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 MM F had a significant reduction of IMPDH activity (65-100%) after administrat ion of the drug. Inhibition persisted for up to 6 hours, and after 11 hours IMPDH activity returned to predose activities. The interindividual variabi lity of IMPDH activity may account for pharmacodynamic differences in MMF-t reated patients. Based on pharmacodynamic monitoring better dosing strategi es for MMF-treated patients may evolve.