Pharmacodynamic Monitoring of Mycophenolate Mofetil

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 1g 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.