Inosine monophosphate dehydrogenase activity depends on plasma concentrations of mycophenolic acid and its glucuronides in kidney transplant recipients

Abstract

Background Inosine 5′-monophosphate dehydrogenase (IMPDH) is a target of the immunosuppressant mycophenolic acid (MPA) which is used for the prevention of acute rejection. We evaluated the concentration-dependent effects of MPA and its phenolic (MPAG) and acyl (AcMPAG) glucuronides on IMPDH activity in erythrocytes in an initial and a stable phase. Methods Eight kidney transplant recipients treated with mycophenolate mofetil (MMF) in an initial phase and 104 recipients [56 received MMF (MMF+) and 48 did not (MMF−)] in a stable phase were enrolled. Results IMPDH activity in erythrocytes was inhibited at the peak plasma concentration of MPA in initial kidney transplant recipients. However, median IMPDH activity in erythrocytes was 1.73 times higher in MMF+ than in MMF− kidney transplant recipients (38.7 to 22.4 nmol/g hemoglobin/h, P < 0.01). The median values of trough plasma concentrations (C 12) of MPA, MPAG, and AcMPAG in stable kidney transplant recipients were 2.86, 49.9, and 0.256 μg/ml, respectively. In a multivariate analysis, AcMPAG C 12, MPAG C 12, MPA C 12, serum creatinine, age, lactate dehydrogenase, and serum albumin were significant predictors, accounting for interindividual variability of IMPDH ( R 2 = 0.537, P = 0.02). Conclusion IMPDH activity in erythrocytes may be useful indicators of short-term immunosuppression and long-term exposure of MPA.