Expression of Inosine Monophosphate Dehydrogenase Type I and Type II After Mycophenolate Mofetil Treatment: A 2-year Follow-up in Kidney Transplantation

Abstract

The objective of the study was to evaluate the effect of mycophenolate mofetil (MMF) on the regulation of inosine monophosphate dehydrogenase (IMPDH) during the first 2 years after renal transplantation. Twelve patients were enrolled, and 10-h time-course evaluations of the effects of MMF were regularly performed during the study. IMPDH activity and gene expression were measured in whole blood and in mononuclear cells, respectively. Type I IMPDH (IMPDH-I) mRNA was increased during the first 3 months following transplantation and reached its maximal level during acute rejection episodes, whereas type II IMPDH mRNA was stable. Furthermore, although no alteration in the predose samples was observed, patients with prolonged MMF treatment exhibited an increase in the induction potency of both IMPDH activity and gene expression. In vitro experiments confirmed that IMPDH-I is inducible, but preferentially in monocytes than in lymphocytes. This finding suggests that the measurement of IMPDH mRNAs may provide reliable information to predict acute rejection.

New Insights Into the Pharmacokinetics and Pharmacodynamics of the Calcineurin Inhibitors and Mycophenolic Acid: Possible Consequences for Therapeutic Drug Monitoring in Solid Organ Transplantation

“…233,234 Moreover, after oral administration of MMF, close temporal associations between MPA plasma levels and IMPDH inhibition have been reported, 186,[235][236][237] but the correlation between MPA trough levels and predose IMPDH activity seems to be rather weak. 238 Large interindividual differences in pretransplant IMPDH activity have been reported, whereas intraindividual variability is relatively small.…”

Polymorphisms in type I and II inosine monophosphate dehydrogenase genes and association with clinical outcome in patients on mycophenolate mofetil

“…In a recent study on IMPDH II expression, Vannozzi et al [19] identified IMPDH II gene as another good candidate for MPA pharmacogenetic studies. Several studies demonstrated that both isoforms of IMPDH are transcribed in response to T cell activation [11] and that the increase of IMPDH activity is linked to activation of both IMPDH isoforms [20,21].…”

Expression of IMPDH1 is regulated in response to mycophenolate concentration

“…Sanquer et al described 10 h time-course measurements of IMPDH 1 and 2 expression in mononuclear cells from renal transplant patients receiving an immunosuppressive regimen of cyclosporine, MMF and prednisone [19]. The gene expression was normalized to a single reference gene (RPL13A).…”

“…Pharmacodynamic monitoring of IMPDH activity has been suggested as an alternative approach for optimizing MPA therapy, providing a more direct measure of the drug efficacy [17]. Long-term MPA therapy has been associated with an induction of IMPDH activity, which is suggested to be mediated through feedback regulation by guanine nucleotides [18][19][20][21][22]. An enzyme induction might have implications for the efficacy of MPA.…”