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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.

Objectives: To study the pharmacologic activity of mycophenolate mofetil in stable kidney transplant recipients receiving mycophenolate mofetil therapy for different periods from 2 months to 3 years., Methods: Seventeen patients were enrolled during a 9-month period. Blood samples were collected before administration and 1/2, 1, 2, 4, and 6 hours after administration. Mycophenolic acid, the active metabolite of mycophenolate mofetil, was measured in plasma with use of the enzyme multiplication immunoassay technique (EMIT) assay and the activity of inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo biosynthesis of purines inhibited by mycophenolate mofetil, was determined in whole blood by the estimation of the 3H-release from [2,8-3H]-hypoxanthine., Results: As the length of mycophenolate mofetil therapy increased, the inhibitory effect of mycophenolate mofetil on IMPDH activity was reduced (0.13+/-0.03 for long-term treatment versus 0.46+/-0.06 for short-term treatment; P = .0006) and a stimulatory effect of mycophenolate mofetil on IMPDH activity was observed (1.16+/-0.56 for long-term treatment, versus 0.03+/-0.01 for short-term treatment; P < .0001). These modifications of IMPDH activity were associated with fluctuations in the pharmacokinetics of mycophenolic acid., Conclusion: Long-term treatment with mycophenolate mofetil was associated with an induction of IMPDH activity. Such induction could be deleterious if it is followed by a restoration or a stimulation of the proliferative capacity of lymphocytes. These results strongly suggest that the place of mycophenolate mofetil in long-term treatment of kidney transplant patients needs to be carefully assessed.