Inosine monophosphate dehydrogenase variability in renal transplant patients on long-term mycophenolate mofetil therapy.
BACKGROUND
* Mycophenolic acid (MPA) is a potent, selective and reversible inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme for de novo guanosine triphosphate biosynthesis. * The large IMPDH interindividual variability could be responsible for the differences in therapeutic effects and side-effects observed with MPA. * Induction of IMPDH activity has been observed in whole blood during immunosuppressive therapy.


CONCLUSIONS
* Our data were acquired in long-term mycophenolate mofetil-treated renal transplant recipients on different combinations of immunosuppressive agents (ciclosporin, tacrolimus, sirolimus) and with different treatment duration (up to 8.8 years post transplant). * The increasing trend in IMPDH activity that we observed throughout our 12-month observation period was significantly higher in rejecting than in nonrejecting subjects.


OBJECTIVE
Long-term mycophenolate mofetil (MMF) therapy may induce inosine 5'-monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells (PBMCs), thus decreasing MMF immunosuppressive properties. Pharmacodynamic monitoring was used to investigate whether biological activity is altered after long-term therapy.


METHODS
IMPDH activity was measured in PBMC samples from 54 stable kidney transplant patients, already on MMF (for at least 3 months), before (t(0)) and 2 h after (t(2)) MMF morning dose administration; levels were monitored for up to 15 months, together with total mycophenolic acid (MPA) and free MPA concentrations.


RESULTS
During the 15 months' monitoring, t(0) IMPDH activity in transplant recipients increased from 5.9 +/- 3.7 nmol h(-1) mg(-1)[95% confidence interval (CI) 4.9, 6.9] to 9.0 +/- 3.9 nmol h(-1) mg(-1) (95% CI 7.2, 10.8), with an intra- and interpatient variability of 28% and 42%. Five patients experienced acute rejection during the follow-up: t(0) IMPDH activity was increased during rejection vs. nonrejection, and the trend was significantly higher in rejecting than in nonrejecting subjects for the whole monitoring period.


CONCLUSIONS
Even though a correlation has been found between IMPDH activity and rejection, its efficacy as a predictive tool in long-term transplant outcomes may be affected by high interpatient variability; on the other hand, continuous monitoring of the IMPDH trend could make an effective prognostic parameter of rejection. Other trials also including pre-transplant data on both IMPDH expression and activity are warranted to better assess their role as biomarkers for MPA effect in clinical practice.
Chiarelli
Laurent R
LR
Department of Biochemistry, University of Pavia, Pharmacokinetics Unit, Pavia, Italy.
Molinaro
Mariadelfina
M
Libetta
Carmelo
C
Tinelli
Carmine
C
Cosmai
Laura
L
Valentini
Giovanna
G
Dal Canton
Antonio
A
Regazzi
Mario
M
D000328:Adult; D000368:Aged; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000378:metabolism / Q000493:pharmacokinetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016030:Kidney Transplantation; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid