Inosine monophosphate dehydrogenase activity in renal allograft recipients during mycophenolate treatment.
OBJECTIVE
Mycophenolic acid (MPA) exerts its immunosuppression by inhibiting inosine 5'-monophosphate dehydrogenase (IMPDH), depleting activated lymphocytes of guanine nucleotides and retarding their proliferation. An optimal strategy for monitoring has not been established for mycophenolate mofetil (MMF) in renal transplantation, and clinical investigations of the pharmacokinetic-pharmacodynamic relationship are warranted.


METHODS
Mycophenolic acid pharmacokinetics and whole blood cell IMPDH activity were investigated in two separate groups of renal allograft recipients. One group was studied within the 12-h dose interval, while the second group was examined by pre-dose samples pre-transplant and then repeatedly during 8 weeks post-transplant.


RESULTS
An inverse relationship between plasma MPA and IMPDH activity within the dose interval was demonstrated. Minimum IMPDH activity was a median 8 % of values pre-MMF dose, coinciding with the MPA peak. Six hours post-dose, IMPDH activity had returned to pre-dose values. Patients receiving MMF had a 4.5-fold higher pre-dose enzyme activity than transplanted patients without MMF. During the 8 weeks post-transplant, the median MPA trough concentration was fairly stable. Following an initial decrease during the first 4 days post-transplant, IMPDH activity gradually increased during the 40 days post-transplant, reaching 5-fold the pre-transplant values.


CONCLUSIONS
Provided that the changes in IMPDH activity in whole blood cells predict the clinical effect, these pharmacokinetic-pharmacodynamic findings may prove useful in the attempts to identify optimal timing and range for the monitoring of mycophenolate in renal transplantation. The question of whether MPA concentrations or measurements of IMPDH activity per se will be the optimal way of monitoring this immunosuppressant remains open and will only be answered by prospective clinical testing.
Vethe
N T
NT
Department of Surgery, Rikshospitalet University Hospital, NO-0027 Oslo, Norway.
Mandla
R
R
Line
P-D
PD
Midtvedt
K
K
Hartmann
A
A
Bergan
S
S
D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000097:blood*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid