Induction of inosine monophosphate dehydrogenase activity after long-term treatment with mycophenolate mofetil.
OBJECTIVE
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.


CONCLUSIONS
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.
Sanquer
S
S
Department of Nephrology, Henri Mondor University Hospital, Créteil, France.
Breil
M
M
Baron
C
C
Dhamane
D
D
Astier
A
A
Lang
P
P
D000328:Adult; D000368:Aged; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D010865:Pilot Projects; D011446:Prospective Studies; D013997:Time Factors
D007166:Immunosuppressive Agents; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid