S. Sanquer et al., Induction of inosine monophosphate dehydrogenase activity after long-term treatment writh mycophenolate mofetil, CLIN PHARM, 65(6), 1999, pp. 640-648
Objectives: To study the pharmacologic activity of mycophenolate mofetil in
stable kidney transplant recipients receiving mycophenolate mofetil therap
y for different periods from 2 months to 3 years,
Methods: Seventeen patients were enrolled during a 9-month period. Blood sa
mples were collected before administration and 1/2, 1, 2, 4, and 6 hours af
ter administration. Mycophenolic acid, the active metabolite of mycophenola
te mofetil, was measured in plasma with use of the enzyme multiplication im
munoassay 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 es
timation of the H-3-release from [2,8-H-3]-hypoxanthine,
Results: As the length of mycophenolate mofetil therapy increased, the inhi
bitory 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 treatm
ent; 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 myco
phenolic acid,
Conclusion: Long-term treatment with mycophenolate mofetil was associated w
ith an induction of IMPDH activity. Such induction could be deleterious if
it is followed by a restoration or a stimulation of the proliferative capac
ity of lymphocytes, These results strongly suggest that the place of mycoph
enolate mofetil in long-term treatment of kidney transplant patients needs
to be carefully assessed.