Induction of inosine monophosphate dehydrogenase activity after long-term treatment writh mycophenolate mofetil

Citation
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
Citations number
22
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology,"Pharmacology & Toxicology
Journal title
CLINICAL PHARMACOLOGY & THERAPEUTICS
ISSN journal
0009-9236 → ACNP
Volume
65
Issue
6
Year of publication
1999
Pages
640 - 648
Database
ISI
SICI code
0009-9236(199906)65:6<640:IOIMDA>2.0.ZU;2-I
Abstract
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.