title: Mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, causes a paradoxical elevation of GTP in erythrocytes of renal transplant patients.
abstract: The immunosuppressant MMF (mycophenolate mofetil) has increasingly replaced AZA (azathioprine) in renal transplantation. MMF is a prodrug of MPA (mycophenolic acid), which inhibits lymphocyte IMPDH (inosine monophosphate dehydrogenase), thereby drastically decreasing GTP concentrations essential to lymphocyte proliferation in vitro and in vivo. Erythrocyte GTP concentrations are commonly elevated in severe renal disease, but normalize following successful engraftment. Consequently, elevated GTP in renal transplant recipients might signal impending loss of immunosuppression and graft failure. In the present study, we compared erythrocyte nucleotides and plasma metabolites in two groups of 25 patients after renal transplantation, both receiving prednisolone and cyclosporin A, but one group receiving MMF and the other AZA. No patients had recent allograft biopsy evidence of rejection. Erythrocyte GTP concentrations at MMF commencement were 50.4+/-23.4 micromol/l. An increase occurred during the first 3 months after transplant when MMF was used de novo, stabilizing at 146.7+/-62.9 micromol/l after 4 months. This was significantly higher (P=2.5 x 10(-6)) than erythrocyte GTP (40.4+/-15.9 micromol/l) in the AZA group, which was essentially unchanged from values immediately after successful transplantation. The effect of MMF on erythrocyte GTP levels was reversible, since GTP levels fell when MMF therapy was terminated. The results demonstrate paradoxically high GTP concentrations in erythrocytes of renal transplant patients receiving MMF. MPA may stabilize reticulocyte IMPDH, allowing the protein to persist during erythropoiesis. This behaviour is in marked contrast with the decrease in GTP levels seen in white blood cells of patients on chronic MMF therapy.
authors.affiliation: Department of Renal Medicine, Guy's Hospital, London SE1 9RT, UK. david.goldsmith@gstt.sthames.nhs.uk
authors.forename: David
authors.initials: D
authors.lastname: Goldsmith
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Carrey
authors.forename: Stephen
authors.initials: S
authors.lastname: Edbury
authors.forename: Ryszard T
authors.initials: RT
authors.lastname: Smolenski
authors.forename: Piotr
authors.initials: P
authors.lastname: Jagodzinski
authors.forename: H Anne
authors.initials: HA
authors.lastname: Simmonds
mesh_terms: D000328:Adult; D001379:Azathioprine / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006160:Guanosine Triphosphate / Q000097:blood*; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011184:Postoperative Period
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D006160:Guanosine Triphosphate; D003404:Creatinine; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; D001379:Azathioprine