GTP Concentrations are Elevated in Erythrocytes of Renal Transplant Recipients when Conventional Immunosuppression is Replaced by the Inosine Monophosphate Dehydrogenase Inhibitor Mycophenolic Acid Mofetil (MMF)

2004 ◽  
Vol 23 (8-9) ◽  
pp. 1407-1409 ◽  
Author(s):  
D. J. A. Goldsmith ◽  
E. A. Carrey ◽  
S. M. Edbury ◽  
A. M. Marinaki ◽  
H. A. Simmonds
Keyword(s):  
Renal Transplant ◽  
Mycophenolic Acid ◽  
Renal Transplant Recipients ◽  
Inosine Monophosphate Dehydrogenase ◽  
Transplant Recipients ◽  
Inosine Monophosphate ◽  
Conventional Immunosuppression ◽  
Monophosphate Dehydrogenase

scholarly journals A Review of Enteric-coated Mycophenolate Sodium for Renal Transplant Immunosuppression

2009 ◽  
Vol 1 ◽  
pp. CMT.S2218 ◽  
Author(s):  
Nathan Newbold ◽  
Brianna Riley ◽  
Karen Hardinger
Keyword(s):  
Renal Transplant ◽  
Mycophenolic Acid ◽  
Renal Transplant Recipients ◽  
Inosine Monophosphate Dehydrogenase ◽  
Transplant Recipients ◽  
Gastrointestinal Complications ◽  
Mycophenolate Sodium ◽  
Delayed Release ◽  
Enteric Coated ◽  
The Impact

Mycophenolic acid inhibits an enzyme, inosine monophosphate dehydrogenase (IMPDH), blocking purine synthesis of lymphocytes and therefore functioning as an effective immunosuppressive agent in transplantation. Currently, there are two available forms of mycophenolic acid (MPA) available; mycophenolate mofetil (MMF) and enteric-coated, delayed-release mycophenolate sodium (EC-MPS). Both products are approved for prophylaxis of organ rejection in renal transplant recipients. The use of MPA may be associated with adverse gastrointestinal effects which can lead to a reduction of the dose or discontinuation of therapy. Enteric-coated MPS was developed to reduce the upper gastrointestinal side effects due to its delayed release in the small intestines. Similar systemic MPA exposure is provided by oral administration of MMF 1000 mg daily and EC-MPS 720 mg, which contain near equimolar MPA content. Clinical trials in renal transplant recipients have demonstrated that EC-MPS is therapeutically equivalent to MMF when used at the time of transplantation and when used for conversion for gastrointestinal complications. The available literature regarding the incidence and severity of gastrointestinal adverse effects and the impact on quality of life remains controversial. Prospective, randomized trials of the available MPA formulations are warranted to further explore the gastrointestinal adverse effect profiles.

Mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, causes a paradoxical elevation of GTP in erythrocytes of renal transplant patients

2004 ◽  
Vol 107 (1) ◽  
pp. 63-68 ◽  
Author(s):  
David GOLDSMITH ◽  
Elizabeth A. CARREY ◽  
Stephen EDBURY ◽  
Ryszard T. SMOLENSKI ◽  
Piotr. JAGODZINSKI ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Renal Transplantation ◽  
Renal Transplant ◽  
Plasma Metabolites ◽  
Renal Transplant Recipients ◽  
Inosine Monophosphate Dehydrogenase ◽  
Inosine Monophosphate ◽  
Transplant Patients ◽  
Renal Transplant Patients ◽  
Monophosphate Dehydrogenase

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 μmol/l. An increase occurred during the first 3 months after transplant when MMF was used de novo, stabilizing at 146.7±62.9 μmol/l after 4 months. This was significantly higher (P=2.5×10−6) than erythrocyte GTP (40.4±15.9 μmol/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.

scholarly journals In Vitro Combination of Amdoxovir and the Inosine Monophosphate Dehydrogenase Inhibitors Mycophenolic Acid and Ribavirin Demonstrates Potent Activity against Wild-Type and Drug-Resistant Variants of Human Immunodeficiency Virus Type 1

2004 ◽  
Vol 48 (11) ◽  
pp. 4387-4394 ◽  
Author(s):  
Katyna Borroto-Esoda ◽  
Florence Myrick ◽  
Joy Feng ◽  
Jerry Jeffrey ◽  
Phillip Furman
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mycophenolic Acid ◽  
Inosine Monophosphate Dehydrogenase ◽  
Wild Type ◽  
Inosine Monophosphate ◽  
Immunodeficiency Virus ◽  
Monophosphate Dehydrogenase

ABSTRACT Amdoxovir [(−)-β-d-2,6-diaminopurine dioxolane (DAPD)] is a nucleoside analogue reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. DAPD is deaminated by adenosine deaminase to the guanosine analogue dioxolane guanosine (DXG), which is subsequently phosphorylated to the corresponding 5′ triphosphate (DXG-TP). DXG-TP competes with the natural substrate dGTP for binding to the enzyme-nucleic acid complex. Mycophenolic acid (MPA) and ribavirin (RBV), inhibitors of inosine monophosphate dehydrogenase (IMPDH), inhibit the de novo synthesis of guanine nucleotides, including dGTP. Reducing the intracellular levels of dGTP would be expected to augment the antiviral activity of analogues of deoxyguanosine. In this study we examined the effect of MPA and RBV on the anti-HIV activity of DAPD and DXG. When tested against wild-type virus, both MPA and RBV decreased the 50% effective concentration (EC50) for DXG by at least 10-fold. In contrast, both MPA and RBV increase the EC50 value for zidovudine. MPA and RBV completely reversed the resistance to DXG observed with HIV isolates containing mutations which confer partial resistance to DAPD and DXG. Similarly, when tested against a mutant virus fully resistant to inhibition by DAPD (K65R/Q151M), MPA and RBV reduced the EC50 for DAPD to within twofold of that for the wild type. The combination of MPA or RBV with DAPD or DXG did not result in increased cytotoxicity or reduced levels of mitochondrial DNA when tested at physiologically relevant concentrations. These studies suggest a potential role for the use of IMPDH inhibitors in combination therapy with amdoxovir in the treatment of HIV.

scholarly journals Regulation of the Interaction of Inosine Monophosphate Dehydrogenase with Mycophenolic Acid by GTP

2005 ◽  
Vol 281 (1) ◽  
pp. 206-212 ◽  
Author(s):  
YanShan Ji ◽  
JingJin Gu ◽  
Alexander M. Makhov ◽  
Jack D. Griffith ◽  
Beverly S. Mitchell
Keyword(s):  
Mycophenolic Acid ◽  
Inosine Monophosphate Dehydrogenase ◽  
Inosine Monophosphate ◽  
Monophosphate Dehydrogenase
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