From the Guidelines
CellCept (mycophenolate mofetil) primarily blocks the de novo purine synthesis pathway by inhibiting the enzyme inosine monophosphate dehydrogenase (IMPDH). This action is crucial in preventing the proliferation of T and B lymphocytes, which are key players in the immune response and rely heavily on this pathway for cell division. The de novo purine synthesis pathway is essential for the production of guanosine nucleotides, which are vital building blocks for DNA and RNA synthesis. By inhibiting IMPDH, CellCept effectively prevents the production of these nucleotides, thereby limiting the ability of lymphocytes to divide and proliferate.
According to the study published in the American Journal of Transplantation 1, antimetabolites, including mycophenolate mofetil (MMF), interfere with purine nucleotide synthesis, leading to the preferential inhibition of T and B lymphocytes. This selective action on lymphocytes makes CellCept an effective immunosuppressant in preventing organ transplant rejection and treating autoimmune disorders. The study highlights the importance of MMF in long-term management of liver transplant patients, often used in conjunction with other immunosuppressive agents to minimize side effects and improve renal function.
Key points about CellCept's mechanism of action include:
- Inhibition of the de novo purine synthesis pathway
- Specific targeting of the enzyme inosine monophosphate dehydrogenase (IMPDH)
- Preferential inhibition of T and B lymphocytes due to their reliance on the de novo pathway for cell division
- Effective immunosuppression with relatively fewer effects on other rapidly dividing cells compared to some other immunosuppressive medications, as noted in the context of liver transplant management 1.
From the FDA Drug Label
MPA is a selective uncompetitive inhibitor of the two isoforms (type I and type II) of inosine monophosphate dehydrogenase (IMPDH) leading to inhibition of the de novo pathway of guanosine nucleotide synthesis and blocks DNA synthesis MPA modulates transcriptional activities in human CD4+ T-lymphocytes by suppressing the Akt/mTOR and STAT5 pathways that are relevant to metabolism and survival, leading to an anergic state of T-cells whereby the cells become less responsive to antigenic stimulation
The pathways that Cellcept blocks are:
- Inosine monophosphate dehydrogenase (IMPDH): type I and type II isoforms
- De novo pathway of guanosine nucleotide synthesis
- DNA synthesis
- Akt/mTOR pathway
- STAT5 pathway 2
From the Research
CellCept Mechanism of Action
- CellCept, also known as mycophenolate mofetil (MMF), is a prodrug of mycophenolic acid (MPA), which inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH) 3, 4, 5, 6, 7.
- IMPDH is a key enzyme in the de novo synthesis of guanosine nucleotides, which are essential for cell division, particularly in T- and B-lymphocytes 3, 4, 5, 6.
- By inhibiting IMPDH, MPA depletes guanosine nucleotides, thereby suppressing the proliferation of T- and B-lymphocytes and inhibiting cell-mediated immune responses and antibody formation 3, 4, 5, 6.
Effects on Immune Response
- CellCept suppresses T-lymphocytic responses to allogeneic cells and other antigens, as well as primary antibody responses 3.
- MPA also inhibits the glycosylation and expression of adhesion molecules, decreasing the recruitment of lymphocytes and monocytes into sites of inflammation and graft rejection 3, 5.
- Additionally, MPA depletes tetrahydrobiopterin, a co-factor for the inducible form of nitric oxide synthase (iNOS), thereby suppressing the production of nitric oxide and consequent tissue damage mediated by peroxynitrite 3, 5.
Clinical Applications
- CellCept is used to prevent acute renal allograft rejection, and has been shown to be effective in combination with cyclosporine and steroids 6.
- It is also used to treat refractory rejection in renal, heart, and liver transplant recipients, and may have efficacy in the treatment of chronic rejection 6.
- CellCept has been shown to reduce acute and chronic rejection in allograft recipients, and may have clinical utility in some autoimmune disorders 5.