## Mycophenolate Mofetil (MMF) Mechanism ### Selective Inhibition of IMPDH Type II **Key Point:** Mycophenolate mofetil is a prodrug that is rapidly hydrolyzed to mycophenolic acid (MPA), which selectively inhibits **inosine monophosphate dehydrogenase type II (IMPDH II)**. This enzyme catalyzes the rate-limiting step in guanosine nucleotide synthesis, which is essential for T and B lymphocyte proliferation. ### Why Selective for Lymphocytes? 1. **IMPDH II is the predominant isoform in activated T and B cells** — resting lymphocytes rely more on the salvage pathway. 2. **Non-lymphoid cells** (e.g., fibroblasts, endothelial cells) express IMPDH I and can use salvage pathways, making them relatively spared. 3. **Result:** Selective depletion of guanosine nucleotides in proliferating lymphocytes without affecting other cell types as severely. ### Comparison with Other Antimetabolites | Drug | Enzyme Target | Mechanism | Selectivity | |------|---------------|-----------|-------------| | **MMF (MPA)** | IMPDH II | Blocks guanosine synthesis | Lymphocyte-selective | | **Azathioprine** | HGPRT, TPMT | Purine antagonism | Non-selective | | **Methotrexate** | DHFR | Blocks folate metabolism | Non-selective (affects all dividing cells) | **High-Yield:** MMF is preferred over azathioprine in modern transplantation because of its superior efficacy and more selective lymphocyte targeting. It is also used in lupus nephritis and other autoimmune conditions. **Clinical Pearl:** The active metabolite is **mycophenolic acid (MPA)**, not the prodrug itself. Enteric-coated mycophenolate sodium (EC-MPS) is an alternative formulation that reduces gastrointestinal side effects. **Warning:** Do NOT confuse IMPDH inhibition (MMF) with DHFR inhibition (methotrexate) or purine antagonism (azathioprine) — each has a different selectivity profile and clinical role.
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