DHFR Inhibition
0%
Normal Flux
dTMP Synthesis Rate
100%
DNA Replication Active
MTX-PG Trap Accumulation
0.0 µM
Intracellular Retention
Predicted Tissue Viability
100%
Healthy
🛡️
Normal Folate Metabolism
Dihydrofolate reductase (DHFR) converts DHF to THF uninhibited. Pyrimidine and purine synthesis rates are sufficient for cell replication.
Pharmacological Mechanism: Why Leucovorin Works While Folic Acid Fails
Methotrexate (MTX) is a potent competitive inhibitor of Dihydrofolate Reductase (DHFR) with a binding affinity over 1,000-fold higher than natural dihydrofolate. Under MTX administration:
- Folic Acid Failure: Dietary or supplementary folic acid must pass through DHFR twice (Folic Acid → DHF → THF). Because DHFR is completely blocked by MTX, administering standard folic acid cannot restore tetrahydrofolate (THF) pools.
- Leucovorin (Folinic Acid / 5-CHO-THF) Rescue: Leucovorin is a reduced folate derivative that enters the metabolic pathway downstream of DHFR. It converts directly into 5,10-methylene-THF and THF without requiring DHFR activity, effectively bypassing the MTX blockade and rescuing normal host cells from fatal bone marrow toxicity and GI mucositis.
- Timing & Selective Rescue: High-dose MTX selectively kills rapidly dividing cancer cells (e.g., osteosarcoma). Timed leucovorin administration (typically at 24 hours) rescues normal tissues before irreversible cell death occurs while preserving tumor killing.
Canonical Simulation State: Initializing...