FOLIC ACID ANALOGS

FOLIC ACID ANALOGS

• A subgroup of antimetabolite drugs.

Drugs included:

• Methotrexate, pemetrexed & pralatrexate.

Important drug details:

1. Methotrexate:

• Dihydrofolate reductase (DHFRase) inhibitors.

MOA:

• Inhibits thymidylate synthase (TS).
• Thymidylate synthase (TS) enzyme involved in early purine synthesis.
• Methotrexate forms polyglutamates inside cell.
• Polyglutamates helps in methotrexate trapping within cells.
• Reason for “cytotoxicity of neoplastic cells”.

Metabolism:

• Clearance depends on renal function.
• Vigorous hydration required to prevent its crystallization in renal tubules.

Uses:

• DOC – Choriocarcinoma treatment.
• Useful for acute leukemias, non-Hodgkin lymphoma, cutaneous, T-cell lymphoma & breast cancer.
• For meningeal leukemias (by intrathecal route).

Adverse effects:

• Prolonged immunosuppresion – Sequestered in third-space collections & reverts back to general circulation.
• Bone marrow suppression & mucositis.
• Long-term use: Hepatotoxicity, pulmonary infiltrates & fibrosis.

Treatment of methotrexate toxicity:

“Leucovorin rescue”:

• Methotrexate toxicity to normal cells reduced by N formyl- tetrahydrofolic acid (folinic acid, citrovorum factor or leucovorin) administration.
• This strategy is “leucovorin rescue”.
• (Note: Leucovorin do not prevent neurotoxicity).
• Urine alkalinization.
• NSAID (aspirin), penicillins & cephalosporins – By decreasing renal methotrexate excretion.

In extreme toxicity:

• Toxicity treated by dialysis or by GLUCARPIDASE administration.
• Glucarpidase – Methotrexate cleaving enzyme.

Methotrexate resistance:

Causes:

• Impaired methotrexate transport into cells.
• Production of altered DHFRase forms decreasing inhibitor affinity.
• Increased intracellular DHFRase concentrations via gene amplification.
• Altered gene regulation.
• Decreased ability synthesizing methotrexate polyglutamates.
• Increased expression of drug efflux transporter of MRP (multidrug resistance protein) class.

2. Pemetrexed:

• Approved for mesothelioma treatment. 
• Folic acid & vitamin B supplementation decreases pemetrexed toxicity – Without interfering with its clinical efficacy.
• Indicated in management of rheumatoid arthritis, psoriasis & ectopic pregnancy.

3. Pralatrexate:

• Indicated for peripheral T-cell lymphoma. 

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