2. ANTIMETABOLITES
Folate Antagonists
• Methotrexate (MTX) is a folic acid (FA) antagonist. It is a prodrug
converted in the liver to its polyglutamates in the normal as well as
tumour cells and the reaction is catalysed by the enzymes
folypolyglutamate synthase (FPGS).
• Polyglutamates of methotrexate remain in the tumour cells.
• They are partly selective for tumour cells.
• Methotrexate binds to dihydrofolate reductase and prevents the
formation of tetrahydrofolate (THF).
• This THF serves as a coenzyme essential in several reactions in DNA,
RNA and protein synthesis (provides methyl groups).
• The deficiency results in inhibition of DNA, RNA and protein synthesis.
3. Actions
• Cytotoxic actions:
• Methotrexate mainly affects the bone marrow, skin and gastrointestinal
mucosa and other rapidly dividing cells.
• It also has immunosuppressant and some anti-inflammatory properties.
Pharmacokinetics
• Methotrexate is well absorbed when given orally with 50% protein
binding. It can also be given parenterally (IM, IV, intrathecal).
• Higher doses should be given IV as absorption is erratic at such doses.
• It poorly crosses the BBB due to low lipid solubility.
• Methotrexate is taken up into the cells by the same active transport
process as that of folic acid.
• It is metabolised in the liver to polyglutamates which are inhibitors of
DHFR.
• Methotrexate is excreted largely by the kidneys—hence dose should be
reduced in renal failure.
4. • Adverse effects to methotrexate include the common adverse effects to
most anticancer drugs—bone marrow suppression, nausea, vomiting,
diarrhoea, alopecia and dermatitis.
• Methotrexate can cause nephrotoxicity because the drug may be
precipitated in the renal tubules and it is contraindicated in patients with
renal impairment.
• When injected intrathecally, methotrexate can cause myelopathy and
encephalopathy.
Drug Interactions
• Salicylates, sulfonamides, penicillin, aspirin and probenecid inhibit the
renal tubular secretion of methotrexate. Some of them also displace
methotrexate from plasma protein binding sites.
Uses
1. Choriocarcinoma
2. ALL in children
3. Psoriasis
4. Rheumatoid arthritis
5. Purine Analogs
• 6-Mercaptopurine, thioguanine, fludarabine, pentostatin and
cladribine are purine analogs which act as purine antagonists.
• They are structurally similar to purines.
• Mercaptopurine Mercaptopurine (6-MP) is converted to an active
metabolite which gets incorporated into the DNA and inhibits purine
synthesis and thereby protein synthesis.
• Mercaptopurine undergoes extensive first pass metabolism and oral
bioavailability is 10–50%.
• It is metabolised by xanthine oxidase
MECHANISM OF ACTION :
• They cause breakages in DNA strands and inhibit protein synthesis.
6. • Adverse effects include bone marrow depression which develops
slowly after several weeks, anorexia, diarrhoea, nausea, vomiting,
stomatitis, jaundice and dermatitis.
• Hyperuricaemia may be significant and would require treatment with
allopurinol—dose of 6-MP should be reduced.
• Increased risk of squamous cell carcinoma of the skin and AML has
been noted after prolonged use of 6-MP.
Uses:
MP is used in acute leukaemias in children, choriocarcinoma and some
solid tumours.
Azathioprine is converted to 6MP in the cells and is a potent
immunosuppressant used in rheumatoid arthritis
