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[Pharmacology](https://durgical.com/en/pharmacology/) · Class

# Antimetabolites

Look-alikes of folate or DNA building blocks that jam the enzymes making nucleotides, so fast-dividing cells cannot copy their DNA.

Updated 2026-11-01

## What they are

Drugs that resemble natural metabolites (folate, purines, pyrimidines) and block nucleotide synthesis or get built into DNA and RNA. They act mainly in the S phase of the cell cycle and are used in cancer and, at low doses, in autoimmune disease.

## Mechanism of action

Folate antagonists such as methotrexate block dihydrofolate reductase, emptying the pool of reduced folates that cells need to make thymidine and purines. Pyrimidine analogues such as fluorouracil are turned into fraudulent nucleotides that inhibit thymidylate synthase and enter RNA and DNA. Either way, DNA synthesis stops in cells that are dividing quickly: tumour cells, but also bone marrow, gut lining and hair follicles.

Target: Folate and nucleotide-synthesis enzymes (dihydrofolate reductase, thymidylate synthase and others)

## Key points

- Cell-cycle specific (S phase): toxicity falls on fast-renewing tissues, giving myelosuppression, mucositis, diarrhoea and hair loss.
- Folinic acid (leucovorin) works in opposite directions: it rescues normal cells from methotrexate (it bypasses DHFR) but strengthens fluorouracil (it stabilises the block on thymidylate synthase).
- Deficiency of DPD, the enzyme that breaks down most of a fluorouracil dose, causes severe and sometimes fatal toxicity; DPYD testing comes before treatment.
- Methotrexate can cause birth defects and fetal death, and is contraindicated in pregnancy when used for non-cancer diseases.
- Methotrexate polyglutamates stay in tissues and inhibit both DHFR and thymidylate synthase.

## Drugs in this class

- [**Methotrexate** A folate look-alike that blocks DHFR. High doses treat cancers; low once-weekly doses calm rheumatoid arthritis and… Dihydrofolate reductase (DHFR)](https://durgical.com/en/pharmacology/methotrexate/)
- [**Fluorouracil** A fake pyrimidine: cells turn it into FdUMP, which jams thymidylate synthase and starves DNA of thymidine. A backbone… Thymidylate synthase](https://durgical.com/en/pharmacology/fluorouracil/)

## Others in the class

- pemetrexed
- pralatrexate
- capecitabine
- tegafur
- gemcitabine
- cytarabine
- mercaptopurine
- thioguanine
- fludarabine

## Test yourself

Think of the answer, then tap the question to see it.

## Why do antimetabolites cause mouth ulcers and low blood counts?

They stop DNA synthesis in dividing cells, and the mouth lining and bone marrow renew themselves quickly.

## How can folinic acid both protect against methotrexate and enhance fluorouracil?

It is already reduced, so it bypasses the DHFR that methotrexate blocks; and it raises the folate cofactor that locks FdUMP onto thymidylate synthase.

## Which enzyme breaks down most of a fluorouracil dose, and why does it matter?

Dihydropyrimidine dehydrogenase (DPD). People with DPD deficiency cannot clear the drug and can suffer severe or fatal toxicity, so DPYD testing comes first.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [METHOTREXATE injection, solution](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a63364d5-4dfa-49d7-8a5e-c8959ae1d37a) (DailyMed (U.S. National Library of Medicine), 2026); [DailyMed - FLUOROURACIL injection, solution](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8eff167f-203a-4a81-b2fc-d8773bc3555e) (DailyMed (U.S. National Library of Medicine), 2026); [ATCDDD - ATC/DDD Index](https://atcddd.fhi.no/atc_ddd_index/?code=L01BA01) (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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Representative model, for educational purposes only.

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