Antimetabolites

Antimetabolites are structural analogues of folate, purines or pyrimidines. They block nucleotide synthesis or are incorporated into DNA and RNA, which halts DNA synthesis. They act mainly in S phase, so they are most active against rapidly proliferating tumours and are schedule-dependent.

Classification. Folate antagonists (methotrexate, pemetrexed, pralatrexate, raltitrexed), purine analogues (mercaptopurine, thioguanine, fludarabine, cladribine, clofarabine, nelarabine, pentostatin), and pyrimidine analogues (fluorouracil, capecitabine, cytarabine, gemcitabine, azacitidine, decitabine, trifluridine with tipiracil).

Pharmacokinetics. Many are prodrugs activated intracellularly; catabolism by dihydropyrimidine dehydrogenase (fluoropyrimidines), thiopurine methyltransferase (thiopurines) and cytidine deaminase (cytarabine, gemcitabine) explains inter-patient variation.

• Methotrexate: 12 mg intrathecal; high dose 3 to 12 g/m2 with folinic acid rescue.
• Pemetrexed 500 mg/m2 every 3 weeks.
• Mercaptopurine 75 mg/m2 orally daily for maintenance in acute lymphoblastic leukaemia.
• Fludarabine 25 mg/m2 daily for 5 days.
• Fluorouracil 2,400 mg/m2 over 46 hours every 2 weeks; capecitabine 1,250 mg/m2 twice daily for 14 days every 21 days.
• Cytarabine 100 to 200 mg/m2 daily for 7 days by continuous infusion.
• Gemcitabine 1,000 mg/m2 on days 1, 8 and 15.
• Azacitidine 75 mg/m2 subcutaneously daily for 7 days every 28 days.

Differences. Folate antagonists cause mucositis and kidney injury; purine analogues cause immunosuppression and neurotoxicity; pyrimidine analogues cause mucositis, diarrhoea, hand and foot syndrome (fluoropyrimidines) and cerebellar toxicity (cytarabine).

• Leukaemia: cytarabine, mercaptopurine, methotrexate, fludarabine.
• Gastrointestinal, breast and head and neck cancer: fluorouracil and capecitabine.
• Pancreatic, lung, bladder and ovarian cancer: gemcitabine.
• Lung cancer (non-squamous) and mesothelioma: pemetrexed.
• Myelodysplasia: azacitidine.
• Before fluoropyrimidines: test for DPYD variants where available; start at a 50 percent dose in intermediate metabolisers.
• Rescue: folinic acid after high-dose methotrexate; uridine triacetate for fluorouracil overdose or early severe toxicity.

Selection. Choose by tumour type and organ function; use oral capecitabine where infusion pumps and central lines are unavailable.

Contraindications. Pregnancy; complete DPD deficiency (fluoropyrimidines); severe kidney impairment (methotrexate, pemetrexed, fludarabine); live vaccines.

Adverse effects. Myelosuppression, mucositis, diarrhoea, hand and foot syndrome, cardiac vasospasm (fluoropyrimidines), neurotoxicity (fludarabine, cytarabine, nelarabine), hepatotoxicity (methotrexate, mercaptopurine), pulmonary toxicity (methotrexate, gemcitabine), haemolytic uraemic syndrome (gemcitabine).

Interactions. Warfarin with capecitabine and fluorouracil (INR rises); allopurinol with mercaptopurine; NSAIDs and penicillins with methotrexate; brivudine contraindicated with fluoropyrimidines.

Special groups.

• Pregnancy: avoid.
• Breastfeeding: avoid.
• Children: acute lymphoblastic leukaemia regimens depend on antimetabolites at precise doses.
• Older adults: reduce doses; greater mucositis.
• Kidney impairment: reduce or avoid methotrexate, pemetrexed, fludarabine and capecitabine (avoid under 30 mL/min).
• Liver impairment: reduce fluorouracil, mercaptopurine and methotrexate by bilirubin.

Monitoring. Full blood count, creatinine, liver function, mucositis, diarrhoea, skin, cardiac symptoms, and INR with warfarin.

Referral and escalation. Severe diarrhoea, mucositis that prevents drinking, chest pain, confusion, ataxia, or febrile neutropenia need urgent assessment.