Pyrimidine Analogs: 5-Fluorouracil and Capecitabine

Mechanism

Pharmacological Class and Group

Pyrimidine analogue antimetabolites, phase-specific of the cell cycle (S phase).

Mechanism of Action

5-FU and its oral prodrug, capecitabine (selectively activated by three hepatic and tumor enzymatic steps, the last being mediated by thymidine phosphorylase), act by inhibiting molecular replication and transcription.

Dual Inhibition Mechanism of DNA and RNA Synthesis

1. Blocking of Thymidylate Synthase (TS): The active metabolite deoxyfluorouridine monophosphate (FdUMP) binds covalently to the enzyme Thymidylate Synthase in the presence of the cofactor 5,10-methylenetetrahydrofolate, consolidating a stable inactive ternary complex. This depletes intracellular dTMP stores, stopping DNA replication:

FdUMP + 5,10-CH₂-THF + Thymidylate Synthase Stable Ternary Complex Stops DNA Synthesis

2. Incorporation into RNA: The triphosphorylated active metabolite fluorouridine triphosphate (FUTP) is mistakenly incorporated into messenger RNA instead of uracil, altering pre-mRNA processing, splicing and protein translation of the tumor cell.

3. Direct Incorporation into DNA: Fluorodeoxyuridine triphosphate (FdUTP) is anomalously coupled to the nascent DNA chain by the action of the polymerase, triggering fragmentation and breakage of the double helix due to failure of the base excision repair system.

Pharmacokinetics

High Resolution Pharmacokinetics

• Capecitabine Absorption: Rapid absorption in the gastrointestinal tract. Its absorption is slightly decreased with food, but it is administered within 30 minutes after a meal to reduce direct local digestive effects.
• Metabolism and Selective Conversion: Free 5-FU is rapidly degraded in the liver and peripheral tissues by the enzyme Dihydropyrimidine Dehydrogenase (DPD) (clearing more than 80% of the administered dose to inactive metabolites). The cellular remnant undergoes phosphorylation to active nucleotide metabolites.
• Elimination: Less than 10% is excreted unchanged via the kidneys; clearance is predominantly metabolic mediated by DPD.
• Half-life (t_1/2): The half-life of 5-FU IV is very short (10 - 20 minutes), justifying its administration in prolonged continuous infusions of 46 hours using elastomeric pumps.

Indicators and dose

Clinical Indications and Frequent Regimens

• Metastatic and adjuvant colorectal cancer: FOLFOX regimen (Fluorouracil in continuous infusion + Leucovorin + Oxaliplatin) or CAPOX (oral Capecitabine + Oxaliplatin).
• Gastric and Esophageal Cancer (FLOT Scheme): Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel.
• Metastatic Breast Cancer: Oral Capecitabine as monotherapy or combined with Docetaxel or Lapatinib in HER2+ tumors.

Dosage and Clinical Adjustment

• 5-Fluorouracil (FOLFOX): 400 mg/m² as a rapid bolus, followed by 2400 mg/m² as a continuous 46-hour infusion every 14 days.
• Capecitabine: 1000 - 1250 mg/m² orally twice a day (morning and night) for 14 consecutive days, followed by 7 days of rest.
• Clinical Adjustments: In patients with renal creatinine clearance between 30-50 mL/min, capecitabine requires an initial dose reduction of 25%; suspend if < 30 mL/min. In case of hand-foot syndrome grade 2 or higher, the dose is interrupted until remission to grade 1 and restarted with a 20% reduction.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Total deficiency of the enzyme Dihydropyrimidine Dehydrogenase (DPD): Causes massive fatal systemic toxicity due to accumulation of active drug.
• Persistent severe myelosuppression.
• Confirmed pregnancy and ongoing breastfeeding.
• Concomitant use of Capecitabine with Sorivudine or analogues.

Relative Contraindications

• Moderate to severe renal dysfunction (capecitabine requires clearance of its water-soluble metabolites).
• Coronary heart disease or underlying cardiac vasospasm.

Adverse Effects (ADR) and Specific Toxicity

• Gastrointestinal: Severe gastrointestinal mucositis (from oral ulcers to severe watery diarrhea, dose-limiting course).
• Dermatological: Hand-Foot Syndrome (Palmo-Plantar Erythrodissection), characterized by painful erythema, bullous exfoliative desquamation and limiting paresthesias in the palms of the hands and soles of the feet (more common with capecitabine and prolonged infusions of 5-FU).
• Cardiological: Myocardial ischemia due to coronary vasospasm, which presents with anginal-type precordial pain during or immediately after the infusion. Requires ECG monitoring and use of vasodilators or nitrates in selected cases.

Critical Toxicity: Screening for DPD Deficiency

The enzyme Dihydropyrimidine Dehydrogenase (DPD), encoded by the DPYD gene, is responsible for the metabolic inactivation of more than 80% of the dose of fluoropyrimidines. The presence of loss-of-function polymorphisms in this gene (for example, the alleles DPYD*2A, c.2846A>T or c.1679T>G) totally or partially abolishes the cellular degradation capacity:

DPD deficiency 5-FU clearance close to 0% Pancytopenia, Severe Mucositis and Fatal Neutropenic Sepsis

It is mandatory to perform pre-treatment determination of DPD deficiency by genotyping or measuring serum levels of plasma free uracil. In partial loss-of-function heterozygotes, the initial dose should be reduced by 25-50%; in homozygotes with total deficiency, fluoropyrimidines are absolutely contraindicated.