Mechanism of Action of Capecitabine

by

Introduction

Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) widely used in the treatment of breast cancer, colorectal cancer, and gastric cancers. Designed for tumor-selective activation, it delivers higher concentrations of active 5-FU to tumor cells while reducing systemic toxicity.

The Mechanism of Action of Capecitabine centers on its stepwise conversion into 5-FU inside tumor tissues, followed by inhibition of thymidylate synthase, incorporation into DNA and RNA, and subsequent disruption of cancer cell replication.

MOA of Capecitabine
Mechanism of action of Capecitabine
Mechanism of action of Capecitabine
Capecitabine 5-FU activation
Capecitabine 5-FU activation
Capecitabine pharmacology

Mechanism of Action (Step-wise)

1. Oral Prodrug Conversion to 5-Fluorouracil (5-FU) – Primary Mechanism

Capecitabine undergoes a three-step enzymatic process:

  1. Carboxylesterase (liver)
    Capecitabine → 5’-deoxy-5-fluorocytidine (5’-DFCR)
  2. Cytidine deaminase (liver + tumor tissue)
    5’-DFCR → 5’-deoxy-5-fluorouridine (5’-DFUR)
  3. Thymidine phosphorylase (high in tumors)
    5’-DFUR → 5-Fluorouracil (active drug)

Tumor-selective activation occurs because thymidine phosphorylase is highly expressed in cancer cells.

2. Inhibition of Thymidylate Synthase (TS)

Once converted to 5-FU, it forms 5-fluoro-2′-deoxyuridine monophosphate (FdUMP).

This binds to:

  • Thymidylate synthase
  • Reduced folate (MTHF)

Creating a stable ternary complex.

Effect:

  • ↓ dTMP (deoxythymidine monophosphate) synthesis
  • ↓ DNA synthesis
  • ↓ Cell proliferation
  • S-phase cell cycle arrest

This is the main cytotoxic mechanism.

3. Incorporation into RNA (Fraudulent RNA Synthesis)

Another metabolite, 5-fluorouridine triphosphate (FUTP), incorporates into RNA.

Results:

  • Faulty RNA processing
  • Impaired ribosomal function
  • Disruption of protein synthesis

Particularly lethal to rapidly dividing tumor cells.

4. Incorporation into DNA

5-FU → FdUTP, which incorporates into DNA.

Effects:

  • DNA strand instability
  • Inhibition of DNA repair
  • Fractured replication forks
  • Apoptosis

5. Selective Tumor Cytotoxicity

Capecitabine is selectively activated within tumor cells due to:

  • ↑ Thymidine phosphorylase expression
  • ↑ Cytidine deaminase in tumors
  • Lower activation in normal tissues

This improves the therapeutic index compared to IV 5-FU.

6. Summary of Mechanism

MechanismEffect
Conversion to 5-FUTumor-selective activation
Thymidylate synthase inhibition↓ DNA synthesis
Incorporation into RNAFaulty RNA → cell death
Incorporation into DNADNA damage
S-phase arrestTumor growth inhibition
Stepwise mechanism of action of Capecitabine
Capecitabine converts to 5-FU via tumor enzymes

Pharmacokinetics

  • Route: Oral (high bioavailability)
  • Activation: Liver + tumor-specific enzymes
  • Peak levels: 1.5–2 hours
  • Half-life: 45–60 minutes
  • Metabolism: Hepatic + tumor enzymes
  • Excretion: Renal (mainly)

Clinical Uses

  • Metastatic and adjuvant colorectal cancer
  • Metastatic breast cancer
  • Gastric cancer
  • Pancreatic cancer (combinations)
  • Off-label: cholangiocarcinoma, neuroendocrine tumors

Adverse Effects

  • Hand-foot syndrome (erythrodysesthesia)
  • Diarrhea
  • Stomatitis
  • Myelosuppression
  • Nausea/vomiting
  • Fatigue
  • Hyperbilirubinemia
  • Cardiovascular toxicity (rare but serious)

DPD deficiency can lead to severe toxicity and must be screened when indicated.

Contraindications

  • Severe renal impairment
  • Pregnancy
  • Dihydropyrimidine dehydrogenase (DPD) deficiency
  • Known hypersensitivity to fluoropyrimidines

Comparative Analysis

FeatureCapecitabine5-Fluorouracil (IV)Tegafur
RouteOralIVOral
Tumor selectivityHighModerateModerate
Enzyme activationThymidine phosphorylaseDirect drugCYP-mediated
Hand-foot syndromeHigherModerateModerate
ConvenienceHighLowHigh

MCQs

1. Capecitabine is converted into its active form mainly by:
a) Thymidylate synthase
b) Thymidine phosphorylase
c) Dihydropyrimidine dehydrogenase
d) Cytochrome P450
Answer: b) Thymidine phosphorylase

2. The principal cytotoxic mechanism of capecitabine involves:
a) DNA alkylation
b) Protein synthesis inhibition
c) Thymidylate synthase inhibition
d) Microtubule stabilization
Answer: c) Thymidylate synthase inhibition

3. A hallmark adverse effect of capecitabine is:
a) Nephrotoxicity
b) Hand-foot syndrome
c) Cardiomyopathy
d) Hepatitis
Answer: b) Hand-foot syndrome

4. Capecitabine primarily arrests the cell cycle in:
a) G1 phase
b) S phase
c) G2 phase
d) M phase
Answer: b) S phase

5. Severe toxicity occurs in patients with deficiency of:
a) COMT
b) GST
c) DPD
d) MAO
Answer: c) DPD

FAQs

Q1. Is capecitabine the same as 5-fluorouracil?
No—capecitabine is an oral prodrug that becomes 5-FU inside tumor cells.

Q2. Why is capecitabine more tumor-selective?
Tumors have higher thymidine phosphorylase, activating more 5-FU locally.

Q3. Can capecitabine be used with radiation therapy?
Yes—often used as a radiosensitizer in GI cancers.

Q4. Why does hand-foot syndrome occur?
Due to high accumulation of metabolites in skin capillaries.

Q5. How long does capecitabine take to work?
Clinical effects usually appear within 6–8 weeks.

References

Goodman & Gilman’s Pharmacological Basis of Therapeutics
https://accesspharmacy.mhmedical.com/book.aspx?bookid=2189

Katzung: Basic and Clinical Pharmacology
https://accessmedicine.mhmedical.com/book.aspx?bookid=2464

Tripathi: Essentials of Medical Pharmacology
https://jaypeebrothers.com/

Harrison’s Principles of Internal Medicine
https://accessmedicine.mhmedical.com/book.aspx?bookid=2129

Leave a Comment