Cytidine Analogues: Cytarabine and Gemcitabine

Mechanism

Pharmacological Class and Group

Modified nucleoside antimetabolites, structural analogues of deoxycytidine, phase-specific of the cell cycle (S phase).

Mechanism of Action

Both drugs penetrate the cell via nucleoside transporters (ENT1) and require intracellular phosphorylation by deoxycytidine kinase (dCK) to transform into their active nucleotide triphosphates.

Chain Termination Mechanism and Ribonucleotide Reductase Inhibition

1. Citarabine (Ara-C): Its phosphorylated metabolite Ara-CTP competes with endogenous dCTP for incorporation into the DNA chain by DNA polymerase. Once incorporated, it suffers a steric hindrance due to the spatial orientation of its arabinose group, inhibiting chain elongation (chain terminator).

2. Gemcitabine (dFdC): Its diphosphorylated metabolite (dFdCDP) potently and allosterically inhibits the enzyme Ribonucleotide Reductase (RNR). This depletes intracellular stores of triphosphate deoxynucleotides necessary for DNA synthesis:

Gemcitabine-Diphosphate Ribonucleotide Reductase ↓ dNTP Pools Self-Enhancing Incorporation

The depletion of endogenous nucleotides facilitates the incorporation of gemcitabine triphosphate (dFdCTP) into DNA by competition. Once incorporated, a normal nucleotide is added before completely blocking polymerization, masking the error from the exonuclease correction mechanism (masking mechanism).

Pharmacokinetics

High Resolution Pharmacokinetics

• Distribution: Both compounds are rapidly distributed in the vascular and tissue compartment. The penetration of cytarabine into the cerebrospinal fluid increases after intravenous infusions at high doses, achieving concentrations of 15% to 40% of those in serum.
• Metabolism: They are massively inactivated in the liver, plasma and kidneys by the action of the enzyme Cytidine Deaminase (CDA), transforming cytarabine into inactive arabinose uracil (Ara-U), and gemcitabine into 2'-deoxy-2',2'-difluorouridine (dFdU).
• Elimination: Predominant renal excretion (>90%) in the form of inactive deaminated metabolites.
• Half-life (t_1/2): The half-life of cytarabine is biphasic, with a rapid elimination phase of 10 - 15 minutes. Gemcitabine has a clearance half-life of 30 - 90 minutes (depending on the sex and age of the patient).

Indicators and dose

Clinical Indications and Frequent Regimens

• High-dose cytarabine (HiDAC): Consolidation in Acute Myeloid Leukemia (AML) at doses of 1.5 - 3 g/m² IV infusion of 3 hours every 12 hours (days 1, 3 and 5).
• Standard cytarabine (7+3 Scheme): Continuous infusion of 100 - 200 mg/m²/day for 7 continuous days in AML induction, combined with daunorubicin.
• Gemcitabine: Advanced pancreatic adenocarcinoma (monotherapy or combined with Nab-Paclitaxel), non-small cell lung cancer, recurrent epithelial ovarian cancer.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Hypersensitivity to the active ingredient or to cytidine analogues.
• Severe kidney dysfunction or marked liver failure.
• Pregnancy and breastfeeding.

Relative Contraindications

• Pre-existing vestibular or cerebellar dysfunction (especially for high-dose cytarabine).
• Severe thrombocytopenia with risk of active bleeding.

Adverse Effects (ADR) and Specific Toxicity

• Myelosuppression: Anemia, thrombocytopenia and profound and prolonged neutropenia, with nadir after 10-14 days.
• Cerebellar Toxicity (Citarabine at high doses): Acute cerebellar ataxia, dysarthria, nystagmus and intentional tremor, of idiosyncratic origin related to metabolic saturation and direct neuronal damage.
• Ocular (Citarabine): Chemical keratoconjunctivitis due to ocular secretion of the active drug. Requires mandatory prophylactic use of 0.1% dexamethasone eye drops every 6 hours.
• Systemic (Gemcitabine): Flu-like syndrome (fever, myalgia, chills) that responds to paracetamol; Thrombotic microangiopathy in rare cases.

Neurological Monitoring and Prevention of Cytarabine Ataxia

Cerebellar neurotoxicity due to cytarabine is associated with high doses and previous renal dysfunction, which delays the clearance of the inactive metabolite Ara-U. A complete neurological evaluation is essential before each dose of cytarabine:

• Evaluation of Handwriting and Gait: Ask the patient for a daily signature or perform the finger-nose and tandem test before starting each infusion.
• Medical Conduct: Upon the appearance of the slightest sign of dysmetria, intentional tremor or slurred speech, the administration of cytarabine should be immediately discontinued to avoid permanent neurological damage.