Gimeracil: A Pivotal Pharmacokinetic Modulator and DNA Repair Inhibitor Defining Modern Oral Fluoropyrimidine Therapy

1.0 Executive Summary

Gimeracil is a small molecule pyridine derivative that functions as a pivotal component of the oral anticancer agent known as S-1 or Teysuno. While not an antineoplastic agent in its own right, Gimeracil is a critical biochemical modulator that enables the therapeutic efficacy and shapes the safety profile of the combination product. Its primary and most well-characterized mechanism of action is the potent, selective, and reversible inhibition of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme responsible for the catabolism of 5-fluorouracil (5-FU). By preventing the rapid degradation of 5-FU, Gimeracil dramatically increases its bioavailability and prolongs its systemic exposure, allowing for therapeutic concentrations to be achieved with a significantly lower oral dose of the 5-FU prodrug, tegafur. This pharmacokinetic modulation is the central principle of the S-1 regimen, designed to replicate the efficacy of continuous intravenous 5-FU infusion in a convenient oral formulation while mitigating certain toxicities.

Beyond its role as a pharmacokinetic enhancer, emerging evidence has identified a secondary, direct pharmacological action for Gimeracil: the inhibition of DNA double-strand break repair via the homologous recombination pathway. This function positions Gimeracil as a potential radiosensitizer, capable of enhancing the cytotoxic effects of radiation therapy by preventing cancer cells from repairing the induced DNA damage. This dual mechanism suggests a broader therapeutic potential than previously understood, particularly in the context of combined-modality chemoradiotherapy.