Stability and Bioavailability on Prodrug of 5-Flurouracil (I). Synthesis, Physicochemical Properties, Stabilities and Antitumor Activities of 1-Glycyloxymethyl-5-fluorouracil Hydrochloride

5-Fluorouracil의 Prodrug에 대한 안정성 및 생체이용율에 관한 연구(I). 1-Glycyloxymethyl-5-fluorouracil HCl의 제조, 물리화학적 성질, 안정성 및 항암효과

To assess its suitability as a prodrug of 5-fluorouracil (5-FU), 1-glycyloxymethyl-5-FU HCl (GFU), a 5-fluorouracil derivative having a glycyloxymethyl group at the N-l position was synthetized. Its physicochemical properties and hydrolysis kinetics, in aqueous solution of pH $1{\sim}10$ and in the presence of human plasma or rat liver homogenate were studied. Its acute toxicity and antitumor activity against sarcoma 180 were also examined, GFU showed higher lipid/water partition coefficient than 5-FU. The calculated $pK_{\alpha}$ values of 5-FU and GFU were 8.02 and 7,20, respectively. The decomposition rates of GFU in aqueous solution showed a pH-dependence over the pH range used, which could be ascribed to solvent catalysed hydrolysis reaction at pH lower than 4,16 and to specific hydroxide ion hydrolysis reaction at pH higher than 4,16, The half-life of GFU was 6,9 min in 80% human plasma solution and less than 3 min in rat liver homogenate at $37^{\circ}C$, The $LD_{50}$ value of 5-FU was 240 mg/kg while that of GFU was 440.6 mg/kg (226 mg as 5-FU). Both of 5FU and GFU showed a strong antitumor activity, Therapeutic ratios of 5-FU and GFU were 3.07 and 3.55, respectively.