Machida H, Watanabe Y, Kano F, Sakata S, Kumagai M, Yamaguchi T
Biology Laboratory, R & D Division, Yamasa Corporation, Choshi, Japan.
Biochem Pharmacol. 1995 Mar 15;49(6):763-6. doi: 10.1016/0006-2952(94)00543-u.
A number of antiherpesviral 5-substituted derivatives of 1-beta-D-arabinofuranosyluracil (araU) were significantly resistant to phosphorolysis by rat liver extract (S-9), but were gradually deglycosylated in a 2% enterobacteria cell suspension. The relative order of the resistance conferred by the different C-5 substituents was: 5-propynyl > 5-(E)-2-bromovinyl > 5-(E)-2-chlorovinyl > 5-methyl > 5-iodo. The 2'-fluoro derivatives of araU were completely resistant to phosphorolysis by both liver extract and enterobacteria, whereas the corresponding ribofuranosyl and 2'-deoxyribofuranosyl nucleosides were easily phosphorolysed by S-9, and were immediately cleaved in a 1% enterobacteria cell suspension. These findings suggest that antiherpesviral 5-substituted araU analogues can be relatively stable in vivo, when injected intravenously, and that degradation of 1-beta-D-arabinofuranosyl-5-(E-2-bromovinyl)uracil (sorivudine) following oral administration is due primarily to the action of enterobacteria.
1-β-D-阿拉伯呋喃糖基尿嘧啶（araU）的多种抗疱疹病毒5-取代衍生物对大鼠肝脏提取物（S-9）的磷酸解作用具有显著抗性，但在2%的肠道细菌细胞悬液中会逐渐去糖基化。不同C-5取代基赋予抗性的相对顺序为：5-丙炔基＞5-（E）-2-溴乙烯基＞5-（E）-2-氯乙烯基＞5-甲基＞5-碘。araU的2'-氟衍生物对肝脏提取物和肠道细菌的磷酸解作用均完全抗性，而相应的呋喃核糖基和2'-脱氧呋喃核糖核苷很容易被S-9磷酸解，并在1%的肠道细菌细胞悬液中立即裂解。这些发现表明，抗疱疹病毒的5-取代araU类似物静脉注射时在体内可能相对稳定，且口服给药后1-β-D-阿拉伯呋喃糖基-5-（E-2-溴乙烯基）尿嘧啶（索立夫定）的降解主要归因于肠道细菌的作用。
