Ashida N, Ijichi K, Watanabe Y, Machida H
Biology Laboratory, Yamasa Corporation, Choshi, Japan.
Biochem Pharmacol. 1993 Dec 14;46(12):2201-7. doi: 10.1016/0006-2952(93)90610-9.
1-beta-D-Arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) is a selective antiherpesviral agent that has been shown to be metabolically stable in mice. However, E-5-(2-bromovinyl)uracil (BVU) is the major metabolite found after oral dosing in animals other than mice. When BV-araU was given orally to germ-free rats, only small amounts of BVU were found in the plasma, suggesting an important role of enterobacteria in the formation of BVU. Then, the metabolism of BV-araU prodrugs was studied in specific-pathogen free rats to select oral prodrugs of BV-araU with enhanced metabolic stability. 5'-O-Ethyl BV-araU (Et-BV-araU) gave about a 2-fold higher BV-araU blood concentration 3 and 6 hr after administration than after oral dosing of BV-araU, while the level of BVU was lower. Other aliphatic alkyl prodrugs also gave a lower level of BVU, but did not give the same elevation in blood concentration of BV-araU as did Et-BV-araU. Dosing of 5'-O-acetyl BV-araU resulted in blood concentrations of BV-araU and BVU similar to those after oral administration of BV-araU. 5'-O-Aromatic alkyl prodrugs showed poor bioavailability. A nearly 2-fold higher urinary recovery rate was seen for Et-BV-araU than for BV-araU or 5'-O-acetyl BV-araU. The conversion of Et-BV-araU to BV-araU was demonstrated in vitro using rat liver extract in the presence of co-factors, although the reaction was slow. The 5'-O-aliphatic alkyl prodrugs were completely resistant to degradation by enterobacteria, whereas the esters were partially degraded to BVU. Et-BV-araU may be a useful oral prodrug of BV-araU due to its increased metabolic stability and bioavailability.
1-β-D-阿拉伯呋喃糖基-E-5-(2-溴乙烯基)尿嘧啶（BV-araU）是一种选择性抗疱疹病毒药物，已证实在小鼠体内代谢稳定。然而，E-5-(2-溴乙烯基)尿嘧啶（BVU）是在除小鼠以外的动物口服给药后发现的主要代谢产物。当给无菌大鼠口服BV-araU时，血浆中仅发现少量BVU，这表明肠道细菌在BVU的形成中起重要作用。然后，在无特定病原体的大鼠中研究了BV-araU前药的代谢，以选择代谢稳定性增强的BV-araU口服前药。5'-O-乙基BV-araU（Et-BV-araU）给药后3小时和6小时的BV-araU血药浓度比口服BV-araU后高约2倍，而BVU水平较低。其他脂肪族烷基前药的BVU水平也较低，但在BV-araU血药浓度升高方面不如Et-BV-araU。5'-O-乙酰基BV-araU给药后的BV-araU和BVU血药浓度与口服BV-araU后相似。5'-O-芳香族烷基前药的生物利用度较差。Et-BV-araU的尿回收率比BV-araU或5'-O-乙酰基BV-araU高近2倍。尽管反应缓慢，但在体外使用大鼠肝提取物和辅助因子证明了Et-BV-araU向BV-araU的转化。5'-O-脂肪族烷基前药对肠道细菌的降解完全耐药，而酯类则部分降解为BVU。由于其代谢稳定性和生物利用度增加，Et-BV-araU可能是一种有用的BV-araU口服前药。
