Jones R J, Bischofberger N
Gilead Sciences, Foster City, CA 94404, USA.
Antiviral Res. 1995 May;27(1-2):1-17. doi: 10.1016/0166-3542(95)00011-a.
Nucleotides have shown interesting biological activities in a wide variety of antiviral, antiproliferative, immunomodulatory and other biological assays, and they present promising drug candidates. Because of their negative charge(s) nucleotides suffer from some disadvantages which can be successfully overcome by the utilization of nucleotide prodrugs. Nucleotide prodrugs were successfully used to increase oral absorption of nucleotides in vivo. By taking advantage of intracellular triggers (reducing potential, enzyme activity, pH), nucleotide prodrugs can be used in vitro for the intracellular delivery of the nucleotide resulting in enhanced potency and in some cases enhanced selectivity. Nucleotide prodrugs have also been utilized for tissue specific delivery of the nucleotides in vivo resulting in altered selectivity and reduced toxicity. For nucleotide prodrugs, their ultimate intended use is (in most cases) in vivo for the treatment of a disease. Thus, it is important to incorporate adequate assays and design criteria into any prodrug effort. In vivo systems are complicated because of metabolism, excretion and tissue distribution of the prodrug and the parent. Thus, results of in vitro assays have to be interpreted cautiously because they may be unsuitable predictors of the in vivo situation.
核苷酸在多种抗病毒、抗增殖、免疫调节及其他生物学检测中表现出有趣的生物学活性，并且它们呈现出有前景的候选药物。由于带有负电荷，核苷酸存在一些缺点，而利用核苷酸前药可成功克服这些缺点。核苷酸前药已成功用于提高核苷酸在体内的口服吸收。借助细胞内触发因素（还原电位、酶活性、pH值），核苷酸前药可在体外用于核苷酸的细胞内递送，从而提高效力，在某些情况下还能提高选择性。核苷酸前药也已用于核苷酸在体内的组织特异性递送，从而改变选择性并降低毒性。对于核苷酸前药，其最终预期用途（在大多数情况下）是在体内用于治疗疾病。因此，在任何前药研发工作中纳入适当的检测方法和设计标准都很重要。由于前药及其母体的代谢、排泄和组织分布，体内系统很复杂。因此，体外检测结果必须谨慎解读，因为它们可能无法准确预测体内情况。
