Plasma pharmacokinetics, biodistribution, excretion, and metabolism of four modified 20-mer antisense oligonucleotides targeted to human intercellular adhesion molecule-1 mRNA have been characterized in rats and compared with a first-generation phosphorothioate oligodeoxynucleotide (PS ODN), ISIS 2302. The modified oligonucleotides contained 2'-O-(2-methoxyethyl) (2'-O-MOE) ribose sugar modifications on all or a portion of the nucleotides in the antisense sequence. The 2'-O-MOE-modified oligonucleotides were resistant to nuclease metabolism in both plasma and tissue. In general, plasma pharmacokinetics was not substantially altered by addition of the 2'-O-MOE modification to PS ODN. Thus, plasma clearance was dominated by distribution to tissues, broadly, with less than 10% of the administered dose excreted in urine or feces over 24 h. However, the 2'-O-MOE modification combined with the phosphodiester (PO) backbone exhibited 10-fold more rapid plasma clearance, with approximately 50% of the dose excreted in urine as intact oligonucleotide. Consistent with its rapid and extensive excretion, the PO 2'-O-MOE modification distributed to very few organs in any substantial amount with the exception of the kidney. Oligonucleotides that contained phosphorothioate backbones were highly bound to plasma proteins. Indeed, the primary characteristic that resulted in the most marked alterations in pharmacokinetics appeared to be the affinity and capacity of these compounds to bind plasma proteins. A balance of greater stability supplied by the 2'-O-MOE modification together with maintenance of plasma protein binding appears to be necessary to ensure favorable pharmacokinetics of this new generation of antisense oligonucleotides.

中文翻译：

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2'-O-（2-甲氧基乙基）修饰的寡核苷酸类似物在大鼠中的药代动力学特性。

已经在大鼠中鉴定了靶向人细胞间粘附分子-1 mRNA的四个修饰的20-mer反义寡核苷酸的血浆药代动力学，生物分布，排泄和代谢，并将其与第一代硫代磷酸酯寡脱氧核苷酸（PS ODN）ISIS 2302进行了比较。寡核苷酸在反义序列的全部或部分核苷酸上包含2'-O-（2-甲氧基乙基）（2'-O-MOE）核糖修饰。2'-O-MOE修饰的寡核苷酸在血浆和组织中均对核酸酶代谢具有抗性。通常，通过向PS ODN添加2'-O-MOE修饰基本上不会改变血浆药代动力学。因此，血浆清除率主要分布在组织中 在24小时内，只有不到10％的给药剂量从尿液或粪便中排出。但是，将2'-O-MOE修饰与磷酸二酯（PO）骨架结合后，血浆清除速度提高了10倍，大约有50％的剂量作为完整的寡核苷酸从尿液中排出。与其快速而广泛的排泄相一致，PO 2'-O-MOE修饰物以相当大的量分布于极少数的器官，肾脏除外。包含硫代磷酸酯骨架的寡核苷酸与血浆蛋白高度结合。实际上，导致药代动力学最明显改变的主要特征似乎是这些化合物结合血浆蛋白的亲和力和能力。2'提供更大稳定性的平衡