Watanabe Tanya A, Geary Richard S, Levin Arthur A
Isis Pharmaceuticals, Inc., Carlsbad, CA 92008, USA.
Oligonucleotides. 2006 Summer;16(2):169-80. doi: 10.1089/oli.2006.16.169.
In vitro ultrafiltration was used to determine the plasma protein-binding characteristics of phosphorothioate oligonucleotides (PS ODNs). Although there are binding data on multiple PS ODNs presented here, the focus of this research is on the protein-binding characteristics of ISIS 2302, a PS ODN targeting human intercellular adhesion molecule-1 (ICAM-1) mRNA, which is currently in clinical trials for the treatment of ulcerative colitis. ISIS 2302 was shown to be highly bound (> 97%) across species (mouse, rat, monkey, human), with the mouse having the least degree of binding. ISIS 2302 was highly bound to albumin and, to a lesser, extent alpha2-macroglobulin and had negligible binding to alpha1-acid glycoprotein. Ten shortened ODN metabolites (8, 10, and 12-19 nucleotides [nt] in length, truncated from the 3' end) were evaluated in human plasma. The degree of binding was reduced as the ODN metabolite length decreased. Three additional 20-nt (20-mer) PS ODNs (ISIS 3521, ISIS 2503, and ISIS 5132) of varying sequence but similar chemistry were evaluated. Although the tested PS ODNs were highly bound to plasma proteins, suggesting a commonality within the chemical class, these results suggested that the protein-binding characteristics in human plasma may be sequence dependent. Lastly, drug displacement studies with ISIS 2302 and other concomitant drugs with known protein-binding properties were conducted to provide information on potential drug interactions. Coadministered ISIS 2302 and other high-binding drugs evaluated in this study did not displace one another at supraclinical plasma concentrations and, thus, are not anticipated to cause any pharmacokinetic interaction in the clinic as a result of the displacement of binding to plasma proteins.
采用体外超滤法测定硫代磷酸酯寡核苷酸（PS ODNs）的血浆蛋白结合特性。尽管本文给出了多种PS ODNs的结合数据，但本研究的重点是ISIS 2302的蛋白结合特性，ISIS 2302是一种靶向人细胞间黏附分子-1（ICAM-1）mRNA的PS ODN，目前正处于治疗溃疡性结肠炎的临床试验阶段。结果表明，ISIS 2302在不同物种（小鼠、大鼠、猴子、人类）中均有高度结合（>97%），其中小鼠的结合程度最低。ISIS 2302与白蛋白高度结合，与α2-巨球蛋白的结合程度次之，与α1-酸性糖蛋白的结合可忽略不计。在人血浆中评估了10种缩短的ODN代谢物（长度为8、10和12 - 19个核苷酸[nt]，从3'端截断）。随着ODN代谢物长度的缩短，结合程度降低。评估了另外三种序列不同但化学性质相似的20 nt（20聚体）PS ODNs（ISIS 3521、ISIS 2503和ISIS 5132）。尽管所测试的PS ODNs与血浆蛋白高度结合，表明该化学类别内具有共性，但这些结果表明人血浆中的蛋白结合特性可能依赖于序列。最后，进行了ISIS 2302与其他具有已知蛋白结合特性的伴随药物的药物置换研究，以提供潜在药物相互作用的信息。在本研究中共同给药的ISIS 2302和其他高结合药物在超临床血浆浓度下不会相互置换，因此预计在临床上不会因与血浆蛋白结合的置换而引起任何药代动力学相互作用。
