Effect of dose and plasma concentration on liver uptake and pharmacologic activity of a 2′-methoxyethyl modified chimeric antisense oligonucleotide targeting PTEN
Effect of dose and plasma concentration on liver uptake and pharmacologic activity of a 2′-methoxyethyl modified chimeric antisense oligonucleotide targeting PTEN
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DOI：
10.1016/j.bcp.2009.04.013
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发表时间：
2009-08-01
影响因子：
5.8
通讯作者：
Bennett, Frank
中科院分区：
文献类型：
--
作者：
Geary, Richard S.;Wancewicz, Ed;Bennett, Frank
在小鼠中评估了剂量和血浆浓度对肝组织摄取的作用以及使用靶向PTEN的化学修饰的反义寡核苷酸（阿索）产生的反义药理学。单次皮下推注在小鼠中60 mg/kg剂量显示肝脏PTEN mRNA的时间依赖性降低，在48-72 h达到最大，并在给药后20天恢复到接近对照水平。这些药效学与阿索的肝脏浓度非常一致，并且与PTEN阿索从Balb/C小鼠肝脏的缓慢消除（t（1/2）= 8天）一致。如预期的，肝脏中的最高阿索浓度由s.c.在所有测试剂量下缓慢输注。出乎意料的是，24小时s.c.缓慢输注比两种推注给药途径高约两倍。基于血浆浓度分析，似乎1-2 μ g/mL阿索血浆浓度是阈值，如果超过该阈值，则导致强反义作用，并且低于该阈值，即使器官中的整体摄取得到改善，肝脏中的反义药理学也会降低或完全丧失。无义阿索的共同给药竞争肝脏摄取，但出乎意料地增加了活性寡核苷酸（ISIS 116847）的药效学应答，支持抑制非生产性大量摄取途径，同时改善生产性摄取（药效学）。无论无义寡核苷酸与阿索共同施用还是在活性阿索注射前24小时施用，这种竞争效应都是相似的。(C)2009 Elsevier Inc. All rights reserved.
The role of dose and plasma concentration on liver tissue uptake and resulting antisense pharmacology using a chemically modified antisense oligonucleotide (ASO) targeting PTEN was assessed in mice. A single bolus s.c. dose of 60 mg/kg in mice showed a time-dependent reduction in liver PTEN mRNA that was maximal at 48-72 h and returned to near control levels by 20 days after administration. These pharmacodynamics are in good agreement with liver concentrations of ASO and are consistent with slow elimination (t(1/2) = 8 days) of the PTEN ASO from Balb/C mouse liver. As expected, highest ASO concentrations in liver resulted from the s.c. slow infusion at all doses tested. Unexpectedly, the liver EC(50) for the 24-h s.c. slow infusion was approximately twofold higher than the two bolus routes of administration. Based on plasma concentration analysis it appears that 1-2 mu g/mL ASO plasma concentration is a threshold that, if exceeded, results in robust antisense effects and below which there is reduced or complete loss of antisense pharmacology in liver even though bulk uptake in the organ is improved. Co-administration of a nonsense ASO competed for liver uptake, but unexpectedly increased pharmacodynamic response for the active oligonucleotide (ISIS 116847) supporting inhibition of a nonproductive bulk uptake pathway while simultaneously improving productive uptake (pharmacodynamics). This competition effect was similar whether the nonsense oligonucleotide was co-administered with ASO or administered up to 24 h prior to active ASO injection. (C) 2009 Elsevier Inc. All rights reserved.