PHARMACOKINETICS, BIODISTRIBUTION, AND STABILITY OF OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATES IN MICE
PHARMACOKINETICS, BIODISTRIBUTION, AND STABILITY OF OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATES IN MICE
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DOI：
10.1073/pnas.88.17.7595
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发表时间：
1991-09-01
影响因子：
11.1
通讯作者：
TANG, JY
中科院分区：
文献类型：
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作者：
AGRAWAL, S;TEMSAMANI, J;TANG, JY
我们描述了一种低聚脱氧核苷酸硫代酸（[S]寡核苷酸）在小鼠体内的药代动力学、生物分布和排泄的初步研究。静脉注射或腹腔注射单剂量（30mg /kg体重）后，在大多数组织中发现[S]寡核苷酸（在每个核苷酸间链上标记S-35）长达48小时。无论何种给药方式，约30%的剂量在24小时内通过尿液排出；排出的[S]寡核苷酸被广泛降解。在血浆、胃、心脏和肠道中，[S]寡核苷酸的降解率仅为15%，而在肾脏和肝脏中，48小时内降解率约为50%。令人惊讶的观察结果是，给药[S]寡核苷酸的链长延长发生在肾脏、肝脏和肠道中。这些结果为反义寡核苷酸的药物开发提供了初步的参数定义。
We describe preliminary studies of the pharmacokinetics, biodistribution, and excretion of an oligodeoxynucleotide phosphorothioate ([S]oligonucleotide) in mice. After either intravenous or intraperitoneal administration of a single dose (30 mg/kg of body weight), [S]oligonucleotide (S-35-labeled at each internucleotide linkage) was found in most of the tissues for up to 48 hr. About 30% of the dose was excreted in urine within 24 hr, irrespective of the mode of administration; the excreted [S]oligonucleotide was found to be extensively degraded. In plasma, stomach, heart, and intestine, the [S]oligonucleotide was degraded by only 15%, whereas in the kidney and liver degradation was about 50% in 48 hr. The surprising observation was made that chain length extension of administered [S]oligonucleotide occurred in kidney, liver, and intestine. These results provide an initial definition of parameters for the pharmaceutical development of antisense oligonucleotides.