Zendegui J G, Vasquez K M, Tinsley J H, Kessler D J, Hogan M E
Triplex Pharmaceutical Corporation, The Woodlands, TX 77380.
Nucleic Acids Res. 1992 Jan 25;20(2):307-14. doi: 10.1093/nar/20.2.307.
Development of oligonucleotide derivatives as therapeutic agents requires an understanding of their pharmacokinetic behavior. The in vivo disposition and stability of a prototype of such compounds are reported here. The compound studied, a relatively G-rich 38 base 3' phosphopropyl amine oligonucleotide (TFO-1), was cleared from the circulation with a half-life of approximately 10 minutes, displaying distribution kinetics consistent with a two compartment model. TFO-1 was also readily absorbed into circulation from the peritoneal cavity. All tissues examined except brain accumulated the compound reaching concentrations calculated to be in the micromolar range. TFO-1 was found to be stable in circulation and in tissues in that a large fraction of intact material was detected 8 hours after injection, as assessed by gel electrophoresis. Approximately 20-30% of the injected dose was excreted in the urine over an 8 hour period. These results suggest that G-rich oligonucleotides, minimally modified at the 3' end, are relatively stable in vivo and have distribution kinetics favorable to use as therapeutic agents.
将寡核苷酸衍生物开发为治疗剂需要了解它们的药代动力学行为。本文报道了这类化合物一种原型的体内处置和稳定性。所研究的化合物是一种相对富含鸟嘌呤的38个碱基的3' 磷丙基胺寡核苷酸（TFO-1），其从循环系统中清除的半衰期约为10分钟，显示出符合二室模型的分布动力学。TFO-1也很容易从腹腔吸收进入循环系统。除大脑外，所有检测的组织都积累了该化合物，达到计算为微摩尔范围的浓度。通过凝胶电泳评估发现，TFO-1在循环系统和组织中是稳定的，因为在注射8小时后检测到很大一部分完整物质。在8小时内，约20 - 30%的注射剂量经尿液排出。这些结果表明，在3' 端进行最小修饰的富含鸟嘌呤的寡核苷酸在体内相对稳定，并且具有有利于用作治疗剂的分布动力学。
