PHARMACOKINETICS OF NITROXIDE NMR CONTRAST AGENTS
PHARMACOKINETICS OF NITROXIDE NMR CONTRAST AGENTS
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DOI：
10.1097/00004424-198411000-00015
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发表时间：
1984-01-01
影响因子：
6.7
通讯作者：
DRAYER, BP
中科院分区：
文献类型：
--
作者：
GRIFFETH, LK;ROSEN, GM;DRAYER, BP
在大鼠中评价了含有该部分的化合物的氮氧稳定自由基官能团的药代动力学。以高剂量（1.75毫摩尔/千克）或低剂量（10微摩尔/千克）静脉内注射试剂，定时抽取血液样品并通过EPR光谱法测定氮氧化物浓度。同样，在注射后的规定时间取出各种器官和组织，并均质化以测定氮氧浓度。通过导管收集尿液，用于估计完整氮氧自由基的尿排泄。在高剂量下，各种氮氧自由基表现出一个初始快速处置阶段，随后是一个终末处置阶段，从血液中消失，表现出约5-30分钟的表观对数线性1/2寿命。在低剂量下，获得了不同的结果。血液水平再次显示双相衰减。然而，所有时间的血药浓度均远低于高剂量动力学预测的血药浓度，表明可能存在非线性药代动力学行为。组织匀浆研究显示氮氧信号水平较低或不可检测，表明血液中的低浓度不能通过快速摄取到特定组织中来解释。此外，只有2-6%的氮氧化物可以在尿液中回收。其他研究表明，在低剂量下发生快速体内生物还原，在较高剂量下似乎可饱和。
Pharmacokinetics of the nitroxide stable free radical functionality of compounds containing this moiety were evaluated in the rat. The agents were injected i.v. at either high (1.75 mmoles/kg) or low (10 .mu.moles/kg) dose, and timed blood samples were drawn and assayed for nitroxide concentration by EPR spectrometry. Similarly, various organs and tissues were removed at specified times after injection and homogenized for determination of nitroxide concentration. Urine was collected by catheter for estimation of urinary excretion of the intact nitroxide free radical. At high doses, the various nitroxides exhibited an initial rapid disposition phase, followed by a terminal disposition phase with disappearance from the blood showing apparent log-linear 1/2-lives of about 5-30 min. Generally, 20-60% of the dose was recovered in the urine. At low doses, dissimilar results were obtained. Blood levels again showed biphasic decay. However, blood concentrations at all times were much lower than those predicted by the high dose kinetics, indicating probably nonlinear pharmacokinetic behavior. Tissue homogenates studies showed low or nondetectable levels of nitroxide signals, demonstrating that the low blood concentrations could not be accounted for by a rapid uptake into specific tissues. Moreover, only 2-6% of the nitroxide could be recovered in the urine. Additional studies demonstrated that at the low dose a rapid in vivo bioreduction occurred which appeared to be saturable at the higher dose.