Pharmacokinetics of lipophilically different 3-substituted 2,2,5,5-tetramethylpyrrolidine-N-oxyl radicals frequently used as redox probes in in vivo magnetic resonance studies
Pharmacokinetics of lipophilically different 3-substituted 2,2,5,5-tetramethylpyrrolidine-N-oxyl radicals frequently used as redox probes in in vivo magnetic resonance studies
复制标题
体内磁共振研究中常用作氧化还原探针的亲脂性不同的 3-取代 2,2,5,5-四甲基吡咯烷-N-氧基自由基的药代动力学
DOI：
10.1016/j.freeradbiomed.2016.06.008
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发表时间：
2016
影响因子：
7.4
通讯作者：
Yuriko Hirose
中科院分区：
文献类型：
--
作者：
Keizo Takeshita;Shoko Okazaki;Yuriko Hirose
3-羧基、3-氨基甲酰基、3-羟甲基和3-甲氧羰基-2，2，5，5-四甲基吡咯烷-N-氧自由基（分别为CxP、CmP、HMP和MCP）作为氧化还原探针被广泛应用于活体磁共振研究中。这些探针的药代动力学知识是必不可少的氧化还原分析。在中性pH条件下，各探针的表观分配系数（Kp）为MCP>HMP>CmP>CxP。在这些探针被静脉注射后，它们的血液水平以双相方式衰减，即快速衰减然后缓慢衰减。曲线下面积（AUC）的大小顺序为CxP> HMP>MCP≥CmP，除CmP外，与K在相反方向上的大小顺序基本一致。缓慢阶段的衰变在很大程度上影响了这些探针的AUC。这些探针的减少有助于它们在慢相中的衰减。血液水平的二室模型分析、循环伏安法和磁共振成像提供了以下药代动力学信息。探针在中央室和外周室之间的分布迅速达到平衡。除了亲脂性，还原电位也可能参与探针的体内还原速率。亲水性探针，如CxP和CmP，主要经尿液排泄。MCP分布到外周组织，然后迅速减少。HMP是独特的，由于其适度的亲脂性和较慢的还原。在检查的探针中，肝脏和肾脏似乎包含在二室模型分析的中央室中。MCP和HMP迅速分布到脑中。
3-Carboxy-, 3-carbamoyl-, 3-hydroxymethyl, and 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl radicals (CxP, CmP, HMP, and MCP, respectively) have been widely used as redox probes inin vivomagnetic resonance studies. Knowledge of the pharmacokinetics of these probes is essential for redox analyses. The apparent partition coefficient (Kp) of these probes at neutral pH was in the order of MCP>HMP>CmP>CxP. After these probes had been injected intravenously, their blood levels decayed in a bi-phasic manner, namely, fast decay followed by slow decay. The order of the area under the curve (AUC) was CxP»HMP>MCP≥CmP, which roughly coincided with that ofKpin the opposite direction, except for CmP. Decay in the slow phase largely affected the AUC of these probes. The reduction of these probes contributed to their decay in the slow phase. A two-compartment model analysis of blood levels, cyclic voltammetry, and magnetic resonance imaging provided the following pharmacokinetic information. The distribution of the probes between the central and peripheral compartments rapidly reached an equilibrium. In addition to lipophilicity, reduction potential may also be involved in the rate ofin vivoreduction of the probes. Hydrophilic probes, such as CxP and CmP, were predominantly excreted in the urine. MCP was distributed to the peripheral tissues and then rapidly reduced. HMP was unique due to its moderate lipophilicity and slower reduction. Among the probes examined, the liver and kidney appear to be included in the central compartment in the two-compartment model analysis. MCP and HMP were rapidly distributed to the brain.