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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Novel Pharmacokinetic Measurement Using Electron Paramagnetic Resonance Spectroscopy and Simulation of in Vivo Decay of Various Nitroxyl Spin Probes in Mouse Blood

Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

A novel approach to measure the time course of paramagnetic spin probe concentration in the circulating blood of a living mouse using X-band (9.4 GHz) electron paramagnetic resonance spectrometer is described. Using this technique, the pharmacokinetics of several nitroxyl spin probes was examined. The decay profiles were also independently simulated using pharmacokinetic properties as well as redox-mediated factors responsible in converting the nitroxyl radicals to the corresponding hydroxylamines. Finally, suitability of nitroxyl radicals as the probes of in vivo redox status and for radioprotection was described. The studies indicate that the six-member piperidine nitroxyls are suitable for estimating redox status in the circulation, whereas the five-member pyrrolidine nitroxyl radicals are suited for tissue redox status determination. For selective protection against radiation of normal tissues rather than cancer/tumor, efficient reoxidation of the hydroxylamine in normal tissue is preferable. Simulation results showed that for carbamoyl-PROXYL, only administration of the radical form might give radioprotection and not the hydroxylamine. However, the hydroxylamine form of TEMPOL, i.e., TEMPOL-H, may give similar radioprotection as the radical form due to efficient reoxidation in vivo.

Address correspondence to: Dr. Murali C. Krishna, Bldg. 10, Rm B3B69, National Institutes of Health, Bethesda, MD 20892-1002. E-mail: murali{at}helix.nih.gov

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