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Pharmacokinetics of the Nitroxide Pca Measured By in Vivo Epr

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PCA (2,2,5,5-tetramethylpiperidine-1-oxyl-3-carboxylic acid) is a relatively stable free radical which has been shown to be useful as a contrast agent for nuclear magnetic resonance imaging and as an imaging/spectroscopy agent for EPR. In an effort to determine the role of the liver and kidney in the pharmacokinetics of PCA, using low frequency in vivo EPR spectroscopy, we followed the clearance of PCA after intravenous injection in mice: under normal conditions, with a restricted blood supply to the kidneys, after exposure to an acute hepatotoxin CCl4, and after exposure to lipopolysaccharide (endotoxin). The observed pharmacokinetics fit a two-component model. The fast component was dramatically affected when the renal vessels were restricted, while CCl4 and endotoxin had a smaller but significant effect. The half times of the slow components were not significantly different (p > 0.05) in the groups treated by renal blood flow occlusion, CCl4, or LPS, compared with the control group. In conclusion, we find that the pharmacokinetics of PCA need to be completely described in term of a two component model: the fast component of the decay is mainly due to the elimination by the kidneys and also is affected by the time for the initial distribution; the slow component is related to the bioreduction of the nitroxide. In addition to the liver other tissues can also effectively metabolize PCA. The effect of oxygen on the rate of metabolism is modest at most.

Affiliations: 1: 'EPR Center, Department of Radiology, Dartmouth Medical School, HB 7252, 308 Strasenburgh Hall, Hanover, NH 03755, USA, Permanent address: the First Department of Surgery, Kagawa Medical School, 1750-1 Ikenobe Miki, Kagawa, 761-07 Japan; 2: Department of Pharmaceutical Sciences, Laboratory of Medicinal Chemistry, University of Louvain, B-1200 Brussels, Belgium; 3: EPR Center, Department of Radiology, Dartmouth Medical School, HB 7252, 308 Strasenburgh Hall, Hanover, NH 03755, USA


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