PHARMACOKINETICS OF THE NITROXIDE PCA MEASURED BY IN-VIVO EPR

PCA (2,2,5,5-tetramethylpiperidine-1-oxyl-3-carboxylic acid) is a rela tively stable free radical which has been shown to be useful as a cont rast agent for nuclear magnetic resonance imaging and as an imaging/sp ectroscopy agent for EPR. In an effort to determine the role of the li ver and kidney in the pharmacokinetics of PCA, using low frequency in vivo EPR spectroscopy, we followed the clearance of PCA after intraven ous injection in mice: under normal conditions, with a restricted bloo d supply to the kidneys, after exposure to an acute hepatotoxin CCl4, and after exposure to lipopolysaccharide (endotoxin). The observed pha rmacokinetics fit a two-component model. The fast component was dramat ically 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 gr oups treated by renal blood flow occlusion, CCl4, or LPS, compared wit h the control group. In conclusion, we find that the pharmacokinetics of PCA need to be completely described in term of a two component mode l: 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 distribu tion; the slow component is related to the bioreduction of the nitroxi de. In addition to the liver other tissues can also effectively metabo lize PCA. Tile effect of oxygen on the rate of metabolism is modest at most.