Metabolic binding of misonidazole to mouse tissues. Comparison between labels on the ring and side chain, and the production of tritiated water.
The 2-nitroimidazole, misonidazole, is of current interest as an imaging agent for hypoxic regions in tumors and in vascular disease such as stroke. The basis of this technique is the reductive activation and binding of nitroheterocycles which is much more efficient in the absence of oxygen. The appropriate molecular location for an active isotope on the nitroheterocyclic probe depends on the nature of the metabolites retained in tissues after the parent drug has been cleared. Previous studies with tumor cells in vitro indicated that a ring label (2-14C) and a side-chain label (3H) were retained equally efficiently in the acid-insoluble fraction, whereas 1.5 to 3 times more side-chain label was retained in the total pool (acid soluble plus acid insoluble) of metabolites in several normal murine tissues. We show here that the excess side-chain label in six normal tissues, plasma and EMT6 tumors was found entirely in the acid-soluble fraction as a volatile component. This volatile component was tentatively identified as tritiated water. It appeared that, in general, molecular products of misonidazole metabolism were retained in mouse tissues, with the exceptions that a small excess of ring label was found in liver and heart and that tritiated water appeared in the acid-soluble fraction of all tissues. Tritiated water would not be important in imaging studies but could be a factor in studies in which scintillation counting of tritiated nitroheterocyles is used.
Franko
A J
AJ
Radiobiology, Cross Cancer Institute, Edmonton, Alberta, Canada.
Raleigh
J A
JA
Sutherland
R G
RG
Soderlind
K J
KJ
D000332:Aerobiosis; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D000860:Hypoxia; D051379:Mice; D008807:Mice, Inbred BALB C; D008920:Misonidazole / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000378:metabolism*; D012995:Solubility; D014018:Tissue Distribution
D008920:Misonidazole