The Metabolism and Pharmacokinetics of the Hypoxic Cell Radiosensitizer and Cytotoxic Agent, Misonidazole, in C3H Mice

Abstract

Misonidazole, a 2-nitroimidazole, is presently of interest because of its radiosensitizing and toxic effects toward hypoxic tumor cells. Metabolism of misonidazole can lead to a loss of its radiosensitizing ability and the formation of toxic products. The plasma and tissue distribution of misonidazole and various products was studied as a function of time and mode of administration in male C3H mice with KHT tumors. Polarographic measurements of nitro-group species in plasma after intravenous or intraperitoneal misonidazole administration indicated apparent half-lives of 1.0-1.5 hr. With an oral dose, a multicomponent curve was obtained, initial drug levels were one-third lower, and half-lives were two to four times longer than after intravenous or intraperitoneal administration. [14C]misonidazole, labeled in the 2-position of the imidazole ring, was widely distributed to all tissues tested after intraperitoneal or oral administration. Qualitatively, tissue radioactivity followed that observed in the blood for intraperitoneal or oral drug administration. Differences of a factor of 2-3 in total radioactivity could occur between different tissues for the same mode of administration. Paper chromatography of plasma and the water-soluble fraction of spleen, liver, kidney, brain, and KHT tumor tissue showed variations in the proportions of misonidazole, its O-demethylation product, the aminoimidazole, and low-RF products (including glucuronides). There was radioactivity in the gastrointestinal lumen 1 hr after intravenous injection. The metabolites present were different for stomach, small intestine, and large intestine. These studies indicate that differences exist in total drug levels as well as in the proportions of metabolites present in various tissue types. Thus the radiosensitization and toxicity of misonidazole may depend on the particular tissue or tumor under study.