Comparison of the fate of misonidazole (RO 07-0582) and its metabolite desmethylmisonidazole (RO 05-9963), two hypoxic cell radiosensitizers: penetration properties in tumor bearing rats.

1. The hypoxic cell radiosensitizers misonidazole (RO 07-0582; Miso) and desmethylmisonidazole (RO 05-9963; Desmiso) were administered by the intraperitoneal route at a single dose of 250 mg/kg to Wistar rats bearing a chemo induced sarcoma. Plasma, tissues and urinary concentrations were measured by HPLC analysis. Pharmacokinetic parameters of the two drugs were compared. 2. The time for diffusion of both drugs in different tissues and the tumor was very short: plasmatic and tissular peak levels were obtained 10 to 30 min after injection. 3. Miso and Desmiso levels, measured in brain, reached 51% and 5% respectively of their plasma concentrations. This observation suggests that Desmiso may penetrate the central nervous system to a lesser extent than the parent compound. 4. No significant differences of both drug concentrations were observed between the central and the peripheral zone of the tumor. However, the half-life of nitroimidazole drugs in the center of tumor was much shorter than in the peripheral zone, demonstrating radiosensitizing properties. 5. Compared with Miso, a greater proportion of injected Desmiso is recovered in the urine: 34% for Desmiso and 22,5% for Miso.