title: Pharmacology of the mixed-function radio- and chemosensitizers CB 1954 and RSU 1069.
abstract: We have studied the pharmacokinetics and metabolism in mice of CB 1954 and RSU 1069. Containing both nitro and alkylating (aziridine) substituents, these are lead compounds in the mixed-function analogue series, which show particular promise for sensitizer development. Both compounds are degraded extensively, via pathways including nitro reduction, aziridine ring hydrolysis and aziridine ring removal RSU 1069 (plasma t1/2 22 min) was eliminated more rapidly than CB 1954 (blood t1/2 84 min), and the AUC was three times less. Tissue/plasma ratios tended to be rather lower than those for simple nitroimidazoles of intermediate lipophilicity, which are usually close to 100%. With CB 1954, for example, tumor/plasma and brain/plasma ratios were 58 and 37% respectively, whereas with RSU 1069 the values were 29 and 26%. Nevertheless, tumor concentrations were consistent with potent sensitization. There is, however, scope for pharmacokinetic fine-tuning to modify tissue penetration as appropriate.
mesh_terms: D000818:Animals; D001388:Aziridines / Q000378:metabolism*; D001389:Azirines / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D008920:Misonidazole / Q000031:analogs & derivatives*; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000378:metabolism*; D013997:Time Factors
chemical_list: D001388:Aziridines; D001389:Azirines; D011838:Radiation-Sensitizing Agents; C100099:tretazicar; C041712:1-(2-nitro-1-imidazolyl)-3-aziridino-2-propanol; D008920:Misonidazole