title: CB 1954 revisited. I. Disposition kinetics and metabolism.
abstract: Although it has been the subject of considerable interest for 15 years, originally as a cytotoxic agent and more recently as a radiosensitizer, there is very little pharmacokinetic information on CB 1954 (2,4-dinitro-5-aziridinylbenzamide). We have developed a rapid high-performance liquid chromatography assay for the drug and its metabolites and applied it to detailed examination of the pharmacokinetics of CB 1954 in mice and dogs. With IV administration a dose of 50 mg/kg gave peak blood concentrations of 100 micrograms/ml in mice, while 25 mg/kg gave peak plasma concentrations of 27 micrograms/ml in dogs. Peak concentrations were 3 to 5-fold lower for the IP route in mice and the oral route in dogs, and the bioavailabilities were 85% and 40%, respectively. Elimination t1/2 values were 1.4-2 h in mice and 2.5-4 h in dogs and were independent of route of administration. Plasma protein binding was 57% but tissue penetration in mice was generally good. Tumour: plasma ratios were 50%-90%, while brain: plasma ratios were lower, at 37%-50%. The parent drug and several metabolites were identified and quantified in mouse urine, the total recovery being 24%-29%, of which 16%-25% was parent drug. The metabolites were also found in the circulation and in tissues. No changes in pharmacokinetics were seen with repeated dosing in mice or with administration of the protective agent phenyl AIC. Phenobarbitone pretreatment produced a small reduction in elimination t1/2, mainly by accelerating aziridine ring removal. Allopurinol increased the blood levels of the 5-amino nitroreduction product. These studies provide a pharmacokinetic basis for interpreting the antitumour activity and toxicity of CB 1954, as well as for the development of new 'mixed-function' sensitizers.
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001388:Aziridines / Q000378:metabolism*; D001389:Azirines / Q000378:metabolism*; D001711:Biotransformation / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004285:Dogs; D004347:Drug Interactions; D007700:Kinetics; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology
chemical_list: D001388:Aziridines; D001389:Azirines; D000493:Allopurinol; C100099:tretazicar; D010634:Phenobarbital