Effects of pretreatment with phenobarbitone and phenytoin on the pharmacokinetics and toxicity of phenytoin on the pharmacokinetics and toxicity of misonidazole in mice.

摘要: Concentrations of the hypoxic cell radiosensitizer misonidazole (MIS) and its O-demethylated metabolite Ro 05-9963 were determined in plasma (or blood), brain tumour after injection 1 g/kg MIS i.p. to control mice or pretreated with 4-6 daily injections phenobarbitone phenytoin. Analysis was by high-performance liquid chromatography (HPLC). Phenobarbitone phenytoin did not alter peak concentration plasma, tumor. However, apparent elimination half-life (t 1/2) for reduced 20-67%, area under curve (AUC) decreased 23-49% tumour. The decrease t 1/2 associated an initially increased concentration. AUC total 2-nitromidazole (MIS + 05-9963) 20-50%. Urinary excretion metabolites accounted 15-42% injected dose, unaltered pretreatment Tumour/plasm brain/plasma ratios MIS, tumour/plasma very similar, but brain/tumour considerably lower. Tissue/plasma acute LD50 from 1.54 1.90 1.78 pretreatment. In addition, either compound shortened duration MIS-induced body temperature. These data suggest that microsomal-enzyme-inducing agents may reduce toxicity without affecting radiosensitization. significance these findings mechanism is also discussed.