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

Abstract

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