Effects of phenytoin, phenobarbital, and ascorbic acid on misonidazole elimination

The kinetics of an oral dose (1.0 gm/m2) of the 2-nitroimidazole radiosensitizer misonidazole were studied in three groups of six healthy subjects before and after a 1-wk course of phenytoin, phenobarbital, or ascorbic acid. Phenytoin and phenobarbital decreased mean misonidazole half-life by 27% and 23% and the decrease was associated with the respective increases in mean clearance of 42% and 31%. The area under the plasma concentration-time curve for the metabolite O-desmethylmisonidazole increased correspondingly. Volume of distribution of misonidazole was unchanged. After treatment with ascorbic acid there was a very small increase in the mean clearance of misonidazole, but there was no significant change in other kinetic parameters. Induction by phenytoin and phenobarbital of the oxidative metabolism of misonidazole is the most likely mechanism responsible. Deliberate induction of a patient's metabolism may help to reduce the neurotoxicity associated with the use of the drug. The efficacy of the radiosensitizing action of the drug is unlikely to be compromised under these conditions since peak plasma concentrations of misonidazole were not affected by treatment with either phenytoin or phenobarbital. The potentiation of the cytotoxic effects of misonidazole by ascorbic acid is unlikely to be related to a direct effect on the oxidative metabolism of misonidazole.