Phenytoin shortens the half-life of the hypoxic cell radiosensitizer misonidazole in man: implications for possible reduced toxicity

Abstract

Previous studies from this laboratory have shown that pretreatment with phenytoin or phenobarbitone shortens the halflife of MISO in mice and dogs through induction of hepatic drug-metabolizing enzymes, which increase the rate of oxidative demethylation of MISO to desmethylmisonidazole (1-(2-nitroimidazol-1 -yl)-2,3-propandiol; Ro 05-9963, Roche Laboratories; NSC 261036; DEMIS) (Workman, 1979; White & Workman, 1979). In addition, pretreatment with these agents significantly reduces the acute lethal effects of MISO in mice (Workman, 1980 Blood samples were taken by venipuncture immediately before MISO administration and at various times after, usually 2, 1, 2, 4, 8, 12, 24 and 30 h. Plasma concentrations of MISO and DEMIS were determined by reverse-phase high-performance liquid chromatography (HPLC) (Workman et al., 1978a). Pharmacokinetic parameters were calculated as described previously (Workman et al., 1978b;Workman, 1979). Statistical analysis was by Student's t test.The pertinent pharmacokinetic data are summarized in Table I. Comparison of the data obtained on the first MISO dose revealed no significant differences between the control and phenytoin groups for any of the kinetic parameters (P> 0 1). This indicated that the pharmacokinetics of MISO were initially very similar for the two groups.For the control group, comparison of the data for the first and second doses of MISO showed that the percentage change for

A randomized study of misonidazole and radiotherapy for grade 3 and 4 cerebral astrocytoma

“…We believe that this is the result of two separate phenomena. We have shown that anticonvulsant therapy with phenytoin (Workman et al, 1980) and phenobarbitone (unpublished) reduce the plasma half-life of MISO because of hepatic microsomal-enzyme induction. The t-of 8-6 h + 0-62 observed in this study, compared to 11*5 h + 3 8 in our experience of patients without brain tumours, suggests that increased drug metabolism may be reducing the peripheral-nerve exposure to MISO.…”

Phenytoin-induced changes in the pharmacokinetics of misonidazole in radiotherapy patients

“…The major dose-limiting toxicity of MISO remains its neurotoxicity, for which the concomitant use of phenytoin has been suggested as a means of reducing this effect (Wasserman et al, 1980;Workman et al, 1980). This study has demonstrated the time-course of the phenytoin-induced change in the pharmacokinetics of MISO in patients receiving radical radiotherapy, and it has shown that the half-life of both T-NITRO and MISO are significantly reduced by it.…”

No significant effect of cimetidine on the pharmacokinetics of misonidazole in man.

“…Studies in this laboratory and elsewhere have shown that the rate of metabolism of misonidazole can be influenced by other drugs such as phenytoin and phenobarbitone (Williams et al, 1983;Workman et al, 1980). Induction of metabolism may reduce the neurotoxicity of misonidazole by decreasing tissue exposure to the drug.…”