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

Kinetic Aspects of Misonidazole and its Major Metabolite in Radiotherapy

“…Plasma elimination half-lives of misonidazole in our patients receiving anticonvulsant therapy ranged between 4.1 and 8.9 h with a mean value of 6.2 h, which was comparable with the half-life values between 5.4 and 7.9 h reported earlier in similar patients (Workman et al , 1980;Williams et al, 1983;Matheson et al, 1984). Metabolic induction of misonidazole could be important, as administration of phenytoin and phenobarbitone might be associated with a reduced neurotoxicity of misonidazole in man (Moore et al, 1981;Williams et al, 1983). In one of our patients with brain glioma (C19) without anticonvulsant therapy a plasma elimination half-life of misonidazole of 9.5 h was measured, which is in agreement with a mean half-life of 10-12 h normally found in patients not enzymically induced Workman et al , 1978).…”

“…C19 was higher than the mean value of 8.9 mg/1 in the group of patients receiving 1.3 g of misonidazole/m2. The plasma levels of desmethylmisonidazole in patients nos Cl-C5 receiving misonidazole in combination with anticonvulsant therapy have to be considered separately, since the liver microsomal-enzyme-inducing drugs phenobarbitone and phenytoin were proven to cause an increase of the plasma desmethylmisonidazole levels and a decrease of the plasma elimination half-life of misonidazole, while plasma misonidazole levels 3-4 h after intake remained unchanged (Workman et al , 1980;Moore et al , 1981;Williams et al , 1983). In our patients with anticonvulsant comedication plasma desmethylmisonidazole levels indeed were higher than those reported in patients without anticonvulsant medication (Notter et al , 1980).…”

Misonidazole neurotoxicity in rats: Part 11

“…Moore et al (6) studied the effects of diphenylhydantoin on the pharmacokinetics of MISO in patients and found that while the half-life of MISO was significantly reduced, peak plasma levels were unchanged. We found that 40 mg/kg of diphenylhydantoin reduced the half-life of MISO in rats (unpublished results).…”