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

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

THE HYPOXIC CELL RADIOSENSITIZER misonidazole (1 -(2 -nitroimidazol -1 -yl) -3methoxypropan-2-ol; Ro 07-0582, Roche Laboratories; NSC 261037; MISO) is currently undergoing clinical trial of its value in the radiotherapy of tumours in several sites, including cerebral gliomas. Patients with brain tumours frequently require anticonvulsants as part of their general medical care, and phenytoin and phenobarbitone are commonly used.
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)-2,3propandiol; 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).
In this paper we describe the results of a preliminary study designed to investigate the effects of phenytoin on the plasma pharmacokinetics of MISO in man.
Six patients with advanced malignancy of various types and with cerebral metastases received MISO (Roche, 3 g/m2 p.o.) before and after a 14-day course of pheny-  man 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.
The above data clearly indicate a marked effect of a short course of phenytoin on the pharmacokinetics ofMISO. The shortened half-life and reduced AUC for plasma MISO were associated with a concomitant increase in the concentrations of oxidative metabolite DEMIS. These effects are similar to our recent observations with both phenytoin and phenobarbitone in mice and dogs (Workman, 1979;White & Workman, 1980). Phenytoin is known to increase the rate of elimination of many drugs, in experimental animals and in man, by acting as a potent inducer of hepatic microsomal drug-metabolizing enzymes (Conney, 1967;Pirttiaho et al., 1978). Our data indicate that such induction increases the rate of oxidative demethylation of MISO to DE-MIS. Clinical doses of MISO are limited by its neurotoxicity, particularly peripheral neuropathy, and a total dose not exceeding 12 g/m2 is now recommended (Dische et al., 1977;Urtasun et al., 1978). Moreover, there is evidence that the incidence of neuropathy is related to the plasma AUC for MISO, and dose adjustment on the basis of plasma pharmacokinetics has been advocated (Saunders et al., 1978). It therefore appears possible that patients exposed to potent hepatic enzyme-inducing agents, such as phenytoin and phenobarbitone, may be protected to some extent from neurotoxicity by rapid drug clearance. It has not yet been determined, however, whether there is any correlation between phenytoin or phenobarbitone administration and the clinical incidence or severity of MISO neurotoxicity. A study on these lines is in progress.
We should also consider the possible effects of phenytoin on the therapeutic action of MISO. The degree of radiosensitization is a function of tumour MISO concentrationduringirradiation (McNallyetal., 1978) and this is closely related to plasma concentration (Dische et at., 1977;Ash et al., 1979). Current clinical practice is to irradiate 4 h after MISO administration, and we have shown that neither the peak plasma MISO concentration nor the 4 h concentration is affected by phenytoin. In addition, we have previously shown that peak tumour MISO concentrations are not altered in mice pretreated with phenytoin or phenobarbitone (Workman, 1979). We therefore feel it is unlikely that phenytoin administration would affect the radiosensitization of tumour cells by MISO. MISO also exhibits selective cytotoxicity towards hypoxic cells (Hall & Roizin-Towle, 1975;Stratford & Adams, 1978). However, its clinical significance and the effects of enzyme induction on that are unknown.
In conclusion, phenytoin, and possibly other potent liver enzyme-inducing agents such as phenobarbitone, may reduce the incidence of dose-limiting neurotoxicity of MISO without compromising the direct tumour radiosensitization by the drug. The possible effects on the drug's antitumour cytotoxicity are uncertain.