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

British Journal of Cancer
Nature Publishing Group
Publication Date
  • Research Article
  • Biology
  • Design
  • Medicine
  • Pharmacology


Br. J. Cancer (1980) 41, 302 Short Communication PHENYTOIN SHORTENS THE HALF-LIFE OF THE HYPOXIC CELL RADIOSENSITIZER MISONIDAZOLE IN MAN: IMPLICATIONS FOR POSSIBLE REDUCED TOXICITY P. WORKMAN, N. M. BLEEHEN AND C. R. WILTSHIRE* From the MRC Unit and University Department of Clinical Oncology and Radiotherapeutics, Cambridge Received 10 September 1979 THE HYPOXIC CELL RADIOSENSITIZER mis- onidazole (1 - (2 - nitroimidazol - 1 - yl) - 3 - methoxypropan-2-ol; Ro 07-0582, Roche Laboratories; NSC 261037; MISO) is cur- rently 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 pheno- barbitone are commonly used. Previous studies from this laboratory have shown that pretreatment with pheny- toin or phenobarbitone shortens the half- life of MISO in mice and dogs through induction of hepatic drug-metabolizing enzymes, which increase the rate of oxida- tive demethylation of MISO to desmethyl- misonidazole (1-(2-nitroimidazol-1 -yl)-2,3- propandiol; Ro 05-9963, Roche Labora- tories; NSC 261036; DEMIS) (Workman, 1979; White & Workman, 1979). In addi- tion, 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 in- vestigate the effects of phenytoin on the plasma pharmacokinetics ofMISO in man. Six patients with advanced malignancy of various types and with cerebral meta- stases received MISO (Roche, 3 g/m2 p.o.) before and after a 14-day course of pheny- Accepted 22 October 1979 toin (5,5-diphenylhydantoin; Epanutin, Parke Davis; 100 mg p.o. t.d.s.). Six other patients, 3 with cerebral metastases, were similarly assessed as controls without phenytoin administration. There were no additional changes in drug regime during the study which would be likely to in- fluence MISO metabolism.

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