Abstract
Many patients being treated for primary and secondary brain tumors receive phenobarbital as an anticonvulsant. The effects of chronic oral administration of phenobarbital on the antitumor activity of BCNU, CCNU and PCNU against the intracerebral 9L tumor in rats were determined. Phenobarbital pretreatment eliminated the antitumor activity of BCNU and reduced the activity of PCNU and CCNU. Pretreatment with phenytoin, sodium methylprednisolone succinate and dexamethasone had little or no effect. Pharmacokinetic data for i.v. BCNU in the plasma of rats showed an increase in drug clearance for phenobarbital pretreated animals, compared to a control group. Larger differences were observed when BCNU was given i.p. The half-life of BCNU in sera from pretreated and control group rats was similar. Finally, the in vitro rate of BCNU disappearance in 9000 X g supernatants and microsomes from the livers of pretreated rats was 5-fold faster than the rate of disappearance of BCNU in supernatants from normal animals. We conclude that the chronic oral administration of phenobarbital induces a change in liver enzymes, which accelerates the clearance of BCNU, thereby reducing the antitumor activity of BCNU and the other nitrosoureas. Phenobarbital pretreatment reduces systemic BCNU toxicity.
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