The interaction of primidone with its metabolites and other antiepileptic drugs is a complex, pertinent, and little investigated subject. Phenobarbital, one of the major metabolites of primidone, usually appears in the serum of patients 24 to 96 hours after initiation of therapy. The conversion of primidone to phenobarbital and the factors that may influence this ratio is an important consideration in patient care. The influence of diphenylhydantoin on the phenobarbital:primidone ratio has been investigated in patients examined in our clinic. Fifteen patients taking only primidone have a low ratio (1.05 ± 0.20); two of these had been taking primidone for several years and have no detectable amounts of phenobarbital. The conversion ratio of 44 patients taking primidone and diphenylhydantoin is significantly higher (4.35 ± 0.50). Apparently diphenylhydantoin promotes the induction of an enzyme system responsible for the oxidation of primidone.
Fincham RW, Schottelius DD, Sahs AL. The Influence of Diphenylhydantoin on Primidone Metabolism. Arch Neurol. 1974;30(3):259–262. doi:10.1001/archneur.1974.00490330067012