THE EFFECT OF NEFAZODONE ON THE SINGLE-DOSE PHARMACOKINETICS OF PHENYTOIN IN HEALTHY MALE-SUBJECTS

The effect of nefazodone on the pharmacokinetics of a single dose of p henytoin was evaluated in 18 healthy male subjects. The subjects recei ved a single oral dose of phenytoin, 300 mg, on day 1 of the study and the pharmacokinetic profile of the drug was determined. After a washo ut period followed by oral administration of nefazodone, 200 mg twice daily for 7 days, subjects received a single dose of phenytoin, 300 mg concomitantly with the morning dose of nefazodone on day 12, and the pharmacokinetic profile of phenytoin was determined again. Minimum pla sma concentrations of nefazodone and its main metabolites indicated th at steady state had been achieved for nefazodone when phenytoin and ne fazodone were administered concomitantly. No significant differences w ere demonstrated between mean single-dose pharmacokinetic parameters o f phenytoin when administered alone on day 1 and concomitantly with ne fazodone on day 12. Assessment of adverse events, clinical laboratory parameters, electrocardiograms, vital signs, and physical examinations indicated that concomitant administration of nefazodone and phenytoin was safe and well tolerated. These data demonstrate that nefazodone d oes not affect the single-dose pharmacokinetics of phenytoin, but do n ot preclude the possibility of such an interaction when phenytoin is a dministered on a long-term basis. A clinically significant interaction between nefazodone and phenytoin through a pharmacokinetic mechanism is unlikely.