EFFECTS OF FELBAMATE ON THE PHARMACOKINETICS OF PHENOBARBITAL

The effects of felbamate on the pharmacokinetics of phenobarbital and one of its main metabolites, parahydroxyphenobarbital, were assessed i n a parallel-group, placebo-controlled, double-blind study, in 24 heal thy volunteers. Pharmacokinetic parameters of phenobarbital and parahy droxyphenobarbital were determined from plasma and urine samples obtai ned after 28 days of daily administration of 100 mg phenobarbital and after a further 9 days of phenobarbital plus 2400 mg/day felbamate or placebo. Felbamate increased phenobarbital values for area under the p lasma concentration-time curve from 0 to 24 hours and maximum concentr ation by 22% and 24%, respectively, whereas placebo had no effect. Thi s increase was caused by a reduction in parahydroxylation of phenobarb ital and possibly through effects on other metabolic pathways. Because felbamate inhibits the S-mephenytoin hydroxylase (CYP2C19) isozyme in vitro, it appears that phenobarbital hydroxylation is mediated in par t by this isozyme.