This article provides an analysis of the degree of agreement between in vivo interaction studies performed in patients with
epilepsy and healthy individuals, and in vitro studies which identified the
cytochromes P450 (CYP) inhibited by
felbamate and those involved in its metabolism. In vitro studies show that
felbamate is a substrate for
CYP3A4 and
CYP2E1. Compounds which induce
CYP3A4 (e.g.
carbamazepine,
phenytoin and
phenobarbital) increase
felbamate clearance. However, the
CYP3A4 inhibitors gestodene,
ethinyl estradiol and
erythromycin have little or no effect on
felbamate trough plasma concentrations, consistent with the fact that the pathway is relatively minor for
felbamate under normal (non-induced) conditions.
Felbamate has been shown in vitro to inhibit
CYP2C19, which would account for its effect on
phenytoin clearance, and it had been postulated that this could be the mechanism underlying the reduced clearance of
phenobarbital by
felbamate. Although not yet examined in vitro,
felbamate appears to induce the activity of
CYP3A4, which would account for it reducing plasma concentrations of
carbamazepine or the
progestin gestodene. Interactions involving
felbamate and non-CYP450-mediated metabolic pathways have also been addressed in clinical studies. The reduction in
valproic acid (
valproate sodium) clearance by
felbamate is through the inhibition of beta-oxidation. No clinically relevant pharmacokinetic interactions were noted between
felbamate and
lamotrigine,
clonazepam,
vigabatrin, nor the active monohydroxy metabolite of
oxcarbazepine. Information on the mechanisms underlying
felbamate's
drug:drug interaction profile permits predictions to be made concerning the likelihood of interactions with other compounds.