2016 Volume 42 Issue 6 Pages 389-399
The purpose of this study was to evaluate interactions between antiepileptic drugs in patients with refractory epilepsy. Firstly, to compare the extent of enzyme induction among hepatic enzyme inducers (phenytoin (PHT), phenobarbital (PB), and carbamazepine (CBZ)), we analyzed the effects of these drugs on the pharmacokinetics of clobazam (CLB) and lamotrigine (LTG). Patients using PHT had significantly lower concentration /dose ratios of CLB and LTG than patients using PB or CBZ. However, an additive inducing effect was not observed when PHT was combined with CBZ and/or PB. Secondly, we retrospectively analyzed 2,724 adult patients and 1,826 pediatric patients treated with valproic acid (VPA) to evaluate whether drug interactions affected the incidence of hyperammonemia. We found that the plasma ammonia level increased markedly in a VPA dose-dependent manner. It was significantly elevated in patients who also used hepatic enzyme inducers, and concomitant administration of PHT was associated with the highest risk of hyperammonemia. Thus, PHT strongly induced CYPs and UGTs, and concomitant administration of PHT accelerated VPA metabolism, resulting in an increase of the ammonia level. These findings could be useful for predicting and minimizing drug interactions in patients receiving polypharmacy with antiepileptic drugs.
