Evaluation of the effects of Citrus aurantium (bitter orange) extract on lamotrigine pharmacokinetics: Insights from in vivo studies in rats.

Citrus aurantium extracts have thermogenic and lipolytic activities and are largely used for weight loss/management. Once epilepsy and obesity are prevalent comorbid conditions and herb-drug interactions can compromise antiepileptic drugs safety, we aimed to evaluate the effects of C. aurantium extract on the pharmacokinetics of lamotrigine (LTG) in rats. In the first pharmacokinetic study, a single oral dose of C. aurantium extract (164 mg/kg; p.o.) was administered with a single oral dose of LTG (10 mg/kg; p.o.). In the following study, the C. aurantium extract was daily administered (164 mg/kg; p.o.) during 14 days followed by a single dose of LTG (10 mg/kg; p.o.) on the 15th day. From the pharmacokinetic analysis, no significant effects were observed after the co-administration of C. aurantium extract and LTG. After the 14-day pre-treatment period, the main effects of the extract were limited to a significantly decrease in the time to reach peak drug concentration (tmax; p < 0.05). Considering the minor effects induced by C. aurantium extract on the pharmacokinetics of LTG in rats, no relevant interactions are expected to occur in the clinical practice. Notwithstanding, C. aurantium safety in patients under LTG therapy should be further assessed in controlled clinical trials.