Purpose: The present study aimed to establish and validate an isotope-dilution-UHPLC-MS/MS method for the determination of perampanel (PER) concentration and investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of PER in rats.
Methods: The rats were randomly divided into the control (0.5% CMC-Na) and experimental groups (ESL, 72 mg/kg), with six rats in each group. A single dose of PER (1 mg/kg) was administered after a week of repetitive 0.5% CMC-Na or ESL dosing (72 mg/kg); then, plasma samples were collected. Perampanel-d₅ (PER-d₅) was used as the internal standard (IS), liquid-liquid extraction of plasma samples was carried out using ethyl acetate, and chromatographic separation was carried out on a Titank C18 column (2.1 mm × 50 mm, 3.0 μm) using a gradient mobile phase consisting of 0.1% formic acid and acetonitrile at a flow rate of 0.3 mL/min.
Results: PER had good linearity (0.3– 600 ng/mL, r > 0.999), and the accuracy, precision, recovery rate, and matrix effects (ME) met the Food and Drug Administration (FDA) guidelines. Compared to the control group, the area under the curve AUC_0→t, AUC_0→∞, and Cmax of PER in the experimental group decreased by 30.28%, 30.34%, and 46.94%, respectively, and CL increased by 32.08%.
Conclusion: ESL could induce the metabolism of PER in rats and decreases plasma exposure to PER. Thus, the concomitant treatment with ESL may require a high dose of PER to achieve the same efficacy.
Keywords: perampanel, eslicarbazepine acetate, pharmacokinetics, UHPLC-MS/MS, drug-drug interactions, Sprague–Dawley rats