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The method shows high sensitivity, very good precision and accuracy with short run time.Simple protein precipitation as sample preparation approach with good recovery from plasma/brain homogenate.The method found to be linear from 0.4 to 400 ng/mL in both biomatrices.Application to pharmacokinetic and brain uptake study of perampanel in SD rats.Perampanel (PER) is a novel AMPA receptor antagonist for antiepileptic therapy and is prospective for the treatment of other neurological disorders. A highly sensitive and rapid UHPLC–QTOF-MS method was developed for the quantification of PER in plasma/brain homogenate of SD rat with alogliptin as an internal standard (IS). Chromatographic separation was carried out on an Acquity UPLC HSS Cyano column (100 mm × 2.1 mm, 1.8 μm) using gradient mobile phase consisting of 0.1% formic acid and acetonitrile at a flow rate of 0. 4 mL/min. Sample preparation was carried out by a simple protein precipitation method. The mass spectrometric analysis of target ions at [M + H]+m/z 350.1288 for PER and m/z 340.1779 for IS was monitored with extracted ion chromatography. The developed analytical method meets the US-FDA and EMA bioanalytical guidelines and was found to be precise, accurate, selective and rugged. It exhibited good sensitivity (0.4 ng/mL) and linearity over a range of 0.4–400 ng/mL in both the bio-matrices. The method was successfully applied to pharmacokinetics and brain uptake study of PER after oral administration to SD rats. The study results showed PER has penetrated the blood-brain barrier, brain to plasma ratio (Kp) was found to be 0.62 ± 0.05 and its rapidly eliminated from the brain.