Pharmacokinetics, tissue distribution, and plasma protein binding ratio of bicuculline following intragastric and intravenous administration in rats using ultra‐high‐performance liquid chromatography–tandem mass spectrometry

Abstract Bicuculline is a natural isoquinoline alkaloid that works as a gamma‐aminobutyric acid receptor antagonist. It is widely found in Papaveraceae plants used in traditional Chinese medicines. Bicuculline not only has been shown to have favorable analgesic, memory‐improving, and anxiolytic effects but may also cause adverse effects such as convulsions and epilepsy. A simple, rapid, and sensitive method was developed and validated for the determination of bicuculline in the plasma and tissue samples in rats by ultra‐high‐performance liquid chromatography–tandem mass spectrometry (MS/MS). The chromatographic separation was performed on a Thermo Scientific C18 column. The MS/MS system was operated in the positive multiple reaction monitoring mode, and the precursor–product ion transitions were optimized as m/z 368.0 → 307.1 for bicuculline and as 354.1 → 188.1 for protopine (internal standard). The linearity, accuracy, precision, recovery, and matrix effect were within acceptable limits. The experimental data showed that bicuculline was rapidly absorbed and eliminated in rats, with a moderate plasma protein binding ratio and low bioavailability. The main tissues of distribution were the kidney, liver, and brain; bicuculline could exert its pharmacological effects across the blood–brain barrier. This study has positive implications for the clinical use of herbal medicines containing bicuculline and for further development.