Comprehensive pharmacokinetics and ADME evaluation of Akuamma alkaloids

The seeds of the akuamma tree (Picralima nitida) have been traditionally used to treat fever and pain. The seed contains at least five major alkaloids: akuammine, akuammicine, akuammiline, picraline, and pseudo-akuammigine, which possess diverse pharmacological effects, including analgesic, anti-inflammatory, and mood-enhancing properties. The present study aimed to assess in vitro and in vivo pharmacokinetics of akuamma alkaloids using a sensitive ultra-performance liquid chromatography−tandem mass spectrometry (UPLC-MS/MS)-based bioanalytical method. The method was found to be simple, sensitive, and rapid, effectively evaluating absorption, distribution, metabolism, and oral/intravenous pharmacokinetics in male Sprague-Dawley rats. These alkaloids demonstrated high permeability using human colorectal adenocarcinoma cell monolayers. Akuammine and akuammiline showed half-lives of 13.5 and 30.3 min in reduced nicotinamide adenine dinucleotide phosphate-supplemented rat liver microsomes. Pseudo-akuammigine showed the highest plasma protein binding, followed by the other alkaloids. Oral dosing of the ground seed suspension revealed significant systemic exposure of only akuammine, with low oral bioavailability. This research is the first comprehensive report on the ADME properties and pharmacokinetics of akuamma alkaloids, providing critical insights for developing these compounds as potential phytotherapeutic agents for pain management or other medicinal uses.