Pharmacokinetics, Tissue Distribution, and Excretion of 9‐Methylfascaplysin, a Potential Anti‐Alzheimer's Disease Agent

ABSTRACT 9‐Methylfascaplysin, a derivative of the marine natural product fascaplysin, has shown promising anti‐ Alzheimer's disease (AD) potential through its anti‐β‐amyloid (Aβ) neuroprotective effects. However, the pharmacokinetics (PK) of 9‐methylfascaplysin, crucial for its preclinical evaluation, have not been thoroughly studied. In this study, we developed and validated a sensitive and accurate ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) method for the quantification of 9‐methylfascaplysin in rat plasma. The method demonstrated a lower limit of detection (LLOD) of 1 ng/mL and a linear quantification range of 5–2000 ng/mL. The PK study in rat plasma was conducted. After intragastric administration, the plasma concentration of 9‐methylfascaplysin peaked at a maximum concentration ( C max ) of 193.4 ng/m and an enterohepatic circulation (EHC) phenomenon was observed. By comparing the area under the plasma concentration‐time curve (AUC) values obtained from intragastric and intravenous administrations, the absolute oral bioavailability (F) of 9‐methylfascaplysin was determined as 18.3%. The tissue distribution study revealed that following a single intragastric administration, 9‐methylfascaplysin was most concentrated in the stomach, followed by the small intestine, large intestine, liver, kidney, brain, lung, spleen, and heart in descending order. Furthermore, the excretion profiles of 9‐methylfascaplysin in rat urine and feces were studied. The results of this study provide valuable insights into the PK behavior of 9‐methylfascaplysin and serve as a foundation for its further preclinical evaluation and potential clinical application as an anti‐AD agent.