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

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.