A unique in vivo pharmacokinetic profile, in vitro metabolic stability, and hepatic first-pass metabolism of garcinol, a promising novel anticancer phytoconstituent, by liquid chromatography-mass spectrometry

Garcinol exhibits promising potential anticancer activity in cancer cells by inhibiting several critical regulatory pathways. Despite its pharmacological activities, information regarding its pharmacokinetics and metabolism is unavailable. Hence, we aimed to systematically determine the in vivo pharmacokinetic parameters, in vitro metabolic stability and hepatic first-pass metabolism of garcinol. We developed and validated a sensitive bioanalytical method for the quantitative determination of garcinol in rat plasma and human liver microsomes using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The developed method was applied to assess the pharmacokinetic parameters, bioavailability, and metabolic stability associated with metabolic half-life and intrinsic hepatic clearance. Further, we calculated the hepatic first-pass metabolism of garcinol from the metabolic stability data. The metabolic stability of garcinol in human liver microsomes demonstrated it as a medium clearance drug with a CLint value of 33.94 µL/min/mg microsomal protein, and 94% of garcinol would escape the hepatic first-pass metabolism. Furthermore, a pharmacokinetics study of garcinol in Sprague Dawley rats showed 26.64 ± 0.23% and 35.72 ± 0.97% oral bioavailability at two doses, i.e., 22.5, and 45 mg/kg, respectively. The Cmax values at these two oral doses were 2317.69 ± 180.44 and 3446.14 ± 190.12 ng/mL. Metabolic stability data showed that garcinol is a medium clearance drug and less fraction of the drug undergoes hepatic first-pass metabolism. The determined pharmacokinetic parameters and metabolic stability data help to understand and optimize the dose and route of administration for designing clinical trials to further develop garcinol as anticancer drug.