A uniquein vivopharmacokinetic profile,in vitrometabolic stability and hepatic first-pass metabolism of garcinol, a promising novel anticancer phytoconstituent, by liquid chromatography–mass spectrometry

Abstract

AbstractObjectivesGarcinol exhibits promising potential anticancer activity in cancer cells by inhibiting several critical regulatory pathways. Despite its pharmacological activity, 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.MethodsWe 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.Key findingsThe 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, that is 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.ConclusionsMetabolic 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 optimise the dose and route of administration for designing clinical trials to further develop garcinol as an anticancer drug.