In vitro metabolism of flavokawains from Piper methysticum using human liver microsomes

Chalcones possess a broad spectrum of biological activities and a high potential for therapeutic application. Although pharmacological properties of chalcones are extensively investigated, little is known about their absorption, bioavailability, and metabolism in general. Flavokawain A, B and C (FKA, FKB, FKC) are naturally occuring chalcones, that have been isolated from Piper methysticum Forst. (Piperaceae) and show anti-inflammatory and anti-cancer activity [1]. In vitro metabolism of FKA, FKB and FKC was investigated using human liver microsomes. Different microsomal incubation systems were used to study both phase I and phase II (glucuronidation) metabolism as well as combined phase I+II metabolism. Metabolites were identified by LC-HRESIMS and exact accordance to the retention times of the references in the chromatographic system. In phase I metabolism, demethylation in position C-4 or C-4' and hydroxylation predominantly in position C-4 occured. This lead to the formation of FKC as major phase I metabolite of FKA. FKC and alpinetin chalcone were found as major phase I metabolites of FKB. Helichrysetin and OH-FKC represented the major phase I metabolites of FKC. The compounds were even more extensively metabolized in presence of uridine diphosphate (UDP) glucuronic acid by microsomal UDP-glucuronosyltransferases. For all test chalcones, the corresponding monoglucuronides were detected as the major metabolites in phase II and combined metabolism. A metabolic profile of investigated chalcones is proposed. The predominance of glucuronides over phase I metabolites generally emphasizes the important role of conjugated chalcones metabolites as possible in vivo active principles.

Acknowledgements: We thank Jörg Heilmann (Institute of Pharmacy, University of Regensburg) for scientific support.

Keywords: flavokawains, metabolism, human microsoms

References:

1. Abu, N. et al. (2013) Cancer Cell Int. 13(1):102 – 108.