In vitro Metabolism studies of Catechol‐Containing Natural Products and Analogues

Abstract

Many biologically active natural products contain phenol groups that are prone to rapid phase‐II metabolism. In order to better understand the structural basis for these metabolic transformations, we have investigated the in vitro metabolism of rooperol, a bis‐catechol with anti‐cancer activity, and caffeic acid phenethyl amide (CAPA), a synthetic analog of a natural product with antioxidant and cytoprotective activities. In the presence of pig liver microsomes supplemented with UDP‐glucuronic acid, both of these catechols undergo rapid phase‐II metabolism to form mono‐ (CAPA and rooperol) and bis‐ (rooperol) glucuronide metabolites. The identity of these metabolites was determined by HPLC‐MS. We followed the kinetics of these in vitro metabolism reactions using HPLC. In both cases, the disappearance of the compound over time corresponded to a first‐order process with half‐life of 4.0 ± 0.5 min for rooperol and 5.1 ± 0.8 min for CAPA. In the case of rooperol, this data is in agreement with previously published pharmacokinetic (PK) studies in humans, in which only phase‐II metabolites were detected after oral administration, as well as PK studies in baboons which also report rapid phase‐II metabolism following IV administration. While human or non‐human primate PK data for CAPA have not been reported, our data suggest that this compound will also suffer from rapid phase‐II metabolism, and thus more metabolically stable analogs of both rooperol and CAPA are required.Support or Funding InformationThis research was supported by the U.S. Department of Education HSI STEM program (841.031c), Award #P021C160036The Robert and Ella Owens Medical Research Foundation