title: Cytochrome P450 enzyme-mediated degradation of Echinacea alkylamides in human liver microsomes.
abstract: Echinacea preparations are widely used herbal remedies for the prevention and treatment of colds. In this study we have investigated the metabolism by human liver microsomes of the alkylamide components from an Echinacea preparation as well as that of pure synthetic alkylamides. No significant degradation of alkylamides was evident in cytosolic fractions. Time- and NADPH-dependent degradation of alkylamides was observed in microsomal fractions suggesting they are metabolised by cytochrome P450 (P450) enzymes in human liver. There was a difference in the susceptibility of 2-ene and 2,4-diene pure synthetic alkylamides to microsomal degradation with (2E)-N-isobutylundeca-2-ene-8,10-diynamide (1) metabolised to only a tenth the extent of (2E,4E,8Z,10Z)-N-isobutyldodeca-2,4,8,10-tetraenamide (3) under identical incubation conditions. Markedly less degradation of 3 was evident in the mixture of alkylamides present in an ethanolic Echinacea extract, suggesting that metabolism by liver P450s was dependent both on their chemistry and the combination present in the incubation. Co-incubation of 1 with 3 at equimolar concentrations resulted in a significant decrease in the metabolism of 3 by liver microsomes. This inhibition by 1, which has a terminal alkyne moiety, was found to be time- and concentration-dependent, and due to a mechanism-based inactivation of the P450s. Alkylamide metabolites were detected and found to be the predicted epoxidation, hydroxylation and dealkylation products. These findings suggest that Echinacea may effect the P450-mediated metabolism of other concurrently ingested pharmaceuticals.
authors.affiliation: MediHerb Research Laboratories, Department of Chemistry, The University of Queensland, Brisbane, Qld 4072, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Matthias
authors.forename: E M J
authors.initials: EM
authors.lastname: Gillam
authors.forename: K G
authors.initials: KG
authors.lastname: Penman
authors.forename: N J
authors.initials: NJ
authors.lastname: Matovic
authors.forename: K M
authors.initials: KM
authors.lastname: Bone
authors.forename: J J
authors.initials: JJ
authors.lastname: De Voss
authors.forename: R P
authors.initials: RP
authors.lastname: Lehmann
mesh_terms: D000577:Amides / Q000737:chemistry / Q000378:metabolism*; D002082:Butylamines / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D020900:Echinacea / Q000737:chemistry*; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010936:Plant Extracts / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000577:Amides; D002082:Butylamines; D010936:Plant Extracts