title: Alamethicin for using in bioavailability studies? - Re-evaluation of its effect.
abstract: A major pathway for the elimination of drugs is the biliary and renal excretion following the formation of more hydrophilic secondary metabolites such as glucuronides. For in vitro investigations of the phase II metabolism, hepatic microsomes are commonly used in the combination with the pore-forming peptide alamethicin, also to give estimates for the in vivo situation. Thus, alamethicin may represent a neglected parameter in the characterization of microsomal in vitro assays. In the present study, the influence of varying alamethicin concentrations on glucuronide formation of selected phenolic compounds was investigated systematically. A correlation between the alamethicin impact and the lipophilicity of the investigated substrates was analyzed as well. Lipophilicity was determined by the logarithm of the octanol-water partition coefficient. For every substrate, a distinct alamethicin concentration could be detected leading to a maximal glucuronidation activity. Further increase of the alamethicin application led to negative effects. The differences between the maximum depletion rates with and without alamethicin addition varied between 2.7% and 18.2% depending on the substrate. A dependence on the lipophilicity could not be confirmed. Calculation of the apparent intrinsic clearance led to a more than 2-fold increase using the most effective alamethicin concentration compared to the alamethicin free control.
authors.affiliation: Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Grindelallee 117, 20146 Hamburg, Germany. Electronic address: Maren.Vollmer@chemie.uni-hamburg.de.
authors.forename: Maren
authors.initials: M
authors.lastname: Vollmer
authors.affiliation: Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Grindelallee 117, 20146 Hamburg, Germany. Electronic address: mikl1710@kdwelt.de.
authors.forename: Mirko
authors.initials: M
authors.lastname: Klingebiel
authors.affiliation: Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Grindelallee 117, 20146 Hamburg, Germany. Electronic address: rohn@chemie.uni-hamburg.de.
authors.forename: Sascha
authors.initials: S
authors.lastname: Rohn
authors.affiliation: Institute of Food Chemistry, Hamburg School of Food Science, University of Hamburg, Grindelallee 117, 20146 Hamburg, Germany. Electronic address: maul@chemie.uni-hamburg.de.
authors.forename: Ronald
authors.initials: R
authors.lastname: Maul
mesh_terms: D020003:1-Octanol / Q000737:chemistry; D000408:Alamethicin / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001682:Biological Availability; D004347:Drug Interactions; D020719:Glucuronides / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D014867:Water / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D020719:Glucuronides; D010636:Phenols; D014867:Water; D000408:Alamethicin; D020003:1-Octanol
keywords: Alamethicin; In vitro glucuronidation; Log P value; Metabolism; Phenolic compounds