title: Metabolism of small antimicrobial β(2,2)-amino acid derivatives by murine liver microsomes.
abstract: We have investigated the in vitro metabolism of three small antimicrobial β(2,2)-amino acid derivatives (M                         (w) < 500) that are highly potent against methicillin resistant Staphylococcus aureus, and are among the first compounds designed from small cationic antimicrobial peptides with potential for oral administration. The β(2,2)-amino acid derivatives are virtually completely resistant against degradation by proteases, and to further explore their drug potential, we have investigated the hepatic Phase I metabolism of this class of antimicrobial compounds. The β(2,2)-amino acid derivatives were incubated with murine liver microsomes and the metabolites analyzed semi-quantitatively by HPLC-MS and qualitatively by ultra performance liquid chromatography coupled to a tandem mass spectrometer which enabled identification of the metabolites by careful interpretation of the collision activated dissociation spectra. The study shows that sterically hindered β(2,2)-amino acid derivatives that otherwise are stable against proteolytic degradation underwent Phase I metabolism and were oxidized to a number of different metabolites depending on the structure of the β(2,2)-amino acid side-chains.
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Norway. Terkel.Hansen@uit.no
authors.forename: Terkel
authors.initials: T
authors.lastname: Hansen
authors.forename: Morten K
authors.initials: MK
authors.lastname: Moe
authors.forename: Trude
authors.initials: T
authors.lastname: Anderssen
authors.forename: Morten B
authors.initials: MB
authors.lastname: Strøm
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D023181:Antimicrobial Cationic Peptides