title: Elimination pathways of cyclosarin (GF) mediated by β-cyclodextrin in vitro: pharmacokinetic and toxicokinetic aspects.
abstract: Cyclodextrins (CD) are promising small molecular scavengers showing favourable degradation of extremely toxic organophosphorus compounds (OP) such as tabun (GA), soman (GD) or cyclosarin (GF). For β-CD derivatives as potential OP antidotes with low intrinsic toxicity it is of great interest to completely understand the modes of interaction of both compounds in terms of OP detoxification. The mechanisms of CD action are not completely understood which prompted us to investigate the interactions of GF and β-cyclodextrin (β-CD) as model compounds. Using positive electrospray ionization mass spectrometry (ESI/MS), the formation of covalent conjugates of β-CD with O-cyclohexylmethylphosphonate (CHMP) residue was detected for the first time and was examined in vitro. With a newly developed LC-MS method the formation of O-cyclohexylmethylphosphonic acid (CHMPA) (i.e. GF hydrolysis) and covalent CHMP-β-CD conjugates was analyzed. Compared to water, tris(hydroxymethyl)aminomethane (TRIS) reduced the formation of covalent conjugates but amplified formation of CHMPA. Depending on experimental conditions the degradation of GF by β-CD may be preferably catalytic or stoichiometric. For illustrating different possible reaction pathways a scheme was established that could support the idea of β-CD acting as an artificial enzyme. These results provide an important insight into the β-CD mediated detoxification pathways of GF.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kranawetvogl
authors.forename: Jan
authors.initials: J
authors.lastname: Schüler
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.forename: Georg
authors.initials: G
authors.lastname: Reiter
mesh_terms: D000931:Antidotes / Q000737:chemistry*; D002021:Buffers; D002384:Catalysis; D002619:Chemical Warfare Agents / Q000737:chemistry / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D006868:Hydrolysis; D007306:Insecticides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000633:toxicity; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000633:toxicity; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D014325:Tromethamine / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D000931:Antidotes; D002021:Buffers; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009943:Organophosphorus Compounds; D047392:beta-Cyclodextrins; D014325:Tromethamine; C073636:cyclohexyl methylphosphonic acid; C031215:betadex; C053914:cyclohexyl methylphosphonofluoridate
keywords: BC; BC(H); BC(H)(2+); BC(TRIS); CD; CHMP; CHMPA; Cyclosarin; Detoxification; ESI/MS; GF; IS; LVI; MC; MC(H); MC(H/NH4)(2+); MC(TRIS); MRM; Metabolism; Nerve agents; O-(1,2,2-trimethylpropyl)methylphosphonic acid; O-cyclohexylmethylphosphonate; O-cyclohexylmethylphosphonic acid; OP; Organophosphorus compounds; PMPA; RVC; TRIS; binary (CHMP)(2)-β-CD conjugate; binary adduct of β-CD and CHMP bearing a proton in positive ESI/MS; binary adduct of β-CD and CHMP bearing a protonated TRIS molecule in positive ESI/MS.; binary adduct of β-CD and CHMP bearing two protons in positive ESI/MS; cyclodextrin; cyclosarin; electrospray ionization mass spectrometry; internal standard; large volume injection; mono CHMP-β-CD conjugate; mono adduct of β-CD and CHMP bearing a proton and another ammonium ion in positive ESI/MS; mono adduct of β-CD and CHMP bearing a proton in positive ESI/MS; mono adduct of β-CD and CHMP bearing a protonated TRIS molecule in positive ESI/MS; multiple reaction monitoring; organophosphorus compound(s); rotation vacuum concentrator; tris(hydroxymethyl)aminomethane; β-CD; β-Cyclodextrin; β-cyclodextrin