title: Method development for quantification of the environmental neurotoxin annonacin in Rat plasma by UPLC-MS/MS and application to a pharmacokinetic study.
abstract: Annonacin is an environmental neurotoxin identified in the pulp of several fruits of the Annonaceae family (for example in Annona muricata, Asimina triloba), whose consumption was linked with the occurrence of sporadic atypical Parkinsonism with dementia. Pharmacokinetic parameters of this molecule are unknown. A method for its quantification in Rat plasma was developed, using its analogue annonacinone as an internal standard. Extraction from plasma was performed using ethylacetate with a good recovery. Quantification was performed by UPLC-MS/MS in SRM mode, based on the loss of the γ-methyl-γ-lactone (-112amu) from the sodium-cationized species [M+Na](+) of both annonacin and internal standard. The limit of quantification was 0.25ng/mL. Despite strong matrix effects, a good linearity was obtained over two distinct ranges 0.25-10ng/mL and 10-100ng/mL. The intra- and inter-day precisions (RSD) were lower than 10%, while accuracy was within ±10%. This method was applied to a pharmacokinetic study in the Rat. After oral administration of 10mg/kg annonacin, a Cmax of 7.9±1.5ng/mL was reached at Tmax 0.25h; T1/2 was 4.8±0.7h and apparent distribution volume was 387.9±64.6L. The bioavailability of annonacin was estimated to be 3.2±0.3% of the ingested dose.
authors.affiliation: Laboratoire de Pharmacognosie-Chimie des Substances Naturelles, UMR-BioCIS, CNRS, University Paris-Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 9290, Châtenay-Malabry, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Bonneau
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Sud, Labex LERMIT, avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Schmitz-Afonso
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Sud, Labex LERMIT, avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Brunelle
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS-ICSN UPR2301, Université Paris-Sud, Labex LERMIT, avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France.
authors.forename: David
authors.initials: D
authors.lastname: Touboul
authors.affiliation: Laboratoire de Pharmacognosie-Chimie des Substances Naturelles, UMR-BioCIS, CNRS, University Paris-Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 9290, Châtenay-Malabry, France. Electronic address: pierre.champy@u-psud.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Champy
mesh_terms: D000818:Animals; D002138:Calibration; D002853:Chromatography, Liquid / Q000379:methods*; D005663:Furans / Q000097:blood* / Q000493:pharmacokinetics; D007783:Lactones / Q000097:blood* / Q000493:pharmacokinetics; D057230:Limit of Detection; D008297:Male; D009498:Neurotoxins / Q000097:blood* / Q000493:pharmacokinetics; D010936:Plant Extracts / Q000097:blood / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012015:Reference Standards; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: D005663:Furans; D007783:Lactones; D009498:Neurotoxins; D010936:Plant Extracts; C053442:annonacin
keywords: Acetogenin; Annonaceae; Annonacin; Bioavailability; Rat plasma; UPLC–MS/MS