title: Blood-brain barrier transport kinetics of the cyclic depsipeptide mycotoxins beauvericin and enniatins.
abstract: The cyclic depsipeptide mycotoxins beauvericin and enniatins are capable of reaching the systemic circulation through various routes of exposure and are hence capable of exerting central nervous system (CNS) effects, if they are able to pass the blood-brain barrier (BBB), which was the main objective of this study. Quantification of the mycotoxins was performed using an in-house developed and validated bio-analytical UHPLC-MS/MS method. Prior to the BBB experiments, the metabolic stability of the mycotoxins was evaluated in vitro in mouse serum and brain homogenate. The BBB permeation kinetics of beauvericin and enniatins were studied using an in vivo mice model, applying multiple time regression for studying the blood-to-brain influx. Additionally, capillary depletion was applied to obtain the fraction of the peptides really entering the brain parenchyma and the fraction loosely adhered to the brain capillary wall. Finally, also the brain-to-blood efflux transport kinetics was studied. Metabolic stability data indicated that the investigated mycotoxins were stable during the duration of the in vivo study. The brain influx study showed that beauvericin and enniatins are able to cross the blood-brain barrier in mice: using the Gjedde-Patlak biphasic model, it was shown that all investigated mycotoxins exert a high initial influx rate into the brain (K1 ranging from 11 to 53μL/(g×min)), rapidly reaching a plateau. After penetration, the mycotoxins reached the brain parenchyma (95%) with only a limited amount residing in the capillaries (5%). Negligible efflux (<0.005min(-1)) from the brain was observed in the 15min post-intracerebroventricular injection.
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Lien
authors.initials: L
authors.lastname: Taevernier
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bracke
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Veryser
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Evelien
authors.initials: E
authors.lastname: Wynendaele
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
authors.forename: Bert
authors.initials: B
authors.lastname: Gevaert
authors.affiliation: Department of Medical Imaging and Small Animal Orthopedics, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
authors.forename: Kathelijne
authors.initials: K
authors.lastname: Peremans
authors.affiliation: Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. Electronic address: Bart.DeSpiegeleer@ugent.be.
authors.forename: Bart
authors.initials: B
authors.lastname: De Spiegeleer
mesh_terms: D053000:Analytic Sample Preparation Methods; D000818:Animals; D001711:Biotransformation; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002199:Capillary Permeability; D002851:Chromatography, High Pressure Liquid; D047630:Depsipeptides / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D005260:Female; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007601:Jugular Veins; D008813:Mice, Inbred ICR; D008954:Models, Biological; D009183:Mycotoxins / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D000072356:Parenchymal Tissue / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution; D066007:Toxicokinetics
chemical_list: D047630:Depsipeptides; D009183:Mycotoxins; C100264:enniatins; C004456:beauvericin
keywords: Beauvericin; Blood-brain barrier permeability; Cyclic depsipeptide mycotoxins; Enniatins; in vivo mice model