Bracke, Nathalie

De Spiegeleer, Bart

Taevernier, Lien

Veryser, Lieselotte

Wynendaele, Evelien

English

Ghent University Academic Bibliography

 DO CYCLIC DEPSIPEPTIDE MYCOTOXINS BEAUVERICIN AND ENNIATINS CROSS THE BLOOD-BRAIN BARRIER? Lien Taevernier, Nathalie Bracke, Lieselotte Veryser, Evelien Wynendaele and Bart De Spiegeleer*   Drug Quality and Registration (DruQuaR) group, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.   * Corresponding author: bart.despiegeleer@ugent.be (O. Ref.: 2016-065c) INTRODUCTION EXPERIMENTAL METHODS RESULTS CONCLUSIONS REFERENCES Taevernier L, Veryser L, Vandercruyssen K, D’Hondt M, Vansteelandt S, De Saeger S, De Spiegeleer B. UHPLC-MS/MS method for the determination of the cyclic depsipeptide mycotoxins beauvericin and enniatins in in vitro transdermal experiments. Journal of Pharmaceutical and Biomedical Analysis. 2014; 100: 50-57, doi.org/ 10.1016/j.jpba.2014.07.021. Taevernier L, Wynendaele E, D’Hondt M, De Spiegeleer B. Analytical quality-by-design approach for sample treatment of BSA-containing solutions. Journal of Pharmaceutical Analysis. 2015; 5: 27-32, doi: 10.1016/j.jpha.2014.06.001. Taevernier L, Bracke N, Veryser L, Wynendaele E, Gevaert B, Peremans K, De Spiegeleer B. Blood-brain barrier transport kinetics of the cyclic depsipeptide mycotoxins beauvericin and enniatins. Submitted for publication. Drug Quality & Registration (DruQuaR) format man06.001.003-v02 FOOD INGESTION DUST INHALATION TOPICAL APPLICATION CYCLIC DEPSIPEPTIDES BEA + ENNs 1. BLOOD-TO-BRAIN TRANSPORT? 3. BRAIN-TO-BLOOD TRANSPORT? 2. CAPILLARY VS. PARENCHYMAL DISTRIBUTION? ? % INTERESTING BIOACTIVITIES: • ACAT inhibitors • Antimicrobial • Insecticidal • Cytotoxic • … HAZARDOUS: • Cytotoxic • Anaphylactic reactions • Antibiotic resistance • Genotoxic? • … • Metabolic stability in vitro: mice serum and brain homogenate • BBB transport study in vivo in ICR-CD-1 mice:  1. Blood-to-brain: multiple time regression influx (MTR) (IV) 2. Brain distribution: capillary depletion (IV) 3. Brain-to-blood: efflux (intracerebroventricular) • Bioanalytical UHPLC-MS/MS method: ‒ Sample preparation ‒ LC/MS conditions ‒ Validation • Kinetic modelling I. METABOLIC STABILITY Stable in serum and brain during the duration of the in vivo study: 80-120% recoveries II. BLOOD-TO-BRAIN TRANSPORT  Formulation = 0.2 mg/kg in 6:94 EtOH:Lactated  Ringer’s solution containing 1% BSA (V/V)  Dose resembling a real-life feed contamination  No influence of the formulation (125I-BSA) Gjedde-Patlak biphasic model  High initial influx rate into the brain:          K1 =11 to 53 μL/(g×min)  Followed by a plateau phase  negligible net brain clearance (very low K-values)  Serum kinetics: 2-compartment model   Very fast transfer from central to peripheral compartment (distribution)  Longer, slower elimination phase Compound Distribution half-life (min-1) Elimination half-life (min-1) Beauvericin 0.10 32.6 Enniatin B 0.11 7.49 Enniatin D 0.09 3.27 Enniatin B1 0.11 4.78 Enniatin E 0.12 3.58 Enniatin A1 0.13 4.50 Enniatin C/F 0.15 3.51 Enniatin A 0.16 4.27 III. CAPILLARY VS. PARENCHYMAL DISTRIBUTION       IV. BRAIN-TO-BLOOD TRANSPORT        III. OVERVIEW 10 min post-injection 95% reached brain parenchyma after permeation through BBB lining endothelial capillaries No significant efflux (kout < 0.005 min-1) Compound MTR blood-to-brain influx(1) Capillary depletion Efflux K (µL/(g×min)) Vg (µL/g) K1 (µL/(g×min)) Parenchymal fraction (%) Capillary fraction (%) Slope (min-1) Beauvericin 0.02272 ± 0.3153 21.91 ± 9.664 11.15 ± 11.42 91.92 ± 1.41 8.08 ± 1.41 -0.1205 ± 0.04218 Enniatin B ≈ 2.071 × 10-16  28.97 ± 11.07 52.95 ± 108.4 96.03 ± 0.19 3.97 ± 0.19 -0.08802 ± 0.06985 Enniatin D 0.001640 ± 0.09873 34.39 ± 6.588 21.66 ± 11.43 96.71 ± 0.15 3.29 ± 0.15 0.005063 ± 0.003091 Enniatin B1 ≈ 1.444 × 10-16 29.94 ± 7.594 30.03 ± 24.19 96.10 ± 0.00 3.90 ± 0.00 0.002408 ± 0.002707 Enniatin E ≈ 9.769 × 10-13 45.77 ± 5.795 25.08 ± 10.86 96.20 ± 0.36 3.80 ± 0.36 -0.005929 ± 0.003019  Enniatin A1 ≈ 2.185 × 10-16 45.38 ± 9.303 25.38 ± 13.12 95.70 ± 0.10 4.30 ± 0.10 -0.01277 ± 0.005588  Enniatin C/F ≈ 1.845 × 10-16 75.43 ± 15.39 23.53 ± 10.22 95.30(2) 4.70(2) -0.02976 ± 0.009449 Enniatin A ≈ 1.840 × 10-16 105.8 ± 21.95 32.41 ± 13.76 94.20 ± 0.71 5.80 ± 0.71 -0.04421 ± 0.02059 (1) V0 = 14.8 µL/g of BSA (2) n = 1 (the other sample was < limit of detection) • Very high influx rate into the brain, with a significant distribution in the brain parenchyma. • No significant serum or brain metabolisation, nor significant brain efflux to the blood was observed.  Possibility that these cyclic depsipeptide mycotoxins exert local central nervous system (CNS) effects once present in the systemic circulation! 125I-BSA 

Do cyclic depsipeptide mycotoxins beauvericin and enniatins cross the blood-brain barrier?

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Do cyclic depsipeptide mycotoxins beauvericin and enniatins cross the blood-brain barrier?

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