Behnam Noorani1,2, Ekram Ahmed Chowdhury1,2,3, Faleh Alqahtani1,2,4, Md Sanaullah Sajib1,2,5, Yeseul Ahn1,2, Ehsan Nozohouri1,2, Dhavalkumar Patel6, Constantinos Mikelis1,2,7, Reza Mehvar8,9, Ulrich Bickel10,11. 1. Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S Coulter St., Amarillo, Texas, 79106, USA. 2. Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, 79106, USA. 3. Department of Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA. 4. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia. 5. Food and Drug Administration, Silver Spring, Maryland, 20903, USA. 6. LC-MS Core Facility, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, 79106, USA. 7. Department of Pharmacy, University of Patras, 26504, Patras, Greece. 8. Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, 79106, USA. mehvar@chapman.edu. 9. Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Rinker Health Science Campus, 9401 Jeronimo Road, Irvine, California, 92618, USA. mehvar@chapman.edu. 10. Department of Pharmaceutical Sciences, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, 1300 S Coulter St., Amarillo, Texas, 79106, USA. Ulrich.Bickel@ttuhsc.edu. 11. Center for Blood-Brain Barrier Research, Jerry H. Hodge School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, 79106, USA. Ulrich.Bickel@ttuhsc.edu.
Abstract
PURPOSE: To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake. METHODS: Stable isotope-labeled [13C]sucrose and [13C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h. Plasma and brain concentrations were quantified by UPLC-MS/MS. Brain uptake clearance (Kin) was analyzed using either the single-time point analysis, the multiple time point graphical method, or by fitting the parameters of a three-compartmental model that allows for symmetrical exchange across the blood-brain barrier and an additional brain efflux clearance. RESULTS: The three-compartment model was able to describe the experimental data well, yielding estimates for Kin of sucrose and mannitol of 0.068 ± 0.005 and 0.146 ± 0.020 μl.min-1.g-1, respectively, which were significantly different (p < 0.01). The separate brain efflux clearance had values of 0.693 ± 0.106 (sucrose) and 0.881 ± 0.20 (mannitol) μl.min-1.g-1, which were not statistically different. Kin values obtained by single time point and multiple time point analyses were dependent on the terminal sampling time and showed declining values for later time points. CONCLUSIONS: Using the three-compartment model allows determination of Kin for small molecule hydrophilic markers with low blood-brain barrier permeability. It also provides, for the first time, an estimate of brain efflux after systemic administration of a marker, which likely represents bulk flow clearance from brain tissue.
PURPOSE: To evaluate a three-compartmental semi-physiological model for analysis of uptake clearance and efflux from brain tissue of the hydrophilic markers sucrose and mannitol, compared to non-compartmental techniques presuming unidirectional uptake. METHODS: Stable isotope-labeled [13C]sucrose and [13C]mannitol (10 mg/kg each) were injected as IV bolus into the tail vein of awake young adult mice. Blood and brain samples were taken after different time intervals up to 8 h. Plasma and brain concentrations were quantified by UPLC-MS/MS. Brain uptake clearance (Kin) was analyzed using either the single-time point analysis, the multiple time point graphical method, or by fitting the parameters of a three-compartmental model that allows for symmetrical exchange across the blood-brain barrier and an additional brain efflux clearance. RESULTS: The three-compartment model was able to describe the experimental data well, yielding estimates for Kin of sucrose and mannitol of 0.068 ± 0.005 and 0.146 ± 0.020 μl.min-1.g-1, respectively, which were significantly different (p < 0.01). The separate brain efflux clearance had values of 0.693 ± 0.106 (sucrose) and 0.881 ± 0.20 (mannitol) μl.min-1.g-1, which were not statistically different. Kin values obtained by single time point and multiple time point analyses were dependent on the terminal sampling time and showed declining values for later time points. CONCLUSIONS: Using the three-compartment model allows determination of Kin for small molecule hydrophilic markers with low blood-brain barrier permeability. It also provides, for the first time, an estimate of brain efflux after systemic administration of a marker, which likely represents bulk flow clearance from brain tissue.
Authors: N Joan Abbott; Michelle E Pizzo; Jane E Preston; Damir Janigro; Robert G Thorne Journal: Acta Neuropathol Date: 2018-02-10 Impact factor: 17.088
Authors: Stefan Liebner; Rick M Dijkhuizen; Yvonne Reiss; Karl H Plate; Dritan Agalliu; Gabriela Constantin Journal: Acta Neuropathol Date: 2018-02-06 Impact factor: 17.088
Authors: Joanna M Wardlaw; Helene Benveniste; Maiken Nedergaard; Berislav V Zlokovic; Humberto Mestre; Hedok Lee; Fergus N Doubal; Rosalind Brown; Joel Ramirez; Bradley J MacIntosh; Allen Tannenbaum; Lucia Ballerini; Ravi L Rungta; Davide Boido; Melanie Sweeney; Axel Montagne; Serge Charpak; Anne Joutel; Kenneth J Smith; Sandra E Black Journal: Nat Rev Neurol Date: 2020-02-24 Impact factor: 42.937