caa a22 4500 445314060 CHVBK 20180317142640.0 cr unu---uuuuu 170323e20110201xx s 000 0 eng 10.1007/s11095-010-0280-x doi (NATIONALLICENCE)springer-10.1007/s11095-010-0280-x Physicochemical Selectivity of the BBB Microenvironment Governing Passive Diffusion—Matching with a Porcine Brain Lipid Extract Artificial Membrane Permeability Model [Elektronische Daten] [Oksana Tsinman, Konstantin Tsinman, Na Sun, Alex Avdeef] ABSTRACT: Purpose: To mimic the physicochemical selectivity of the blood-brain barrier (BBB) and to predict its passive permeability using a PAMPA model based on porcine brain lipid extract (PBLE 10%w/v in alkane). Methods: Three PAMPA (BD pre-coated and PBLE with 2 different lipid volumes) models were tested with 108 drugs. Abraham solvation descriptors were used to interpret the in vitro-in vivo correlation with 282 in situ brain perfusion measurements, spanning over 5 orders of magnitude. An in combo PAMPA model was developed from combining measured PAMPA permeability with one H-bond descriptor. Results: The in combo PAMPA predicted 93% of the variance of 197 largely efflux-inhibited in situ permeability training set. The model was cross-validated by the "leave-many-out” procedure, with q2 = 0.92 ± 0.03. The PAMPA models indicated the presence of paramembrane water channels. Only the PBLE-based PAMPA-BBB model with sufficient lipid to fill all the internal pore space of the filter showed a wide dynamic range window, selectivity coefficient near 1, and was suitable for predicting BBB permeability. Conclusion: BBB permeability can be predicted by in combo PAMPA. Its speed and substantially lower cost, compared to in vivo measurements, make it an attractive first-pass screening method for BBB passive permeability. Springer Science+Business Media, LLC, 2010 blood-brain barrier nationallicence brain permeability-surface area (PS) nationallicence in combo PAMPA-BBB nationallicence P-glycoprotein nationallicence rodent in situ brain perfusion nationallicence (ε/δ)2 : porosity of paramembrane aqueous pores divided by the length of the water-filled channels in thin PAMPA-BBB membranes (δ ~0.01 cm) nationallicence ABL : aqueous boundary layer—thin stagnant layer adjacent to the surface of a membrane nationallicence BLM : bilayer lipid membrane, unilamellar barrier formed from egg lecithin nationallicence Daq : aqueous diffusivity (cm2·s−1) nationallicence DRW : dynamic range window: DRW = log PABL-log Ppara nationallicence hABL : ABL thickness (cm) nationallicence in combo : methodology where a measured property (e.g., PAMPA permeability coefficient) is aditively "combined” with a calculated (in silico) descriptor (e.g., H-bond potential) nationallicence PABL : ABL permeability coefficient (cm·s−1): PABL = Daq / hABL nationallicence Pe : PAMPA effective permeability coefficient (cm·s−1)—the experimentally-determined value nationallicence Pm : PAMPA transmembrane permeability (cm·s−1)—Pe corrected for ABL and aqueous pore diffusion effects nationallicence pH dependence follows Henderson-Hasselbalch equation nationallicence Po : PAMPA intrinsic permeability coefficient of the uncharged-form of permeant nationallicence for ionizable compounds, Po = Pm (10 ±(pH-pKa) + 1), where ‘+' for acids, ‘−' for bases nationallicence Ppara : PAMPA paramembrane permeability coefficient (cm·s−1)—diffusion of permeant via aqueous pores formed in the thin PAMPA-BBB membrane: Ppara = (ε/δ)2 Daq nationallicence Pc in situ : BBB transendothelial permeability coefficient (cm·s−1) from in situ brain perfusion technique: Pcin situ = (PS)/S, where S = microcapillary surface area = 100 cm2 g−1 nationallicence Po in situ : BBB intrinsic permeability coefficient of the uncharged-form of permeant nationallicence for ionizable compounds, Poin situ = Pcin situ (10 ±(pH-pKa) + 1), ‘+' for acids, ‘−' for bases nationallicence PAMPA-BBB : parallel artificial membrane permeability assay, based on PBLE formulation nationallicence PBLE : porcine brain lipid extract nationallicence PS : capillary permeability-surface area product (mL·s−1·g−1), determined from the uptake rate constant (Kin) using Crone-Renkin equation: Kin = Fpf ( 1-e -PS/Fpf ), where Fpf is the regional cerebral flow of perfusion fluid (mL·s−1·g−1) nationallicence SC : selectivity coefficient nationallicence slope in the log-log in vitro—in vivo correlation plot nationallicence Tsinman Oksana pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut Tsinman Konstantin pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut Sun Na pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut Avdeef Alex pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/2(2011-02-01), 337-363 0724-8741 28:2<337 2011 28 11095 https://doi.org/10.1007/s11095-010-0280-x text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0280-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Tsinman Oksana pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut NATIONALLICENCE 700 1- Tsinman Konstantin pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut NATIONALLICENCE 700 1- Sun Na pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut NATIONALLICENCE 700 1- Avdeef Alex pION INC, 5 Constitution Way, 01801, Woburn, Massachusetts, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/2(2011-02-01), 337-363 0724-8741 28:2<337 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer