Surface Activity Profiling of Drugs Applied to the Prediction of Blood−Brain Barrier Permeability

Abstract

The present study describes a novel in vitro platform for physicochemical profiling of compounds, based on their impact on the air/water interfacial tension. Interfacial partitioning coefficient, cross-sectional area, and critical micelle concentration were derived from the Gibbs adsorption isotherms recorded for 76 structurally diverse drugs. An approximation for the membrane partitioning coefficient, K(memb), is introduced and calculated for the measured compounds. This methodology provides a fully automatic, high-throughput screening technique for compound characterization, yielding precise thermodynamic information on the partitioning behavior of molecules at air/water interfaces, which can be directly related to their anisotropic interaction with lipid bilayers in biological membranes. The latter represents the barrier for the passive entry of compounds into cells. The surface activity profiles are shown to correlate to the ability of the compounds to pass passively through the blood-brain barrier.

Interaction of the Macrolide Antibiotic Azithromycin with Lipid Bilayers: Effect on Membrane Organization, Fluidity, and Permeability

“…One of the major goals of current research in biophysics is to characterize the fundamental interactions between drugs or macromolecules and multimolecular structures such as lipid monolayers or bilayers (30)(31)(32)(33)(34)(35)(36). Formation of lateral microdomains is particularly important in this respect both from the structural and functional points of view.…”

Modification of Permeability Transition Pore Arginine(s) by Phenylglyoxal Derivatives in Isolated Mitochondria and Mammalian Cells

“…Log P values were calculated for the nonionic species using KowWin version 1.67 (www.syrres.com/esc/est_kowdemo.htm). The surface activity profiles of the phenylglyoxal derivatives (the surface tension versus concentration isotherms) were measured in modification medium containing 250 mM sucrose, 10 mM succinate, 10 mM Hepes-KOH, pH 8.0, 100 M EGTA, 1 M rotenone, supplemented with 10% Me 2 SO, using a Delta-8 instrument (Kibron Inc.) as described (32). The apparent air/ water partition coefficient was determined from the isotherms as described (32).…”

“…The surface activity profiles of the phenylglyoxal derivatives (the surface tension versus concentration isotherms) were measured in modification medium containing 250 mM sucrose, 10 mM succinate, 10 mM Hepes-KOH, pH 8.0, 100 M EGTA, 1 M rotenone, supplemented with 10% Me 2 SO, using a Delta-8 instrument (Kibron Inc.) as described (32). The apparent air/ water partition coefficient was determined from the isotherms as described (32). The pK a of the OH group of OH-PGO and CamOH-PGO was 7.50 and 7.15, respectively, as determined by the absorbance spectra of the protonated ( max at 282 and 278 nm) and deprotonated ( max at 335 and 333 nm) molecules.…”

Rapid Screening of Blood-Brain Barrier Penetration of Drugs Using the Immobilized Artificial Membrane Phosphatidylcholine Column Chromatography

“…Of these, β-estradiol, caffeine, chlorpromazine, clonidine, desipramine, ibuprofen, imipramine, progesterone, promazine, propranolol, and testosterone were classified in the literature as "high brain penetration" (CNS+) drugs and aldosterone, atenolol, cefuroxime, cimetidine, corticosterone, enalapril, hydrocortisone, lomefloxacin, loperamide, nadolol, piroxicam, and timolol as "low brain penetration" (CNS-) drugs. 6,11,23,[29][30][31][32][33][34][35][36][37][38] These literature classifications were based on the measurement of the rate by which the drug enters the brain, the blood-brain distribution under steady state, or the pharmacological activity directly linked to brain penetration. The pKa and PAMPA effective permeability (P e ) values were used as reported in literature.…”

“…In silico approaches include the determination of physicochemical properties such as octanol-water partition coefficient (log P), 5 hydrogen-bonding potential (∆ log P), 6 molecular polar surface area (PSA), 7 linear free energy, 8,9 and surface tension. 10,11 In vivo biological approaches include microdialysis, 12,13 cerebrospinal fluid sampling, 12,14 autoradiography, 15 nuclear magnetic resonance, 16 and positron emission spectroscopy. 17 In vitro methods use isolated brain capillaries 18 and cultured cells such as bovine brain microvessel endothelial cells, 19 brain capillary endothelial cells, 20 mouse brain endothelial cells 4, 21 and Caco-2 cells.…”