Blood-Brain Barrier Permeation: Molecular Parameters Governing Passive Diffusion

Abstract. 53 compounds with clinically established ability to cross or not to cross the blood-brain barrier by passive diffusion were characterized by means of surface activity measurements in terms of three parameters, i.e., the air-water partition coefficient, Kaw, the critical micelle concentration, CMCD, and the cross-sectional area, AD. A three-dimensional plot in which the surface area, AD, is plotted as a function of K−1aw and CMCD shows essentially three groups of compounds: (i) very hydrophobic compounds with large air-water partition coefficients and large cross-sectional areas, AD > 80 Å2 which do not cross the blood-brain barrier, (ii) compounds with lower air-water partition coefficients and an average cross-sectional area, AD≅ 50 Å2 which easily cross the blood-brain barrier, and (iii) hydrophilic compounds with low air-water partition coefficients (AD < 50 Å2) which cross the blood-brain barrier only if applied at high concentrations. It was shown that the lipid membrane-water partition coefficient, Klw, measured previously, can be correlated with the air-water partition coefficient if the additional work against the internal lateral bilayer pressure, πbi= 34 ± 4 mN/m is taken into account. The partitioning into anisotropic lipid membranes decreases exponentially with increasing cross-sectional areas, AD, according to Klw=const. Kaw exp(−ADπbi/kT) where kT is the thermal energy. The cross-sectional area of the molecule oriented at a hydrophilic-hydrophobic interface is thus the main determinant for membrane permeation provided the molecule is surface active and has a pKa > 4 for acids and a pKa < 10 for bases.

[1]  G. Zaccai,et al.  Neutron diffraction studies on selectively deuterated phospholipid bilayers , 1978, Nature.

[2]  D. D. Perrin,et al.  pKa prediction for organic acids and bases , 1981 .

[3]  C. Niemegeers,et al.  Domperidone, a novel and safe gastrokinetic anti-nauseant for the treatment of dyspepsia and vomiting. , 1978, Arzneimittel-Forschung.

[4]  D. Marsh.  Lateral pressure in membranes. , 1996, Biochimica et biophysica acta.

[5]  J. Seelig,et al.  Lipid conformation in model membranes and biological membranes , 1980, Quarterly Reviews of Biophysics.

[6]  A. Seelig.  A general pattern for substrate recognition by P-glycoprotein. , 1998, European journal of biochemistry.

[7]  A. Seelig,et al.  Local anesthetics and pressure: a comparison of dibucaine binding to lipid monolayers and bilayers. , 1987, Biochimica et biophysica acta.

[8]  J. Seelig,et al.  Cholesterol-induced rod-like motion of fatty acyl chains in lipid bilayers a deuterium magnetic resonance study. , 1976, Hoppe-Seyler's Zeitschrift fur physiologische Chemie.

[9]  J. Drewe,et al.  Transport of clonidine across cultured brain microvessel endothelial cells. , 1997, The Journal of pharmacology and experimental therapeutics.

[10]  D Mackay,et al.  A novel method for measuring membrane-water partition coefficients of hydrophobic organic chemicals: comparison with 1-octanol-water partitioning. , 1988, Journal of Pharmacy and Science.

[11]  A. Blume,et al.  Thermodynamics of Micelle Formation as a Function of Temperature: A High Sensitivity Titration Calorimetry Study , 1995 .

[12]  Martindale.,et al.  THE EXTRA PHARMACOPOEIA , 1937 .

[13]  A. Tsuji,et al.  Physicochemical Properties of β-Lactam Antibiotics: Oil-Water Distribution , 1977 .

[14]  S. McLaughlin,et al.  The electrostatic properties of membranes. , 1989, Annual review of biophysics and biophysical chemistry.

[15]  T R Stouch,et al.  Solute diffusion in lipid bilayer membranes: an atomic level study by molecular dynamics simulation. , 1993, Biochemistry.

[16]  J. Heykants,et al.  Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 5: the pharmacokinetics of loperamide in rats and man. , 1974, Arzneimittel-Forschung.

[17]  L. Mayer,et al.  Influence of ion gradients on the transbilayer distribution of dibucaine in large unilamellar vesicles. , 1988, Biochemistry.

[18]  J. Seelig,et al.  Nonclassical hydrophobic effect in membrane binding equilibria. , 1991, Biochemistry.

[19]  M. J. Rosen.  Surfactants and Interfacial Phenomena , 1978 .

[20]  J. Seelig,et al.  Peptide binding to lipid bilayers. Nonclassical hydrophobic effect and membrane-induced pK shifts. , 1992, Biochemistry.

[21]  B. Roelofsen,et al.  Relation between various phospholipase actions on human red cell membranes and the interfacial phospholipid pressure in monolayers. , 1975, Biochimica et biophysica acta.

[22]  R. Macdonald.  THE RELATIONSHIP AND INTERACTIONS BETWEEN LIPID BILAYERS VESICLES AND LIPID MONOLAYERS AT THE AIR/WATER INTERFACE , 1996 .

[23]  H. M. Bender,et al.  A pharmacological profile of the novel, peripherally‐selective k‐opioid receptor agonist, EMD 61753 , 1994, British journal of pharmacology.

[24]  D. Marsh,et al.  Phospholipid Bilayers: Physical Principles and Models , 1987 .

[25]  R. Laruel,et al.  [Research on the benzofuran series. XXXVII. Comparative study of transit and metabolism of amiodarone in different species of animals and humans]. , 1969, Archives internationales de pharmacodynamie et de therapie.

[26]  K. Chan,et al.  Metabolic disposition of terfenadine in laboratory animals. , 1982, Arzneimittel-Forschung.

[27]  Bernard Testa,et al.  Lipophilicity and hydrogen-bonding capacity of H1-antihistaminic agents in relation to their central sedative side-effects , 1994 .

[28]  G van Meer,et al.  Lipid sorting in epithelial cells. , 1988, Biochemistry.

[29]  V. Schuermans,et al.  Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 6: Clinical pharmacology. Placebo-controlled comparison of the constipating activity and safety of loperamide, diphenoxylate and codeine in normal volunteers. , 1974, Arzneimittel-Forschung.

[30]  R. Lewis,et al.  Analgesic and mechanistic evaluation of spiradoline, a potent kappa opioid. , 1988, The Journal of pharmacology and experimental therapeutics.

[31]  R. Kaliszan.  High Performance Liquid Chromatographic Methods and Procedures of Hydrophobicity Determination , 1990 .

[32]  A. Sedman,et al.  Diuretic Effects, Pharmacokinetics, and Safety of a New Centrally Acting Kappa‐Opioid Agonist (CI‐977) in Humans , 1994, Journal of clinical pharmacology.

[33]  S. McLaughlin,et al.  Effect of monolayer surface pressure on the activities of phosphoinositide-specific phospholipase C-beta 1, -gamma 1, and -delta 1. , 1994, Biochemistry.

[34]  J. Seelig,et al.  Deuterium magnetic resonance studies of phospholipid bilayers. , 1974, Biochemical and biophysical research communications.

[35]  C. Pidgeon,et al.  Immobilized Artificial Membranes — screens for drug membrane interactions , 1997 .

[36]  C. Altenbach,et al.  Binding of the lipophilic cation tetraphenylphosphonium to phosphatidylcholine , 1985 .

[37]  C. Pidgeon,et al.  Membrane partition coefficients chromatographically measured using immobilized artificial membrane surfaces. , 1995, Analytical chemistry.

[38]  M. Wenk,et al.  Octyl-beta-D-glucopyranoside partitioning into lipid bilayers: thermodynamics of binding and structural changes of the bilayer. , 1997, Biophysical journal.

[39]  J. Overbeek,et al.  Physical chemical studies of short-chain lecithin homologues. 3. Phase separation and light scattering studies on aqueous dioctanoyllecithin solutions. , 1974, Biophysical chemistry.

[40]  A. Seelig,et al.  A method to determine the ability of drugs to diffuse through the blood-brain barrier. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. W. Newton,et al.  pKa Values of Medicinal Compounds in Pharmacy Practice , 1978 .