The chromatographic capacity factors (kIAM) of 23 structurally diverse drugs were measured by the immobilized artificial membrane (kIAM) phosphatidylcholine chromatography for the prediction of blood-brain barrier (BBB) penetration. The kIAM was determined using themobile phase consisting of acetonitrile:DPBS (20:80 v/v) and corrected for the molar volume of the solutes (kIAM/MWn). The correlation between kIAM/MWn and CNS penetration was highest when measured at pH 5.5 with the power function of n = 4. This in vitro predictionmethod was validated with 7 newly synthesized PDE-4 inhibitors. The relationship between in vivo plasma-to-brain concentration ratios and in vitro CNS penetration was excellent (r= 0.959). The developed in vitro prediction method may be used as a rapid screening tool for BBB penetration of drugs with passive transport mechanism, with high success, low cost, and reproducibility.
Pardridge WM: CNS drug design based on principles of blood-brain barrier transport. J Neurochem1998;7:1781-1792.
2.
Tamai I, Tsuji A: Transporter-mediated permeation of drugs across the bloodbrain barrier. J Pharm Sci2000;89:1371-1388.
3.
Clark DE, Pickett S: Computational methods for the prediction of “ druglikeness.” Drug Discov Today2000;5:49-58.
4.
Kerns E: High throughput physicochemical profiling for drug discovery. J Pharm Sci2001;90:1838-1858.
5.
Pardridge WM:Transport of small molecules through the blood-brain barrier: biology and methodology. Adv Drug Deliv Rev1995;15:5-36.
6.
Young C, Mitchell RC, Brown TH, Ganellin CR, Griffiths R, JonesM, et al: Development of a new physicochemical model for brain penetration and its application to the design of centrally acting H2 receptor histamine antagonists. J Med Chem1988;31:656-671.
7.
Clark DE: Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena 2. Prediction of blood-brain barrier penetration. J Pharm Sci1999;88:815-826.
8.
Platts JA, Abraham MH, Zhao YH, Heresy A, Ijaz L, Butina D: Correlation and prediction of a large blood-brain distribution data set: anLFER study. Eur J Med Chem2001;36:719-730.
9.
Gratton JA, Abraham MH, Bradbury MW, Chadha HS:Molecular factors influencing drug transfer across the blood-brain barrier. J Pharm Pharmacol1997;49:1211-1216.
10.
Seelig A, Gottschlich R, Devant RM: A method to determine the ability of drugs to diffuse through the blood-brain barrier. Proc Natl Acad Sci U S A1994;91:68-72.
11.
Suomalainen P, Johans C, Söderlund T, Kinnunen PK: Surface activity profiling of drugs applied to the prediction of blood-brain barrier permeability. Med Chem2004;47:1783-1788.
12.
de Lange EC, de Boer BA, Breimer DD: Microdialysis for pharmacokinetic analysis of drug transport to the brain. Adv Drug Deliv Rev1999;36:211-227.
13.
Mano Y, Higuchi S, Kamimura H: Investigation of the high partition of YM992, a novel antidepressant, in rat brain: in vitro and in vivo evidence for the high binding in brain and the high permeability at the BBB. Biopharm Drug Dispos2002;23:351-360.
14.
Shen DD, Artru AA, Adkison KK: Principles and applicability of CSF sampling for the assessment of CNS drug delivery and pharmacodynamics. Adv Drug Deliv Rev2004;56:1825-1857.
15.
Ross TM, Martinez PM, Renner JC, Thorne RG, Hanson LR, Frey WH: Intranasal administration of interferon beta bypasses the blood-brain barrier to target the central nervous system and cervical lymph nodes: a non-invasive treatment strategy for multiple sclerosis. J Neuroimmunol2004;151:66-77.
16.
Lüdemanm L, Hamm B, Zimmer C: Pharmacokinetic analysis of glioma compartments with dynamicGd-DTPA-enhanced magnetic resonance imaging. Magn Reson Imaging2000;18:1201-1214.
17.
Luurtsema G, Molthoff CF, Schuit RC, Windhorst AD, Lammertsma AA, Franssen EJ: Evaluation of (R)-[11C]verapamil as PET tracer of Pglycoprotein function in the blood-brain barrier: kinetics and metabolism in the rat. Nucl Med Biol2005;32:87-93.
18.
Siakotos AN, Rouser G, Fleischer S: Isolation of highly purified human and bovine brain endothelial cells and nuclei and their phospholipid composition. Lipids1969;4:234-239.
19.
Otis KW, Avery ML, Broward-Partin SM, Hansen DK, Behlow HW Jr, Scott DO, et al:Evaluation of the BBMEC model for screening the CNS permeability of drugs. J Pharmacol Toxicol Meth2001;45:71-77.
20.
Yamazaki M, Terasaki T,Yoshioka K, Nagata O, Kato H, Ito Y, et al: Carriermediated transport of H1-antagonist at the blood-brain barrier: mepyramine uptake into bovine brain capillary endothelial cells in primarymonolayer cultures. Pharm Res1994;11:975-978.
21.
Murakami H, Sawada N, Koyabu N, Ohtani H, Sawada Y: Characteristics of choline transport across the blood-brain barrier in mice: correlationwith in vitro data. Pharm Res2000;17:1526-1530.
22.
Faassen F, Vogel G, Spanings H, Vromans H: Caco-2 permeability, Pglycoprotein transport ratios and brain penetration of heterocyclic drugs. Int J Pharm2003;263:113-122.
23.
Di L, Kerns EH, Fan K, McConnell OJ, Carter GT: High throughput artificial membrane permeability assay for blood-brain barrier. Eur J Med Chem2003;38:223-232.
24.
Dash AK, Elmquist WF: Separation methods that are capable of revealing blood-brain barrier permeability. J Chromatogr B2003;797:241-254.
25.
Reichel A, Begley DJ: Potential of immobilized artificial membranes for predicting drug penetration across the blood-brain barrier. Pharm Res1998;15:1270-1274.
26.
Sugano K, Hamada H, Machida M, Ushio H: High throughput prediction of oral absorption: improvement of the composition of the lipid solution used in parallel artificial membrane permeation assay. J Biomol Screen2001;6:189-196.
27.
Ong S, Liu H, Pidgeon C: Immobilized-artificial-membrane chromatography: measurements of membrane partition coefficient and predicting drug membrane permeability. J Chromatogr A1996;728:113-128.
28.
Yoon CH, Shin BS, Chang HS, Kwon LS, Kim HY, Yoo SE, et al: Rapid screening of drug absorption potential using the immobilized artificial membrane phosphatidylcholine column and molar volume. Chromatographia2004;60:399-204.
29.
Crivori P, Cruciani G, Carrupt P, Testa B: Predicting blood-brain barrier permeation from three-dimensional molecular structure. J Med Chem2000;43:2204-2216.
30.
Pardridge WM: Transport of protein-bound hormones into tissues in vivo. Endocr Rev1981;2:103-123.
31.
Bayliss PFC, Duncan ASM: The effects of atenolol (tenormin) and methyldopa on simple tests of central nervous function. Br J Clin Pharmacol1975;2:527-531.
32.
Jolliet P, Simon N, Bree F, Urien S, Pagliara A, Carrupt PA, et al: Blood-tobrain transfer of various oxicams: effects of plasma binding on their brain delivery. Pharm Res1997;14:650-656.
33.
Heykants J, Michiels M, Knaeps A, Brugmans J: Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 5: the pharmacokinetics of loperamide in rats and man. Arzneimittelforschung1974;24:1649-1653.
34.
Scheld WM: Quinolone therapy for infections of the central nervous system. Rev Infect Dis1989;11:S1194-S1202.
35.
McCall AL, Millington WR, Wurtman RJ: Blood-brain barrier transport of caffeine: dose-related restriction of adenine transport. Life Sci1982;31:2709-2715.
36.
Reynolds JEF: Martindale: The Extra Pharmacopoeia. London: Pharmaceutical Press, 1989.
37.
Kulkarni SK, Mehta AK, Kunchandy J: Anti-inflammatory actions of clonidine, guanfacine and B-HT 920 against various inflammagen-induced acute paw oedema in rats. Drugs Today1984;20:497-507.
38.
Tsai TH, Cheng FC, Chen KC, Chen YF, Chen CF: Simultaneous measurement of cefuroxime in rat blood and brain by microdialysis andmicrobore liquid chromatography application of pharmacokinetics. J Chromatogr B1999;735:25-31.
Raevsky OA, Schaper KJ: Quantitative estimation of hydrogen bond contribution to permeability and absorption processes of some chemicals and drugs. Eur J Med Chem1998;33:799-807.
41.
Yang CY, Cai SJ, Liu H, Pidgeon C: Immobilized artificial membranes: screens for drug-membrane interactions. Adv Drug Deliv Rev1996;23:229-256.
Xiang TX, Anderson BD: Molecular distributions in interphases: statistical mechanical theory combined with molecular dynamics simulation of a model lipid bilayer. Biophys J1994;66:561-573.
44.
Palm K, Luthman K, Ungell AL, Strandlund G, Beigi F, Lundahl P, et al: Evaluation of dynamic polar molecular surface area as predictor of drug absorption: comparison with other computational and experimental predictors. J Med Chem1998;41:5382-5392.
45.
Clark DE: Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption. J Pharm Sci1999;88:807-814.
46.
Zhu C, Jiang L, Chen TM, Hwang KK: A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential. Eur J Med Chem2002;37:399-407.
47.
Kelder J, Grootenhuis PD, Bayda DM, Delbressine LP, Ploemen JP: Polar molecular surface as a dominating determinant for oral absorption and brain penetration of dugs. Pharm Res1997;16:1514-1519.
48.
van de Waterbeemd H, Camenisch G, Folkers G, Chretien JR, Raevsky OA: Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. J Drug Target1998;6:151-165.
49.
Lennernas H: Dose fluid flow across the intestinal mucosa affect quantitative oral drug absorption? Is it time for a reevaluation?Pharm Res1997;12:1573-1582.
