Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems.
Because of the physiological nature of the blood-brain barrier (BBB), transport of chemical compounds between blood and brain has been widely believed to occur by means of passive diffusion, depending upon the lipophilicity of the compounds. However, discrepancies exist between the lipophilicity and apparent BBB permeation properties in many cases, and these discrepancies can be ascribed to the existence of multiple mechanisms of drug transport through the BBB. Molecular identification and functional analysis of influx transport proteins (from blood to brain) and efflux transport proteins (from brain to blood) have progressed rapidly. Therefore, the BBB is now considered to be a dynamic interface that controls the influx and efflux of a wide variety of substances, including endogenous nutrients and exogenous compounds such as drugs, to maintain a favorable environment for the CNS. This review focuses on the role of transport systems in the uptake of xenobiotics, including organic anionic/cationic and neutral drugs, across the BBB into the brain, as well as on strategies to increase drug delivery into the brain by blocking efflux transport protein function, or to reduce CNS side effects by modulating BBB transport processes.
Tsuji
Akira
A
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. tsuji@kenroku.kanazawa-u.ac.jp
D000818:Animals; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier; D002352:Carrier Proteins / Q000378:metabolism*; D002491:Central Nervous System Agents / Q000378:metabolism*; D004337:Drug Carriers; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D010455:Peptides / Q000378:metabolism
D002352:Carrier Proteins; D002491:Central Nervous System Agents; D004337:Drug Carriers; D027701:Organic Cation Transport Proteins; D010455:Peptides
J Pharmacol Exp Ther. 2004 Feb;308(2):438-45
14610227
Biochim Biophys Acta. 1994 Jul 13;1193(1):24-30
8038191
Stroke. 1974 Jan-Feb;5(1):81-4
4811317
Life Sci. 2000;66(7):649-62
10794520
J Biol Chem. 1996 Apr 19;271(16):9754-8
8621654
Brain Res. 2003 Apr 4;968(1):69-79
12644265
Br J Clin Pharmacol. 1988 Nov;26(5):497-502
2905150
Biochem Biophys Res Commun. 1998 May 29;246(3):589-95
9618255
Biopharm Drug Dispos. 2003 Nov;24(8):357-65
14595704
J Pharmacol Exp Ther. 2003 Aug;306(2):703-8
12724351
J Pharmacol Exp Ther. 1999 Nov;291(2):778-84
10525100
J Drug Target. 2000;8(6):383-93
11328664
N Engl J Med. 1984 Feb 23;310(8):483-8
6694694
J Pharm Pharmacol. 1996 Feb;48(2):136-46
8935161
Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):12079-84
10518579
J Biol Chem. 1998 Dec 4;273(49):32776-86
9830022
J Pharmacol Exp Ther. 1999 May;289(2):768-73
10215651
J Pharmacol Exp Ther. 2000 Jul;294(1):73-9
10871297
J Biol Chem. 1999 Jul 9;274(28):19745-51
10391916
J Pharm Sci. 2003 Aug;92(8):1531-44
12884241
Adv Drug Deliv Rev. 2003 Jan 21;55(1):83-105
12535575
Biochem Biophys Res Commun. 1998 Oct 20;251(2):586-91
9792817
Nat Genet. 2004 May;36(5):471-5
15107849
J Neurochem. 1985 May;44(5):1541-50
3921665
Am J Physiol. 1973 Jun;224(6):1450-3
4712154
J Histochem Cytochem. 1999 Oct;47(10):1255-64
10490454
Mol Pharmacol. 2001 Feb;59(2):358-66
11160873
Cell. 1994 Mar 11;76(5):865-73
8124722
J Pharmacol Exp Ther. 2003 Apr;305(1):40-7
12649351
J Pharmacol Exp Ther. 1996 Mar;276(3):1189-200
8786552
J Neurochem. 1988 Jul;51(1):252-7
3132534
FEBS Lett. 1997 Dec 8;419(1):107-11
9426230
J Pharm Pharmacol. 1991 Mar;43(3):172-6
1675273
Physiol Rev. 1990 Jan;70(1):43-77
2404290
J Pharm Pharmacol. 2001 Apr;53(4):497-503
11341366
J Neurochem. 2003 Mar;84(6):1322-31
12614332
Brain Res. 1984 Jun 3;301(2):201-7
6547363
J Pharmacol Exp Ther. 1993 Dec;267(3):1085-90
8263769
Arzneimittelforschung. 1994 Jan;44(1):55-9
7907872
J Biol Chem. 1998 Aug 7;273(32):20378-82
9685390
News Physiol Sci. 2002 Dec;17:231-4
12433976
Biol Pharm Bull. 2002 Oct;25(10):1351-5
12392093
Mol Pharmacol. 1998 Aug;54(2):342-52
9687576
Nat Genet. 1999 Jan;21(1):91-4
9916797
Biol Pharm Bull. 1994 May;17(5):676-9
7920432
J Biol Chem. 2000 Dec 22;275(51):40064-72
11010964
Pharm Res. 2000 Jan;17(1):55-62
10714609
Peptides. 1992 Nov-Dec;13(6):1289-94
1494505
J Pharmacol Exp Ther. 1991 Sep;258(3):932-7
1890627
Biochem Biophys Res Commun. 1994 May 30;201(1):402-8
8198602
J Neurochem. 1999 Jul;73(1):390-9
10386992
Annu Rev Pharmacol Toxicol. 1998;38:431-60
9597162
Pharm Res. 1994 Feb;11(2):305-11
8165193
Pflugers Arch. 2000 Jul;440(3):337-50
10954321
Physiol Rev. 1983 Oct;63(4):1481-535
6361813
J Biol Chem. 1998 Sep 11;273(37):23629-32
9726963
Pharm Res. 2001 Sep;18(9):1262-9
11683238
Am J Physiol. 1997 Jul;273(1 Pt 1):E207-13
9252498
Biochem Biophys Res Commun. 2000 Jun 24;273(1):251-60
10873595
J Biol Chem. 1999 Jul 9;274(28):19738-44
10391915
J Pharm Pharmacol. 1999 Oct;51(10):1113-21
10579682
J Biol Chem. 1999 May 7;274(19):13675-80
10224140
Brain Res Bull. 1987 Dec;19(6):629-33
3440215
Eur Neurol. 1971-1972;6(1):49-55
5153453
J Pharmacobiodyn. 1990 Feb;13(2):158-63
2117062
Drug Metab Dispos. 1999 Aug;27(8):866-71
10421612
Nature. 1998 Sep 17;395(6699):288-91
9751058
Carbohydr Res. 1997 Mar 26;299(1-2):15-21
9129293
J Pharmacol Exp Ther. 1997 Feb;280(2):551-60
9023263
Neurosci Res. 1995 Mar;22(1):13-22
7792078
Pharm Res. 1994 Nov;11(11):1516-8
7870663
Biochim Biophys Acta. 1990 Jun 27;1025(2):191-8
2364078
Biochim Biophys Acta. 1997 Nov 27;1359(2):174-80
9409814
Psychopharmacology (Berl). 1988;96(2):262-6
2852821
Pharm Res. 1994 Jul;11(7):975-8
7937557
J Pharmacol Exp Ther. 1999 Sep;290(3):1482-92
10454528
J Pharmacol Exp Ther. 1999 May;289(2):1084-9
10215691
J Biol Chem. 1997 Jul 25;272(30):18526-9
9228014
J Pharmacol Exp Ther. 1997 Jul;282(1):81-5
9223542
Biol Pharm Bull. 2004 Jun;27(6):932-5
15187451
J Pharmacol Exp Ther. 1992 Dec;263(3):964-70
1469653
Arzneimittelforschung. 1994 Jan;44(1):59-64
7907873
Br J Pharmacol. 1998 Aug;124(7):1516-22
9723966