title: The impact of P-gp functionality on non-steady state relationships between CSF and brain extracellular fluid.
abstract: In the development of central nervous system (CNS)-targeted drugs, the prediction of human CNS target exposure is a big challenge. Cerebrospinal fluid (CSF) concentrations have often been suggested as a 'good enough' surrogate for brain extracellular fluid (brainECF, brain target site) concentrations in humans. However, brain anatomy and physiology indicates prudence. We have applied a multiple microdialysis probe approach in rats, for continuous measurement and direct comparison of quinidine kinetics in brainECF, CSF, and plasma. The data obtained indicated important differences between brainECF and CSF kinetics, with brainECF kinetics being most sensitive to P-gp inhibition. To describe the data we developed a systems-based pharmacokinetic model. Our findings indicated that: (1) brainECF- and CSF-to-unbound plasma AUC0-360 ratios were all over 100 %; (2) P-gp also restricts brain intracellular exposure; (3) a direct transport route of quinidine from plasma to brain cells exists; (4) P-gp-mediated efflux of quinidine at the blood-brain barrier seems to result of combined efflux enhancement and influx hindrance; (5) P-gp at the blood-CSF barrier either functions as an efflux transporter or is not functioning at all. It is concluded that in parallel obtained data on unbound brainECF, CSF and plasma concentrations, under dynamic conditions, is a complex but most valid approach to reveal the mechanisms underlying the relationship between brainECF and CSF concentrations. This relationship is significantly influenced by activity of P-gp. Therefore, information on functionality of P-gp is required for the prediction of human brain target site concentrations of P-gp substrates on the basis of human CSF concentrations.
authors.affiliation: Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Westerhout
authors.forename: Jean
authors.initials: J
authors.lastname: Smeets
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Elizabeth C M
authors.initials: EC
authors.lastname: de Lange
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D045604:Extracellular Fluid / Q000737:chemistry; D008297:Male; D017551:Microdialysis; D008959:Models, Neurological; D011802:Quinidine / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D011804:Quinolines / Q000097:blood / Q000134:cerebrospinal fluid* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011804:Quinolines; D011802:Quinidine; C402343:tariquidar
references.citation: J Pharm Sci. 2011 Sep;100(9):3577-93
references.pmid: 21544824
references.citation: Epilepsia. 2002 Jul;43(7):675-84
references.pmid: 12102668
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:357-400
references.pmid: 17067280
references.citation: J Neurol Neurosurg Psychiatry. 1949 Feb;12(1):39-51
references.pmid: 18111229
references.citation: J Pharmacokinet Biopharm. 1999 Dec;27(6):625-44
references.pmid: 11153449
references.citation: Cell Mol Neurobiol. 2000 Apr;20(2):165-81
references.pmid: 10696508
references.citation: J Clin Invest. 2000 Feb;105(3):279-85
references.pmid: 10675353
references.citation: J Pharmacol Exp Ther. 2011 Dec;339(3):935-44
references.pmid: 21934030
references.citation: J Pharmacokinet Pharmacodyn. 2001 Apr;28(2):171-92
references.pmid: 11381569
references.citation: J Clin Invest. 1981 Oct;68(4):1065-74
references.pmid: 6270193
references.citation: Pharmacol Rev. 2001 Dec;53(4):569-96
references.pmid: 11734619
references.citation: J Pharmacol Methods. 1991 Mar;25(1):41-52
references.pmid: 2030585
references.citation: Radiology. 1991 Jan;178(1):115-22
references.pmid: 1984289
references.citation: Cell. 1994 May 20;77(4):491-502
references.pmid: 7910522
references.citation: J Neurosci Methods. 1991 Nov;40(1):31-8
references.pmid: 1795551
references.citation: Adv Drug Deliv Rev. 1999 Apr 5;36(2-3):179-194
references.pmid: 10837715
references.citation: Am J Physiol. 1965 Dec;209(6):1219-26
references.pmid: 5846924
references.citation: Brain Res Brain Res Rev. 1997 Sep 30;25(1):27-49
references.pmid: 9370049
references.citation: Curr Drug Metab. 2008 Jan;9(1):46-59
references.pmid: 18220571
references.citation: J Anat. 1971 Apr;108(Pt 3):447-51
references.pmid: 5575312
references.citation: Curr Top Med Chem. 2009;9(2):148-62
references.pmid: 19200002
references.citation: Nat Rev Drug Discov. 2010 Mar;9(3):215-36
references.pmid: 20190787
references.citation: Cancer Res. 2001 Jan 15;61(2):749-58
references.pmid: 11212278
references.citation: Drug Metab Dispos. 2005 Jan;33(1):175-81
references.pmid: 15502010
references.citation: J Pharmacokinet Biopharm. 1985 Aug;13(4):425-40
references.pmid: 4087170
references.citation: J Neurophysiol. 2004 Dec;92(6):3471-81
references.pmid: 15269225
references.citation: Anesthesiology. 2008 Dec;109(6):1092-9
references.pmid: 19034106
references.citation: Pharm Res. 2006 Apr;23(4):705-17
references.pmid: 16575498
references.citation: Trends Biochem Sci. 1992 Jan;17(1):18-21
references.pmid: 1374941
references.citation: J Pharmacol Exp Ther. 1997 Nov;283(2):574-80
references.pmid: 9353372
references.citation: J Med Chem. 2009 Oct 22;52(20):6233-43
references.pmid: 19764786
references.citation: Am J Physiol. 1981 Apr;240(4):F319-28
references.pmid: 7223889
references.citation: J Histochem Cytochem. 2006 Oct;54(10):1159-67
references.pmid: 16801529
references.citation: AAPS J. 2012 Mar;14(1):87-96
references.pmid: 22215264
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3900-5
references.pmid: 10097135
references.citation: BMC Med Imaging. 2011 Jan 03;11:1
references.pmid: 21199574
references.citation: Mol Pharmacol. 1994 Apr;45(4):763-72
references.pmid: 7910372
references.citation: Proc Soc Exp Biol Med. 1974 Dec;147(3):813-5
references.pmid: 4445171
references.citation: Drug Metab Dispos. 2003 Nov;31(11):1337-45
references.pmid: 14570765
references.citation: Brain Res Dev Brain Res. 1990 Oct 1;56(1):47-53
references.pmid: 2279331
references.citation: Adv Drug Deliv Rev. 2004 Oct 14;56(12):1825-57
references.pmid: 15381336
references.citation: Drug Metab Dispos. 2006 Sep;34(9):1443-7
references.pmid: 16760229
references.citation: J Nucl Med. 2008 Aug;49(8):1328-35
references.pmid: 18632828
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):4028-33
references.pmid: 9108099
references.citation: Basic Clin Pharmacol Toxicol. 2010 Mar;106(3):215-20
references.pmid: 20050843
references.citation: J Pharmacol Exp Ther. 1996 Jun;277(3):1550-9
references.pmid: 8667222
references.citation: J Histochem Cytochem. 2005 Apr;53(4):517-31
references.pmid: 15805426
references.citation: Adv Drug Deliv Rev. 2000 Dec 15;45(2-3):125-48
references.pmid: 11108971
references.citation: Drug Metab Dispos. 2009 Apr;37(4):787-93
references.pmid: 19116265
references.citation: Brain Res. 2007 Nov 21;1181:44-50
references.pmid: 17915195
references.citation: Expert Rev Anticancer Ther. 2007 Apr;7(4):447-59
references.pmid: 17428165
references.citation: J Biomol Screen. 2011 Sep;16(8):886-94
references.pmid: 21832259
references.citation: J Pharmacol Exp Ther. 2001 Jun;297(3):991-1000
references.pmid: 11356921
references.citation: Fluids Barriers CNS. 2013 Feb 22;10(1):12
references.pmid: 23432852
references.citation: J Pharmacokinet Pharmacodyn. 2013 Jun;40(3):315-26
references.pmid: 23400635
references.citation: J Neurosci Res. 2000 Jun 1;60(5):594-601
references.pmid: 10820430
references.citation: J Nucl Med. 1985 Jan;26(1):72-6
references.pmid: 3965655
references.citation: Epilepsy Res. 2002 Oct;51(3):257-68
references.pmid: 12399076
references.citation: Lancet. 1986 Jun 14;1(8494):1355-7
references.pmid: 2872473
references.citation: Brain Res. 1973 Mar 30;52:323-32
references.pmid: 4739806
references.citation: J Pharm Sci. 2005 Dec;94(12):2632-43
references.pmid: 16258992
references.citation: Biochem Cell Biol. 2006 Dec;84(6):979-92
references.pmid: 17215884
references.citation: J Neurochem. 1997 Mar;68(3):1278-85
references.pmid: 9048775
references.citation: Int J Pharm. 2005 Apr 27;294(1-2):185-92
references.pmid: 15814243
references.citation: J Neurosurg. 1978 Feb;48(2):190-2
references.pmid: 624967
references.citation: Neuroscience. 2004;129(4):957-70
references.pmid: 15561411
references.citation: J Neurochem. 2010 Aug;114(3):717-27
references.pmid: 20477935
references.citation: J Pharmacol Exp Ther. 2001 Jul;298(1):110-5
references.pmid: 11408531
references.citation: Neurochem Int. 2004 Sep;45(4):545-52
references.pmid: 15186921
references.citation: J Histochem Cytochem. 1986 Feb;34(2):189-95
references.pmid: 3003182
references.citation: J Membr Biol. 1997 Dec 1;160(3):161-75
references.pmid: 9425600
references.citation: Drug Metab Dispos. 2005 Jan;33(1):165-74
references.pmid: 15502009
references.citation: Clin Pharmacokinet. 2002;41(10):691-703
references.pmid: 12162757
references.citation: Pharm Res. 2008 Aug;25(8):1737-50
references.pmid: 18058202
references.citation: Annu Rev Physiol. 1986;48:241-50
references.pmid: 2871806
references.citation: Drug Metab Dispos. 2009 Jan;37(1):137-42
references.pmid: 18936112
references.citation: Biopharm Drug Dispos. 2002 Nov;23(8):327-38
references.pmid: 12415573
references.citation: AAPS J. 2012 Sep;14(3):543-53
references.pmid: 22588644
references.citation: Eur J Pharm Sci. 2000;10(4):275-84
references.pmid: 10838017