title: Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid/plasma concentration ratio.
abstract: The ratio of drug levels in cerebrospinal fluid (CSF) to plasma (CSF/plasma) at equilibrium has been viewed as in vivo free fraction (fp) in plasma [CSF/plasma = fp], if no active transport is involved in brain penetration. We determined the CSF/plasma level following oral administration in rats and in vitro rat plasma protein binding for 20 compounds that were synthesized in our institute and have similar physicochemical properties. However, results indicated that the CSF/plasma was not only poorly correlated with fp but remarkably lower than fp in most of the compounds tested, suggesting that certain transporters such as P-glycoprotein (P-gp) located in blood-brain barrier (BBB) may decrease the unbound drug concentration in the brain. We evaluated P-gp-mediated transport activity of the 20 compounds with P-gp (mdr1a)-transfected LLC-PK1 cells and calculated P-gp efflux index (PEI), indicating the extent of P-gp-mediated transport. A plot of the CSF/plasma versus fp/PEI showed a strong correlation (r = 0.93), and the absolute values were almost identical [CSF/plasma = fp/PEI]. These results suggest that P-gp quantitatively shifts the equilibrium of unbound drugs across the BBB. Although we cannot rule out the possibility that endogenous transporters other than P-gp on BBB and/or blood-CSF barrier may affect CSF levels of compounds, the present study indicated that fp and PEI measurements may be useful in predicting in vivo CSF/plasma fractions for central nervous system-targeting drugs.
authors.affiliation: Banyu Tsukuba Research Institute, Ibaraki, Japan. ooetm@banyu.co.jp
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ohe
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sato
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tanaka
authors.forename: Naoko
authors.initials: N
authors.lastname: Fujino
authors.forename: Mikiko
authors.initials: M
authors.lastname: Hata
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Shibata
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
authors.forename: Takehiro
authors.initials: T
authors.lastname: Fukami
authors.forename: Masayo
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Masato
authors.initials: M
authors.lastname: Chiba
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ishii
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood* / Q000134:cerebrospinal fluid*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D002460:Cell Line; D006801:Humans; D008297:Male; D051379:Mice; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations