Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid/plasma concentration ratio.
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.
Ohe
Tomoyuki
T
Banyu Tsukuba Research Institute, Ibaraki, Japan. ooetm@banyu.co.jp
Sato
Masahiko
M
Tanaka
Sachiko
S
Fujino
Naoko
N
Hata
Mikiko
M
Shibata
Yoshihiro
Y
Kanatani
Akio
A
Fukami
Takehiro
T
Yamazaki
Masayo
M
Chiba
Masato
M
Ishii
Yasuyuki
Y
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
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations