Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid/plasma concentration ratio

Tomoyuki Ohe, Masahiko Sato, Sachiko Tanaka, Naoko Fujino, Mikiko Hata, Yoshihiro Shibata, Akio Kanatani, Takehiro Fukami, Masayo Yamazaki, Masato Chiba, Yasuyuki Ishii

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1251-1254
Number of pages4
JournalDrug Metabolism and Disposition
Volume31
Issue number10
DOIs
Publication statusPublished - 2003 Oct 1
Externally publishedYes

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Cerebrospinal fluid
P-Glycoprotein
Cerebrospinal Fluid
Plasmas
Blood-Brain Barrier
Rats
Brain
Pharmaceutical Preparations
Central Nervous System Agents
LLC-PK1 Cells
Active Biological Transport
Neurology
Protein Binding
Oral Administration
Blood Proteins
Blood

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid/plasma concentration ratio. / Ohe, Tomoyuki; Sato, Masahiko; Tanaka, Sachiko; Fujino, Naoko; Hata, Mikiko; Shibata, Yoshihiro; Kanatani, Akio; Fukami, Takehiro; Yamazaki, Masayo; Chiba, Masato; Ishii, Yasuyuki.

In: Drug Metabolism and Disposition, Vol. 31, No. 10, 01.10.2003, p. 1251-1254.

Research output: Contribution to journalArticle

Ohe, T, Sato, M, Tanaka, S, Fujino, N, Hata, M, Shibata, Y, Kanatani, A, Fukami, T, Yamazaki, M, Chiba, M & Ishii, Y 2003, 'Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid/plasma concentration ratio', Drug Metabolism and Disposition, vol. 31, no. 10, pp. 1251-1254. https://doi.org/10.1124/dmd.31.10.1251
Ohe, Tomoyuki ; Sato, Masahiko ; Tanaka, Sachiko ; Fujino, Naoko ; Hata, Mikiko ; Shibata, Yoshihiro ; Kanatani, Akio ; Fukami, Takehiro ; Yamazaki, Masayo ; Chiba, Masato ; Ishii, Yasuyuki. / Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid/plasma concentration ratio. In: Drug Metabolism and Disposition. 2003 ; Vol. 31, No. 10. pp. 1251-1254.
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