Abstract
This study investigated the impact of the active efflux mediated by P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) at the blood-brain barrier (BBB) on the predictability of the unbound brain concentration (Cu,brain) by the concentration in the cerebrospinal fluid (CSF) (Cu,CSF) in rats. Cu,brain is obtained as the product of the total brain concentration and unbound fraction in the brain (fu,brain) determined in vitro in brain slices. Twenty-five compounds, including P-gp and/or Bcrp substrates, were given a constant intravenous infusion, and their plasma, brain, and CSF concentrations were determined. P-gp and/or Bcrp substrates, such as verapamil, loperamide, flavopiridol, genistein, quinidine, dantrolene, daidzein, cimetidine, and pefloxacin, showed a higher CSF-to-brain unbound concentration ratio (Kp,uu,CSF/brain) compared with non-P-gp and non-Bcrp substrates. Kp,uu,CSF/brain values of P-gp-specific (quinidine and verapamil) and Bcrp-specific (daidzein and genistein) substrates were significantly decreased in Mdr1a/1b(−/−) and Bcrp(−/−) mice, respectively. Furthermore, consistent with the contribution of P-gp and Bcrp to the net efflux at the BBB, Kp,uu,CSF/brain values of the common substrates (flavopiridol and erlotinib) were markedly decreased in Mdr1a/1b(−/−)/Bcrp(−/−) mice, but only moderately or weakly in Mdr1a/1b(−/−) mice and negligibly in Bcrp(−/−) mice. In conclusion, predictability of Cu,brain by Cu,CSF decreases along with the net transport activities by P-gp and Bcrp at the BBB. Cu,CSF of non-P-gp and non-Bcrp substrates can be a reliable surrogate of Cu,brain for lipophilic compounds.
Footnotes
This study was supported in part by the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (A) 20249008 (to Y.S.) and Grant-in-Aid for Scientific Research (B) 23390034 (to H.K.)].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.180398.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- CNS
- central nervous system
- BBB
- blood-brain barrier
- CSF
- cerebrospinal fluid
- CCSF
- total drug concentration in cerebrospinal fluid
- Cbrain
- total drug concentration in brain
- Cu,CSF
- unbound drug concentration in cerebrospinal fluid
- Cu,brain
- unbound drug concentration in brain
- Kp,brain
- brain-to-plasma drug concentration ratio
- Kp,CSF
- cerebrospinal fluid-to-plasma drug concentration ratio
- Kp,uu,brain
- brain-to-plasma unbound drug concentration ratio
- Kp,uu,CSF
- cerebrospinal fluid-to-plasma unbound drug concentration ratio
- Kp,uu,CSF/brain
- cerebrospinal fluid-to-brain unbound drug concentration ratio
- Mdr
- multidrug resistance protein
- P-gp
- P-glycoprotein
- Bcrp
- breast cancer resistance protein
- MDCK
- Madin-Darby canine kidney
- GFP
- green fluorescent protein
- L-Mdr1a
- LLC-PK1 cells expressing mouse Mdr1a
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- PBS
- phosphate-buffered saline
- ABC
- ATP-binding cassette.
- Received February 8, 2011.
- Accepted September 19, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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