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Research ArticleArticle

Use of Cassette Dosing Approach to Examine the Effects of P-Glycoprotein on the Brain and Cerebrospinal Fluid Concentrations in Wild-Type and P-Glycoprotein Knockout Rats

Xingrong Liu, Jonathan Cheong, Xiao Ding and Gauri Deshmukh
Drug Metabolism and Disposition April 2014, 42 (4) 482-491; DOI: https://doi.org/10.1124/dmd.113.055590
Xingrong Liu
Genentech, Inc., South San Francisco, California
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Jonathan Cheong
Genentech, Inc., South San Francisco, California
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Xiao Ding
Genentech, Inc., South San Francisco, California
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Gauri Deshmukh
Genentech, Inc., South San Francisco, California
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Abstract

The study objectives were 1) to test the hypothesis that the lack of P-glycoprotein (P-gp) and the inhibition of breast cancer resistance protein (Bcrp) at the blood-brain barrier after cassette dosing of potent P-gp and Bcrp inhibitors were due to low plasma concentrations of those inhibitors and 2) to examine the effects of P-gp on the unbound brain (Cu,brain) and cerebrospinal fluid (CSF) concentrations (Cu,CSF) of P-gp substrates in rats. In vitro inhibition of 11 compounds (amprenavir, citalopram, digoxin, elacridar, imatinib, Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxopyrazino[1′,2′:1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], loperamide, prazosin, quinidine, sulfasalazine, and verapamil) on P-gp and Bcrp was examined in P-gp– and Bcrp-expressing Madin-Darby canine kidney cells, respectively. An in vivo study was conducted in wild-type and Mdr1a(−/−) rats after subcutaneous cassette dosing of the 11 compounds at 1–3 mg/kg, and the brain, CSF, and plasma concentrations of these compounds were determined. At the maximal unbound concentrations observed in rats at 1–3 mg/kg, P-gp and Bcrp were not inhibited by a cassette of the 11 compounds. For non–P-gp/Bcrp substrates, similar Cu,brain, Cu,CSF, and unbound plasma concentrations (Cu,plasma) were observed in wild-type and P-gp knockout rats. For P-gp/Bcrp substrates, Cu,brain ≤ Cu,CSF ≤ Cu,plasma in wild-type rats, but Cu,brain and Cu,CSF increased in the P-gp knockout rats and were within 3-fold of Cu,plasma for six of the seven P-gp substrates. These results indicate that P-gp and Bcrp inhibition at the blood-brain barrier is unlikely in cassette dosing and also suggest that P-gp and Bcrp activity at the blood–CSF barrier is functionally not important in determination of the CSF concentration for their substrates.

Footnotes

    • Received October 26, 2013.
    • Accepted January 7, 2014.
  • dx.doi.org/10.1124/dmd.113.055590.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleArticle

Brain Penetration in Wild-Type and P-gp Knockout Rats

Xingrong Liu, Jonathan Cheong, Xiao Ding and Gauri Deshmukh
Drug Metabolism and Disposition April 1, 2014, 42 (4) 482-491; DOI: https://doi.org/10.1124/dmd.113.055590

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Research ArticleArticle

Brain Penetration in Wild-Type and P-gp Knockout Rats

Xingrong Liu, Jonathan Cheong, Xiao Ding and Gauri Deshmukh
Drug Metabolism and Disposition April 1, 2014, 42 (4) 482-491; DOI: https://doi.org/10.1124/dmd.113.055590
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