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Research ArticleArticle

The Effect of Breast Cancer Resistance Protein and P-Glycoprotein on the Brain Penetration of Flavopiridol, Imatinib Mesylate (Gleevec), Prazosin, and 2-Methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic Acid (PF-407288) in Mice

Lin Zhou, Kari Schmidt, Frederick R. Nelson, Veronica Zelesky, Matthew D. Troutman and Bo Feng
Drug Metabolism and Disposition May 2009, 37 (5) 946-955; DOI: https://doi.org/10.1124/dmd.108.024489
Lin Zhou
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Kari Schmidt
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Frederick R. Nelson
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Veronica Zelesky
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Matthew D. Troutman
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Bo Feng
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Abstract

The role of breast cancer resistance protein (Bcrp) and the combined activities of Bcrp and P-glycoprotein (P-gp, Mdr1a/1b) in limiting the brain penetration of drugs at the blood-brain barrier (BBB) were investigated using wild-type FVB, Mdr1a/1b(–/–), (–/–), Bcrp(–/–), and Mdr1a/1b(–/–), (–/–)Bcrp(–/–) mice. Four drugs, flavopiridol, imatinib mesylate (Gleevec), PF-407288, and prazosin, with different transport specificity for BCRP/Bcrp and MDR1/Mdr1a were selected, and the drug levels in plasma, cerebrospinal fluid, and brain of mice were determined. Flavopiridol and prazosin were identified as substrates for both mouse Bcrp and Mdr1a with greater transport associated with Bcrp. The brain/plasma (B/P) ratios at 0.5 and 2 h in Mdr1a/1b(–/–), (–/–) and Bcrp(–/–) mice were 1- to 2-fold for both compounds, whereas the ratios in Mdr1a/1b(–/–), (–/–)Bcrp(–/–) mice were more than 5-fold of those observed in FVB mice. For imatinib, a better substrate of P-gp than Bcrp, the B/P ratios in Bcrp(–/–) were comparable to those in FVB mice, whereas the B/P ratios in Mdr1a/1b(–/–), (–/–) and Mdr1a/1b(–/–), (–/–)Bcrp(–/–) mice were more than 4- and 28-fold of those in FVB mice at both time points, respectively. Finally, the Bcrp-specific substrate PF-407288 exhibited comparable B/P ratios in Mdr1a/1b(–/–), (–/–) and Bcrp(–/–) mice and slightly but significantly increased B/P ratios in Mdr1a/1b(–/–), (–/–)Bcrp(–/–) mice compared with those in FVB mice. The B/P ratios of compounds in Mdr1a/1b(–/–), (–/–)Bcrp(–/–) mice compared with those in Mdr1a/1b(–/–), (–/–) mice clearly demonstrate that Bcrp impairs the brain penetration of its substrates. Moreover, P-gp and Bcrp at BBB function synergistically to limit the brain penetration of shared substrates.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.024489.

  • ABBREVIATIONS: BBB, blood-brain barrier; P-gp, P-glycoprotein; Mdr1/MDR1, ABCB1, multidrug resistance protein; Bcrp/BCRP, ABCG2, breast cancer resistance protein; CNS, central nervous system; WT, wild-type; KO, knockout; MDCK, Madin-Darby canine kidney; PF-407288, 2-methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic acid; HPLC, high-performance liquid chromatography; MEM, minimal essential medium; PBS, phosphate-buffered saline; A, apical; B, basolateral; LC-MS/MS, liquid chromatography-tandem mass spectrometry; ER, efflux ratio; RR, ratio of ratios; CSF, cerebrospinal fluid; B/P, brain/plasma ratio; CP-018857, benzyl 3-(dimethylamino)-3-oxo-2-phenyl-propanoate; CP-660551, 4-chloro-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide; CE-267266, 7-hydroxy-3-(2-methoxyphenyl)-8-(piperidin-1-ylmethyl)-4H-chromen-4-one; PF-548939, 2-(4-(2-(2-(4-methoxyphenyl)-5-methyloxazol-4-yl)ethoxy)benzyl)-tetrahydrofuran-2-carboxylic acid.

    • Received September 9, 2008.
    • Accepted February 12, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 37 (5)
Drug Metabolism and Disposition
Vol. 37, Issue 5
1 May 2009
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Research ArticleArticle

The Effect of Breast Cancer Resistance Protein and P-Glycoprotein on the Brain Penetration of Flavopiridol, Imatinib Mesylate (Gleevec), Prazosin, and 2-Methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic Acid (PF-407288) in Mice

Lin Zhou, Kari Schmidt, Frederick R. Nelson, Veronica Zelesky, Matthew D. Troutman and Bo Feng
Drug Metabolism and Disposition May 1, 2009, 37 (5) 946-955; DOI: https://doi.org/10.1124/dmd.108.024489

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Research ArticleArticle

The Effect of Breast Cancer Resistance Protein and P-Glycoprotein on the Brain Penetration of Flavopiridol, Imatinib Mesylate (Gleevec), Prazosin, and 2-Methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic Acid (PF-407288) in Mice

Lin Zhou, Kari Schmidt, Frederick R. Nelson, Veronica Zelesky, Matthew D. Troutman and Bo Feng
Drug Metabolism and Disposition May 1, 2009, 37 (5) 946-955; DOI: https://doi.org/10.1124/dmd.108.024489
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