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Research ArticleArticle

FUNCTIONAL ASSESSMENT OF MULTIPLE P-GLYCOPROTEIN (P-GP) PROBE SUBSTRATES: INFLUENCE OF CELL LINE AND MODULATOR CONCENTRATION ON P-GP ACTIVITY

Mitchell E. Taub, Lalitha Podila, Diane Ely and Iliana Almeida
Drug Metabolism and Disposition November 2005, 33 (11) 1679-1687; DOI: https://doi.org/10.1124/dmd.105.005421
Mitchell E. Taub
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Lalitha Podila
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Diane Ely
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Iliana Almeida
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Abstract

Compounds known to modulate P-glycoprotein (P-gp) activity were evaluated in cell monolayers expressing P-gp for their effects on the secretory transport of P-gp substrates paclitaxel, vinblastine, and digoxin. Paclitaxel has been proposed to selectively interact with a binding site on P-gp that is distinct from the vinblastine and digoxin-binding site. Using Madin-Darby canine kidney (MDCK)-multidrug resistance-1 (MDR1), MDCK-wild-type (WT), and Caco-2 cell monolayers, the basal-to-apical (BL-AP) apparent permeability (Papp) of [3H]paclitaxel, [3H]vinblastine, and [3H]digoxin in the presence of various concentrations of a series of structurally diverse P-gp substrates and modulators of P-gp function were determined. MDCK-WT cell monolayers demonstrated active secretory transport of all P-gp substrate probes, although the sensitivity to inhibition by verapamil was lower than that demonstrated in MDCK-MDR1 cell monolayers. When evaluated as competitive inhibitors, several known P-gp substrates had no effect or only a slight modulatory effect on the BL-AP Papp of all probe substrates in MDCK-MDR1 cells. The secretory transport of P-gp substrates in MDCK-WT cells was more sensitive to inhibition by known P-gp modulators compared with MDCK-MDR1 cells. Low concentrations of ketoconazole (1–3 μM) activated the BL-AP Papp of [3H]vinblastine and [3H]digoxin in MDCK-MDR1 cells but not in MDCK-WT or Caco-2 cells. Determination of secretory transport in P-gp expressing cell monolayers, such as MDCK-MDR1 and Caco-2, may be complicated by substrate cooperativity and allosteric binding, which may result in the activation of P-gp. In addition, expression of other efflux transporters in these cell lines introduces additional complexity in distinguishing which transporter is responsible for substrate recognition and transport.

Footnotes

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

  • doi:10.1124/dmd.105.005421.

  • ABBREVIATIONS: P-gp, P-glycoprotein; MDCK, Madin-Darby canine kidney cells; Caco-2, human adenocarcinoma cells; DDI, drug-drug interaction; WT, wild type; AP, apical; BL, basolateral; HIV, human immunodeficiency virus; TEER, trans-epithelial electrical resistance; AM, acetoxymethyl ester; HBSS, Hanks' balanced salt solution; MDR1, multidrug resistance protein-1; MRP2, multidrug resistance protein-associated protein-2; BCRP, breast cancer resistance protein; LY335979, zosuquidar trihydrochloride; GF120918, Elacridar.

    • Received May 5, 2005.
    • Accepted August 10, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (11)
Drug Metabolism and Disposition
Vol. 33, Issue 11
1 Nov 2005
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Research ArticleArticle

FUNCTIONAL ASSESSMENT OF MULTIPLE P-GLYCOPROTEIN (P-GP) PROBE SUBSTRATES: INFLUENCE OF CELL LINE AND MODULATOR CONCENTRATION ON P-GP ACTIVITY

Mitchell E. Taub, Lalitha Podila, Diane Ely and Iliana Almeida
Drug Metabolism and Disposition November 1, 2005, 33 (11) 1679-1687; DOI: https://doi.org/10.1124/dmd.105.005421

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Research ArticleArticle

FUNCTIONAL ASSESSMENT OF MULTIPLE P-GLYCOPROTEIN (P-GP) PROBE SUBSTRATES: INFLUENCE OF CELL LINE AND MODULATOR CONCENTRATION ON P-GP ACTIVITY

Mitchell E. Taub, Lalitha Podila, Diane Ely and Iliana Almeida
Drug Metabolism and Disposition November 1, 2005, 33 (11) 1679-1687; DOI: https://doi.org/10.1124/dmd.105.005421
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