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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Effect of Age on P-Glycoprotein Expression and Function in the Fischer-344 Rat

Jill S. Warrington, David J. Greenblatt and Lisa L. von Moltke
Journal of Pharmacology and Experimental Therapeutics May 2004, 309 (2) 730-736; DOI: https://doi.org/10.1124/jpet.103.061234
Jill S. Warrington
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David J. Greenblatt
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Lisa L. von Moltke
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Abstract

We investigated the effect of age on P-glycoprotein (P-gp) expression and function in rat liver, intestine, kidney, and endothelial cells of the blood-brain barrier (BBB) and lymphocytes. Flow cytometric analysis was used to examine P-gp expression in lymphocytes from male Fischer-344 rats from three age groups (young at 3-4 months, intermediate at 13-14 months, and old at 25-26 months). In addition, P-gp function in lymphocytes was assessed by measuring the ability of the P-gp inhibitor verapamil to limit the efflux of the fluorescent P-gp substrate rhodamine 123. P-gp expression was evaluated in the remaining four tissues by Western blot analysis. The effect of age on P-gp expression was tissue-specific. Although lymphocytic and hepatic P-gp expression increased with age, renal P-gp content was lower in the old kidneys. No statistical difference was observed in P-gp expression in intestinal microsomes or in BBB cell lysates among the three age groups. P-gp function was also increased by 6- to 8-fold in lymphocytes from the old rats. When P-gp expression was compared with CYP3A expression in these rats (reported elsewhere in this journal), we found that P-gp expression increased with age, whereas CYP3A expression and activity declined in the old livers. The converse pattern was observed in the kidney. Thus, age-related changes in P-gp expression and function are likely to be tissue-specific, and these changes may be inversely related to differences in CYP3A expression.

Footnotes

  • This work was supported in part by Grants MH-58435, DA-05258, DA-13209, DK/AI-58496, DA-13834, AG-17880, and RR-00054 from the Department of Health and Human Services.

  • DOI: 10.1124/jpet.103.061234.

  • ABBREVIATIONS: P-gp, P-glycoprotein; MDR1, multidrug resistance gene 1; P450, cytochrome P450; BBB, blood-brain barrier; PBMC, peripheral blood mononuclear cell; FITC, fluorescein isothiocyanate; PE, phycoerythrin; ANOVA, analysis of variance.

    • Received October 8, 2003.
    • Accepted February 2, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 309 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 309, Issue 2
1 May 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Effect of Age on P-Glycoprotein Expression and Function in the Fischer-344 Rat

Jill S. Warrington, David J. Greenblatt and Lisa L. von Moltke
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 730-736; DOI: https://doi.org/10.1124/jpet.103.061234

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

The Effect of Age on P-Glycoprotein Expression and Function in the Fischer-344 Rat

Jill S. Warrington, David J. Greenblatt and Lisa L. von Moltke
Journal of Pharmacology and Experimental Therapeutics May 1, 2004, 309 (2) 730-736; DOI: https://doi.org/10.1124/jpet.103.061234
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