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Regulation of Transporters by Nuclear Hormone Receptors: Implications during Inflammation

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Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada
* To whom correspondence should be addressed. Mailing address: Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College St., Toronto, ON M5S 3M2, Canada. Phone: (416) 946-3057. Fax: (416) 978-8511. E-mail: [email protected]
Cite this: Mol. Pharmaceutics 2008, 5, 1, 67–76
Publication Date (Web):December 12, 2007
Copyright © 2008 American Chemical Society

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    Abstract Image

    Membrane transporters play a critical role in the absorption, distribution, and elimination of both endogenous substrates and xenobiotics. Defects in transporter function can lead to altered drug disposition including toxicity or loss of efficacy. Inflammation is one condition during which variable drug response has been demonstrated, and this can be attributed, at least in part, to changes in the expression of transporter genes. Thus, knowledge of the mechanisms behind transporter regulation can significantly contribute to our ability to predict variations in drug disposition among individuals and during inflammatory disease. The discovery of several xenobiotic-activated nuclear hormone receptors during the past decade including the pregnane X receptor, constitutive androstane receptor, and farnesoid X receptor has contributed greatly toward this endeavor. These receptors regulate the expression of transporters such as P-glycoprotein, MRP2, MRP3, BCRP, and OATP2 (Oatp1a1/OATP1B1), all of which undergo altered expression during an inflammatory response. Nuclear receptors may therefore play an important role in mediating this effect. This review presents what is currently known about the role of nuclear receptors in transporter regulation during inflammation. The use of this knowledge toward understanding interindividual variation in drug response and drug interactions during inflammation as well toward the development of therapeutics to treat transporter-related diseases will also be discussed.

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