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Drug Metabolism and Disposition Fast Forward
First published on December 20, 2007; DOI: 10.1124/dmd.107.019547

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Received for publication October 31, 2007.
Revised December 18, 2007.
Accepted for publication December 19, 2007.

HIV protease inhibitor A-792611 is a novel functional inhibitor of human PXR

Christine Healan-Greenberg 1, Jeffrey French Waring 1*, Dale J Kempf 1, Eric A.G. Blomme 1, Rommel G Tirona 2, Richard B Kim 2

1 Abbott Laboratories 2 The University of Western Ontario

* Address correspondence to: E-mail: jeff.waring{at}abbott.com

Abstract

Drug-drug interactions involving induction of cytochrome P450 enzymes (CYPs) can lead to loss of drug efficacy. Certain drugs, particularly those used to treat mycobacterial and human immunodeficiency virus (HIV) infections, are especially prone to induce CYPs. During studies to examine drug-interaction potential of compounds in cultured human hepatocytes, exposure with A-792611, a novel HIV protease inhibitor (PI) previously under investigation for the treatment of HIV infection, resulted in significant downregulation of constitutive CYP3A4 expression. Furthermore, co-administration of A-792611 was found to attenuate CYP3A4 induction mediated by known inducers rifampin and efavirenz. A-792611 also attenuated the rifampin and ritonavir-mediated activation of the human pregnane X receptor (PXR) in luciferase reporter assays. Microarray analysis on cultured human hepatocytes revealed that A-792611 treatment downregulated the expression of PXR target genes CYP3A4, CYP2B6, CYP2C8, and CYP2C9, whereas there was a lack of inductive effect observed in treated rat hepatocytes. A-792611 did not interact with other ligand-activated nuclear receptors that regulate CYP expression such as constitutive androstane receptor, farnesoid X receptor, vitamin D receptor and peroxisome proliferator-activated receptor a. These data suggest that A-792611 is a functional and effective human PXR inhibitor. Among the class of HIV-PIs, which are typically PXR activators, A-792611 appears to have a unique property for PXR antagonism and could be a useful tool for studying nuclear receptor pathway regulation.


Key words: CAR, CYP3A, cytochrome P450, drug discovery, genomics, inhibition, microarrays, PXR


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Computational Discovery of Novel Low Micromolar Human Pregnane X Receptor Antagonists
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[Abstract] [Full Text] [PDF]


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