Abstract
Drug-drug interactions involving induction of cytochrome P450 enzymes (P450s) 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 P450s. During studies to examine drug-interaction potential of compounds in cultured human hepatocytes, exposure with (S)-1-[(1S,3S,4S)-4-[(S)-2-(3-benzyl-2-oxo-imidazolidin-1-yl)-3,3-dimethyl-butyrylamino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-yl-benzyl)-pentylcarbamoyl]-2,2-dimethyl-propyl-carbamic acid methyl ester (A-792611), a novel HIV protease inhibitor (PI) previously under investigation for the treatment of HIV infection, resulted in significant down-regulation of constitutive CYP3A4 expression. Furthermore, coadministration 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 down-regulated 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 P450 expression such as constitutive androstane receptor, farnesoid X receptor, vitamin D receptor, and peroxisome proliferator-activated receptor α. 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 seems to have a unique property for PXR antagonism and could be a useful tool for studying nuclear receptor pathway regulation.
Footnotes
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This work was supported by U.S. Public Health Service Grant GM31304 (to R.B.K.).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.019547.
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ABBREVIATIONS: A-792611, (S)-1-[(1S,3S,4S)-4-[(S)-2-(3-benzyl-2-oxo-imidazolidin-1-yl)-3,3-dimethyl-butyrylamino]-3-hydroxy-5-phenyl-1-(4-pyridin-2-yl-benzyl)-pentylcarbamoyl]-2,2-dimethyl-propyl-carbamic acid methyl ester; PXR, pregnane X receptor; RXR, retinoid X receptor; CAR, constitutive androstane receptor; HIV, human immunodeficiency virus; PI, protease inhibitor; P450, cytochrome P450; DMSO, dimethyl sulfoxide; BSEP, bile salt export pump; FXR, farnesoid X receptor; VDR, vitamin D receptor; PPARα, peroxisome proliferator-activated receptor α; MDR, multidrug resistant; AhR, aryl hydrocarbon receptor; PCR, polymerase chain reaction; CDCA, chenodeoxycholate; CITCO, 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-3,4-dichlorobenzyl)oxime; Wy-14643, [4-chloro-6-(2,3-xylidino)-2-pyrimidylthio]acetic acid; ET-743, ecteinascidin 743; SR12813, 3,5-di-tert-butyl-4-hydroxystyrene-β,β-diphosphate acid tetraethyl ester.
- Received October 31, 2007.
- Accepted December 19, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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