Abstract
Rifaximin, a rifamycin analog approved for the treatment of travelers' diarrhea, is also beneficial in the treatment of multiple chronic gastrointestinal disorders. However, the mechanisms contributing to the effects of rifaximin on chronic gastrointestinal disorders are not fully understood. In the current study, rifaximin was investigated for its role in activation of the pregnane X receptor (PXR), a nuclear receptor that regulates genes involved in xenobiotic and limited endobiotic deposition and detoxication. PXR-humanized (hPXR), Pxr-null, and wild-type mice were treated orally with rifaximin, and rifampicin, a well characterized human PXR ligand. Rifaximin was highly concentrated in the intestinal tract compared with rifampicin. Rifaximin treatment resulted in significant induction of PXR target genes in the intestine of hPXR mice, but not in wild-type and Pxr-null mice. However, rifaximin treatment demonstrated no significant effect on hepatic PXR target genes in wild-type, Pxr-null, and hPXR mice. Consistent with the in vivo data, cell-based reporter gene assay revealed rifaximin-mediated activation of human PXR, but not the other xenobiotic nuclear receptors constitutive androstane receptor, peroxisome proliferator-activated receptor (PPAR)α, PPARγ, and farnesoid X receptor. Pretreatment with rifaximin did not affect the pharmacokinetics of the CYP3A substrate midazolam, but it increased the Cmax and decreased Tmax of 1′-hydroxymidazolam. Collectively, the current study identified rifaximin as a gut-specific human PXR ligand, and it provided further evidence for the utility of hPXR mice as a critical tool for the study of human PXR activators. Further human studies are suggested to assess the potential role of rifaximin-mediated gut PXR activation in therapeutics of chronic gastrointestinal disorders.
Footnotes
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This study was supported by the National Cancer Institute Intramural Research Program. J.R.I. is grateful to United States Smokeless Tobacco Company for a grant for collaborative research.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.121913.
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ABBREVIATIONS: RIFax, rifaximin, 4-deoxy-4′-methylpyrido[1′,2′-1,2]imidazo[5,4-c]rifamycin SV; CD, Crohn's disease; IBD, inflammatory bowel disease; PXR, pregnane X receptor; DSS, dextran sulfate sodium; PCN, pregnenolone 16α-carbonitrile; RIF, rifampicin, 3-(4-methylpiperazinyliminomethyl)rifamycin SV; hPXR, PXR-humanized; MDZ, midazolam; 1′-OH-MDZ, 1′-hydroxymidazolam; WT, wild-type; AUC, area under the serum concentration-time curve; LC-MS/MS, liquid chromatography-tandem mass spectrometry; qPCR, quantitative real-time polymerase chain reaction; GSTA, glutathione S-transferase α; MRP, multidrug resistance protein; OATP, organic anion transporting polypeptide; CAR, constitutive androstane receptor; PPAR, peroxisome proliferator-activated receptor; FXR, farnesoid X receptor; DMSO, dimethyl sulfoxide; Wy-14,643, pirinixic acid, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid; WT, wild-type mice; Fwd, forward; Rev, reverse; S. intestine, small intestine; GW4064, 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic.
- Received February 24, 2007.
- Accepted April 17, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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