Rifaximin (Xifaxan)

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Background

Rifaximin, a rifamycin derivative, is a nonabsorbable antibiotic. Rifaximin inhibits RNA synthesis by binding the β subunit of the bacterial DNA-dependent RNA polymerase.
In vitro:Rifaximin, a gut-specific ligand for the human nuclear receptor pregnane-X receptor (PXR), contributes to the maintenance of the intestinal immune homeostasis. Rifaximin abrogates the binding of NF-κB caused by LPS. In human colon biopsies from inflammatory bowel diseases patients, exposure of rifaximin (100 μM) reduced mRNA levels of IL-8, Rantes, MIP-3α and TNFα induced by LPS stimulation [1]. Rifaximin acted on the β subunit of the deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase enzyme of bacteria to inhibit bacterial RNA synthesis. The susceptibility of Gram-positive organisms to rifaximin was greater than that of Gram-negative organisms [2]. In the DPX2 cell line transfected with stable recombinant human PXR expression, hPXR was significantly activated at RIFax concentrations over 1 μM and the EC50 was about 20 μM[3].
In vivo:In the small intestine of hPXR mice treated with rifaximin, several PXR target genes such as CYP3A11, GSTA1, MRP2, and OATP2 were up-regulated. Rifaximin treatment demonstrated no significant effect on hepatic PXR target genes in wild-type, Pxr-null, and hPXR mice [3]. In PXR-humanized mice, long-term administration of rifaximin for 6 months on the liver up-regulated the expression of hepatic genes related to triglyceride synthesis and lipid accumulation [4].
Clinical trials: Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy effectively. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy [5]. Among patients with irritable bowel syndrome (IBS) without constipation, treatment with rifaximin for 2 weeks provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools [6]. Rifaximin could improve the symptom in IBS patients, such as abdominal bloating and flatulence [7].

[1]. Mencarelli A, Renga B, Palladino G, et al. Inhibition of NF-κB by a PXR-dependent pathway mediates counter-regulatory activities of rifaximin on innate immunity in intestinal epithelial cells[J]. European journal of pharmacology, 2011, 668(1): 317-324.
[2]. Gillis J C, Brogden R N. Rifaximin[J]. Drugs, 1995, 49(3): 467-484.
[3]. Ma X, Shah Y M, Guo G L, et al. Rifaximin is a gut-specific human pregnane X receptor activator[J]. Journal of Pharmacology and Experimental Therapeutics, 2007, 322(1): 391-398.
[4]. Cheng J, Krausz K, Tanaka N, et al. Chronic exposure to rifaximin causes hepatic steatosis in pregnane X receptor-humanized mice[J]. Toxicological Sciences, 2012: kfs211.
[5]. Bass N M, Mullen K D, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy[J]. New England Journal of Medicine, 2010, 362(12): 1071-1081.
[6]. Pimentel M, Lembo A, Chey W D, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation[J]. New england journal of medicine, 2011, 364(1): 22-32.
[7]. Sharara A I, Aoun E, Abdul-Baki H, et al. A randomized double-blind placebo-controlled trial of rifaximin in patients with abdominal bloating and flatulence[J]. The American journal of gastroenterology, 2006, 101(2): 326-333.