Chemical Properties
Red-Orange Crystalline Powder
Usage
antibacterial, RNA synthesis inhibitor
Usage
Non-absorbable semisynthetic Rifamycin antibiotic
Description
Rifaximin is an antibiotic structurally related to rifamycin. It is reported to be efficacious
in the treatment of gastrointestinal infections and hepatic encephalopathy, being highly
active against Gram-positive and -negative aerobic and anaerobic bacteria. Due to poor
systemic absorption, rifaximin is effective in presurgical sterilization of the GI tract.It displays good activity against a wide spectrum of bacteria,
including Salmonella spp., S. aureus, and E. coli.
Uses
antibacterial, RNA synthesis inhibitor
Uses
Non-absorbable semisynthetic Rifamycin antibiotic
Definition
ChEBI: A semisynthetic member of the class of rifamycins and non-systemic gastrointestinal site-specific broad spectrum antibiotic. Used in the treatment of traveller's diarrhoea, hepatic encephalopathy and irritable bowel syndrome.
Brand name
Xifaxan (Salix);Normix.
Antimicrobial activity
The in-vitro activity is slightly inferior to that of rifampicin. The MIC90 for Gram-positive cocci is well below 1 mg/L, with the exception of enterococci (MIC 2–8 mg/L). Among intestinal pathogens C. difficile is sensitive (MIC90 0.8 mg/L), Esch. coli, Salmonella spp. and Shigella spp. are inhibited by 4–8 mg/L. Campylobacter jejuni is mostly insensitive.
Pharmaceutical Applications
A semisynthetic derivative of rifamycin S formulated for oral administration. It is poorly absorbed from the gastrointestinal tract, where its high concentrations are effective against a variety of gastrointestinal pathogens.
Mechanism of action
The mechanism of action of pyrazinamide is unknown, but recent findings suggest that pyrazinamide may be active either totally or in part as a pro-drug. Susceptible organisms produce pyrazinamidase, which is responsible for conversion of pyrazinamide to pyrazinoic acid intracellularly. Mutation in the pyrazinamidase gene (pncA) results in resistant strains of M . tuberculosis. Pyrazinoic acid has been shown to possess biological activity at a pH 5.4 or lower, in contract in vitro tests that show pyrazinoic acid is 8- to 16-fold less active than pyrazinamide . Pyrazinoic acid may lower the pH in the immediate surroundings of the M . tuberculosis to such an extent that the organism is unable to grow, but this physicochemical property appears to account for only some of the activity. The protonated pyrazinoic acid also can permeate the mycobacterial membrane to lower the pH of the cytoplasm. Recent evidence suggests that pyrazinoic acid decreases membrane potential in older, nonreplicating bacilli, thus decreasing membrane transport, and interferes with the energetics of the membrane.
Pharmacokinetics
Oral absorption is very low. However, a fraction of the dose may be absorbed and rapidly eliminated through the bile. A 400 mg oral dose produces a maximum plasma concentration of 3.8 mg/L after 1.2 h. The plasma half-life is 5.8 h. Up to 90% of the administered dose is concentrated in the gut, less than 0.2% in the liver and kidney, and less than 0.01% in other tissues.
Clinical Use
It is used for a variety of gastrointestinal diseases, including the treatment of traveler’s diarrhea. Preliminary results
suggest clinical efficacy in the therapy of hepatic encephalopathy and of C. difficile infections.
Side effects
Oral doses up to 100 mg/kg for 6 months produced no significant signs of toxicity to rats. Teratogenic effects in rats and rabbits have been reported (pregnancy category C).
Very few adverse effects were reported during human treatment, mostly gastrointestinal discomfort. Prolonged therapy was associated with infrequent urticarial skin reactions.
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].
Drug interactions
Potentially hazardous interactions with other drugs
Ciclosporin: concentration increased by ciclosporin.
Metabolism
Pyrazinamide is readily absorbed after oral administration, but little of the intact molecule is excreted unchanged. The major metabolic route consists of hydrolysis by hepatic microsomal pyrazinamidase to pyrazinoic acid, which may then be oxidized by xanthine oxidase to 5-hydroxypyrazinoic acid. The latter compound may appear in the urine either free or as a conjugate with glycine.
References
[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.
