Rifaximin (BRN-3584528; L-105SV; Fatroximin; Normix; Rifacol; Rifaxidin; Rifaxin; Ritacol; Rifaximin; RCIFAX, Rifagut, Xifaxan, Zaxine) is an orally bioavailable and semi-synthetic RNA synthesis inhibitor used to treat traveler's diarrhea caused by certain bacteria. It functions by attaching itself to the β subunit of the RNA polymerase that is dependent on bacterial DNA.
Physicochemical Properties
| Molecular Formula | C43H51N3O11 | |
| Molecular Weight | 785.88 | |
| Exact Mass | 785.352 | |
| Elemental Analysis | C, 65.72; H, 6.54; N, 5.35; O, 22.39 | |
| CAS # | 80621-81-4 | |
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| PubChem CID | 6436173 | |
| Appearance | Yellow to orange solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Melting Point | 200-205ºC(dec) | |
| Index of Refraction | 1.634 | |
| LogP | 3.22 | |
| Hydrogen Bond Donor Count | 5 | |
| Hydrogen Bond Acceptor Count | 12 | |
| Rotatable Bond Count | 3 | |
| Heavy Atom Count | 57 | |
| Complexity | 1590 | |
| Defined Atom Stereocenter Count | 9 | |
| SMILES | CC1=CC(N2C=C1)=NC3=C2C(NC(/C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H](C)[C@H](OC)/C=C\O[C@@](C4=O)(C)O5)=O)=C(O)C6=C(O)C(C)=C5C4=C63 |
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| InChi Key | NZCRJKRKKOLAOJ-XRCRFVBUSA-N | |
| InChi Code | InChI=1S/C43H51N3O11/c1-19-14-16-46-28(18-19)44-32-29-30-37(50)25(7)40-31(29)41(52)43(9,57-40)55-17-15-27(54-10)22(4)39(56-26(8)47)24(6)36(49)23(5)35(48)20(2)12-11-13-21(3)42(53)45-33(34(32)46)38(30)51/h11-18,20,22-24,27,35-36,39,48-51H,1-10H3,(H,45,53)/b12-11+,17-15+,21-13-/t20-,22+,23+,24+,27-,35-,36+,39+,43-/m0/s1 | |
| Chemical Name | [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,36-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22,30-octamethyl-6,23-dioxo-8,37-dioxa-24,27,33-triazahexacyclo[23.10.1.14,7.05,35.026,34.027,32]heptatriaconta-1(35),2,4,9,19,21,25(36),26(34),28,30,32-undecaen-13-yl] acetate | |
| Synonyms | BRN-3584528; L-105; BRN 3584528; L105; BRN3584528; L 105SV; Fatroximin; Normix; Rifacol; Rifamycin L 105; Rifaxidin; Rifaximin; Rifaxin; Ritacol; Rifaximin; trade names: RCIFAX, Rifagut; Xifaxan; Zaxine | |
| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | RNA polymerase | |
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| ln Vivo |
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| Cell Assay | Cell Line: Caco-2 cells Concentration: 0.1, 1.0 and 10.0 μM Incubation Time: 48 hours Result: Caused a significant and concentration-dependent reduction in cell proliferation. Reduced the expression of PCNA in a concentration-dependent manner. | |
| Animal Protocol |
Balb/c mice (6–8 weeks old) bearing 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis 10, 30 and 50 mg/kg/day Orally, p.o. daily for 7 days |
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| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Low absorption in both the fasting state and when administered within 30 minutes of a high-fat breakfast. In a mass balance study, after administration of 400 mg 14C-rifaximin orally to healthy volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was recovered in feces almost exclusively as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug.Rifaximin accounted for 18% of radioactivity in plasma. This suggests that the absorbed rifaximin undergoes metabolism with minimal renal excretion of the unchanged drug Metabolism / Metabolites In vitro drug interactions studies have shown that rifaximin, at concentrations ranging from 2 to 200 ng/mL, did not inhibit human hepatic cytochrome P450 isoenzymes: 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4. In an in vitro hepa-tocyte induction model, rifaximin was shown to induce cytochrome P450 3A4 (CYP3A4), an isoenzyme which rifampin is known to induce. Biological Half-Life Approximately 6 hours. |
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| Toxicity/Toxicokinetics |
Hepatotoxicity Despite widespread use, there is little evidence that rifaximin when given orally causes liver injury, either in the form of serum enzyme elevations or clinically apparent liver disease. Likelihood score: E (unlikely cause of clinically apparent liver injury). Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Rifaximin is poorly absorbed orally and used only for gastrointestinal infections. It is not likely to reach the breastmilk or bloodstream of the infant or cause any adverse effects in breastfed infants after maternal use. However, no published experience exists with rifaximin during breastfeeding; therefore, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk Relevant published information was not found as of the revision date. |
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| References |
[1]. Eur J Pharmacol . 2011 Oct 1;668(1-2):317-24. [2]. Clin Infect Dis . 2006 Feb 15;42(4):541-7. [3]. J Pharmacol Exp Ther . 2007 Jul;322(1):391-8. [4]. Toxicol Sci . 2012 Oct;129(2):456-68. |
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| Additional Infomation |
Rifaximin is 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. It has a role as a gastrointestinal drug, an orphan drug and an antimicrobial agent. It is a member of rifamycins, an acetate ester, a lactam, an organic heterohexacyclic compound, a macrocycle, a semisynthetic derivative and a cyclic ketal. Rifaximin is a semisynthetic, rifamycin-based non-systemic antibiotic, meaning that the drug will not pass the gastrointestinal wall into the circulation as is common for other types of orally administered antibiotics. It has multiple indications and is used in treatment of traveller's diarrhea caused by E. coli; reduction in risk of overt hepatic encephalopathy recurrence; as well as diarrhea-predominant irritable bowel syndrome (IBS-D) in adult women and men. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals. Rifaximin is a Rifamycin Antibacterial. Rifaximin is a nonabsorbable antibiotic that is used as treatment and prevention of travelers’ diarrhea and, in higher doses, for prevention of hepatic encephalopathy in patients with advanced liver disease and to treat diarrhea in patients with irritable bowel syndrome. Rifaximin has minimal oral absorption and has not been implicated in causing liver test abnormalities or clinically apparent liver injury. Rifaximin has been reported in Bos taurus with data available. Rifaximin is an orally administered, semi-synthetic, nonsystemic antibiotic derived from rifamycin SV with antibacterial activity. Rifaximin binds to the beta-subunit of bacterial DNA-dependent RNA polymerase, inhibiting bacterial RNA synthesis and bacterial cell growth. As rifaximin is not well absorbed, its antibacterial activity is largely localized to the gastrointestinal tract. A synthetic rifamycin derivative and anti-bacterial agent that is used for the treatment of GASTROENTERITIS caused by ESCHERICHIA COLI INFECTIONS. It may also be used in the treatment of HEPATIC ENCEPHALOPATHY. See also: Cefuzonam Sodium (annotation moved to). Drug Indication Rifaximin has multiple indications by the FDA: for the treatment of patients (≥12 years of age) with traveller's diarrhea caused by noninvasive strains of Escherichia coli; for the reduction of overt hepatic encephalopathy recurrence in patients ≥18 years of age; and in May 2015 it was approved for irritable bowel syndrome with diarrhea (IBS-D) treatment in adult men and women. FDA Label Mechanism of Action Rifaximin acts by inhibiting RNA synthesis in susceptible bacteria by binding to the beta-subunit of bacterial deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase enzyme. This binding blocks translocation, which stops transcription. Pharmacodynamics Rifaximin is a structural analog of rifampin and a non-systemic, gastrointestinal site-specific antibiotic. This non-systemic property of the drug is due to the addition of a pyridoimidazole ring, which renders it non-absorbable. Rifaximin acts by inhibiting bacterial ribonucleic acid (RNA) synthesis and contributes to restore intestinal microflora imbalance. Other studies have also shown rifaximin to be an pregnane X receptor (PXR) activator. As PXR is responsible for inhibiting the proinflammatory transcription factor NF-kappa B (NF-κB) and is inhibited in inflammatory bowel disease (IBD), rifaximin was proven to be effective for the treatment of IBS-D. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (3.82 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 3 mg/mL (3.82 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 30.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 3: 2.08 mg/mL (2.65 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2725 mL | 6.3623 mL | 12.7246 mL | |
| 5 mM | 0.2545 mL | 1.2725 mL | 2.5449 mL | |
| 10 mM | 0.1272 mL | 0.6362 mL | 1.2725 mL |