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General Description:

Rifamycin, identified by CAS number 6998-60-3, is a notable compound with significant therapeutic applications. Rifamycin is the prime member of the rifamycin family which are represented by drugs that are a product of fermentation from the gram-positive bacterium _Amycolatopsis mediterranei_, also known as _Streptomyces mediterranei_. The parent compound of rifamycin was rifamycin B which was originally obtained as a main product in the presence of diethylbarburitic acid. Some small modifications where performed in this inactive compound and with the creation of rifamycin SV there was the first antibiotic used intravenously for the treatment of tuberculosis. Rifamycin has had several direct derivative products such as rifamycin SV, rifaximin, rifampin and rifamycin CV. All of the derivatives have slight different physicochemical properties when compared to the parent structure. Rifamycin was further developed by Cosmo Technologies Ltd and approved in November 16, 2018 by the FDA as a prescription drug after being granted the designation of Qualified Infectious Disease Product which allowed it to have a status a priority review. This drug was also sent for review to the EMA in 2015 by Dr. Falk Pharma Gmbh and it was granted a waiver for the tested conditions.

Indications:

This drug is primarily indicated for: Rifamycin is indicated for the treatment of adult patients with travelers' diarrhea caused by noninvasive strains of _E. coli_. The status of the disease should not be complicated by fever or blood in the stool. To prevent drug-resistant bacteria, it is important to mention that the use of rifamycin for this indication should be only done in cases where the infection is proven or strongly suspected to be caused by bacteria. Travallers' diarrhea is very common problem affecting 20-60% of the travellers and it is defined as an increase in frequency of bowel movements to three or more loose stools per day during a trip abroad. This condition is rarely life threatening but in severe cases it can produce dehydration and sepsis. The most common cause of travellers' diarrhea is a pathogen and from the pathogens identified, bacteria is the most common cause followed by norovirus, rotavirus and similar viruses. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Rifamycin undergoes metabolic processing primarily in: When absorbed, rifamycin is mainly metabolzied in hepatocytes and intestinal microsomes to a 25-deacetyl metabolite. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Rifamycin are crucial for its therapeutic efficacy: Rifamycin has a very poor absorption and thus, the generation of an oral modified-release formulation using the technology of the multi-matrix structure was required for the generation of the FDA approved product. This preparation allows the delivery of the active ingredient in the distal small bowel and colon without interfering with the flora in the upper gastrointestinal tract. The multi-matrix is made by a lipophiic matrix surrounded in a hydrophilic matrix which allows for the protection of the active ingredient from dissolution in the intestinal aqueous fluids before it arrives in the cecum. All this matrix is surrounded by a gastro-resistant polymer that only desintegrate in a pH lower than 7. All this administration-customed formulation allows for a bioavailability of <0.1% and the plasma concentrations are reported to be of <2 ng/ml in patients receiving a dose of 400 mg. This confirms that the site of action of rifamycin stays in the small intestine and colon which prevents the need for dose adjustments in special populations as well as systemic drug interactions. The reported Cmax, tmax, AUC and mean residence time after a dosage of 250 mg of rifamycin is 36 mg/L, 5 min, 11.84 mg.h/L and 0.49 h respectively. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Rifamycin is an important consideration for its dosing schedule: The reported half-life when a dose of 250 mg of rifamycin was administered is 3 h. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Rifamycin exhibits a strong affinity for binding with plasma proteins: The protein binding of rifamycin is of about 80-95%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Rifamycin from the body primarily occurs through: From the administered dose, 18%, 50% and 21% is recovered in feces during the first 24, 48 and 72h after administration. This will represent about 90% of the administered dose eliminated by the feces while the urinary secretion is negligible. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Rifamycin is distributed throughout the body with a volume of distribution of: The reported volume of distribution after measured after a dosage of 250 mg of rifamycin is 101.8 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Rifamycin is a critical factor in determining its safe and effective dosage: The reported clearance when a dose of 250 mg of rifamycin was administered is 23.3 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Rifamycin exerts its therapeutic effects through: Rifamycin is known to be effective against Gram-positive and Gram-negative pathogens and mycobacteria. It is very effective against _E. coli_ reporting a MIC90 of 64-128 mcg/ml without showing cross-resistance with other antimicrobial agents. The specific indication of rifamycin is extremely important as ther were previous reports that indicated a high risk factor in the generation of resistant _E. coli_ strains in patients with inflammatory bowel disease. In clinical trials, rifamycin was tested in a randomized clinical trial of travellers' coming from Mexico and Guatemala. In this trial, rifamycin was proven to significantly reduce the symptoms of travellers' diarrhea. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Rifamycin functions by: Rifamycins, as well as all the other members of this group, present an antibacterial mechanism of action related to the inhibition of RNA synthesis. This mechanism of action is done by the strong binding to the DNA-dependent RNA polymerase of prokaryotes. The inhibition of the RNA synthesis is thought to be related with the initiation phase of the process and to involve stacking interactions between the naphthalene ring and the aromatic moiety in the polymerase. As well, it has been suggested that the presence of zinc atoms in the polymerase allows for the binding of phenolic -OH groups of the naphthalene ring. In eukaryotic cells, the binding is significantly reduced making them at least 100 to 10,000 times less sensitive to the action of rifamycins. The members of the rifamycin family present the same mechanism of action and the structural modifications are usually related to pharmacokinetic properties as well as to the interaction with eukaryotic cells. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Rifamycin belongs to the class of organic compounds known as macrolactams. These are cyclic amides of amino carboxylic acids, having a 1-azacycloalkan-2-one structure, or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. They are nitrogen analogues (the a nitrogen atom replacing the o atom of the cyclic carboxylic acid group ) of the naturally occurring macrolides, classified under the direct parent group Macrolactams. This compound is a part of the Organic compounds, falling under the Phenylpropanoids and polyketides superclass, and categorized within the Macrolactams class, specifically within the None subclass.

Categories:

Rifamycin is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Anti-Bacterial Agents, Anti-Infective Agents, Antibiotics for Topical Use, Antidiarrheals, Intestinal Antiinflammatory/antiinfective Agents, Antiinfectives for Systemic Use, Antimycobacterials, Antirheumatic Agents, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (strength unknown), Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (strength unknown), Cytochrome P-450 CYP2B6 Inhibitors, Cytochrome P-450 CYP2B6 Inhibitors (strength unknown), Cytochrome P-450 CYP2C19 Inducers, Cytochrome P-450 CYP2C19 Inducers (strong), Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 inhibitors (strength unknown), Cytochrome P-450 CYP2C8 Inducers, Cytochrome P-450 CYP2C8 Inducers (strength unknown), Cytochrome P-450 CYP2C8 Inhibitors, Cytochrome P-450 CYP2C8 Inhibitors (strength unknown), Cytochrome P-450 CYP2C9 Inducers, Cytochrome P-450 CYP2C9 Inducers (strength unknown), Cytochrome P-450 CYP2C9 Inhibitors, Cytochrome P-450 CYP2C9 Inhibitors (strength unknown), Cytochrome P-450 CYP2D6 Inhibitors, Cytochrome P-450 CYP2D6 Inhibitors (strength unknown), Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Inducers (strong), Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (strong), Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (strength unknown), Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Dermatologicals, Drugs for Treatment of Tuberculosis, Heterocyclic Compounds, Fused-Ring, Intestinal Antiinfectives, Lactams, Macrocyclic, MATE 1 Inhibitors, MATE inhibitors, OATP1B1/SLCO1B1 Inhibitors, OATP1B3 inhibitors, Ophthalmologicals, Organic Anion Transporting Polypeptide 2B1 Inhibitors, Otologicals, P-glycoprotein inhibitors, P-glycoprotein substrates, Rifamycin Antibacterial, Rifamycins, Sensory Organs. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Rifamycin include:

• Water Solubility: Insoluble
• Melting Point: 171 ºC
• Boiling Point: 972.8 ºC at 760 mm Hg
• logP: 5
• pKa: 1.8