Rifampicin

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Used in Switzerland

Red to orange platelets from acetone

Red-brown crystalline powder

Freely sol in methyl chloride, dimethyl sulfoxide; sol in tetrahydrofuran; slightly sol in water (pH less than 6), acetone, carbon tetrachloride

Freely soluble in chloroform, soluble in ethyl acetate and in methanol.

In water, 1,400 mg/L at 25 °C

Breast Feeding; Lactation; Milk, Human; Anti-infective Agents; Antitubercular Agents; Leprostatic Agents; Rifamycins

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Antileprosy medicines

Very stable in dimethyl sulfoxide; rather stable in water.

Unstable in light, heat, air and moisture

1.7

Zwitterion with pKa 1.7 related to the 4-hydroxy and pKa 7.9 related to the 3-piperazine nitrogen

Warning

H302 (98.4%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 61 reports by companies from 17 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hazard Traits - Developmental Toxicity; Reproductive Toxicity

Rifampin: Does not have an individual approval but may be used under an appropriate group standard

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl rifampin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Intensive support measures should be instituted and individual symptoms treated as they arise. Since nausea and vomiting are likely to be present, gastric lavage is probably preferable to induction of emesis. Following evacuation of the gastric contents, the instillation of activated charcoal slurry into the stomach may help absorb any remaining drug from the gastrointestinal tract. Antiemetic medication may be required to control severe nausea and vomiting. Active diuresis (with measured intake and output) will help promote excretion of the drug. Hemodialysis may be of value in some patients. (L1712)

Interaction between ethambutol and rifampicin (rifampin) may have caused occurrence of overt Stevens-Johnson syndrome in 40 yr old male tuberculosis patient.

Concurrent daily consumption of alcohol may increase the risk of rifampin-induced hepatotoxicity and increased metabolism of rifampin; dosage adjustment of rifampin may be necessary, and patients should be monitored closely for signs of hepatotoxicity.

Rifampin may increase metabolism of theophylline, oxtriphylline, and aminophylline by induction of hepatic microsomal enzymes, resulting in increased theophylline clearance.

Chronic use of hepatic enzyme-inducing agents prior to anesthesia, except isoflurane, may increase anesthetic metabolism, leading to increased risk of hepatotoxicity.

For more Interactions (Complete) data for RIFAMPIN (40 total), please visit the HSDB record page.

Liver injury from rifampin is uncommon, but well documented. Long term therapy with rifampin is associated with minor, transient elevations in serum aminotransferase levels in 10% to 20% of patients, abnormalities that usually do not require dose adjustment or discontinuation. Rifampin has unusual and paradoxical effects on serum bilirubin levels. In most patients, serum bilirubin levels (both total and indirect) increase during the first few days of rifampin therapy, whereupon they usually decrease to below baseline. In addition, rifampin therapy can be associated with a prominent increase in both direct and total bilirubin within a few weeks of starting therapy without evidence of liver injury. This effect is seen in patients with significant underlying liver disease such as cirrhosis, as well as in the rare individual with Dubin Johnson syndrome or mutations in the hepatic canicular protein known as ABC C2 or MRP2 which is responsible for transport of conjugated bilirubin from the hepatocyte into the bile canalicus.

IDENTIFICATION: Rifampicin is an antibiotic used to treat tuberculosis. Rifampicin is a semisynthetic derivative of rifamycin antibiotics which are produced by the fermentation of a strain of Streptomyces mediterranei. The fermentation produces rifamycin B. Rifamycin B is transformed by a series of synthesis reactions. Color: Red to orange odorless powder. It is very slightly soluble in water, acetone, carbon tetrachloride, alcohol and ether. It is freely soluble in chloroform, DMSO; soluble in ethyl acetate and methyl alcohol and tetrahydrofuran. Solubility in aqueous solutions is increased at acidic pH. Melting point 138 to 188 °C. Rifampicin has 2 pKa since it is a Zwitterion, pKa 1.7 related to 4-hydroxy and pKa 7.9 related to 3-piperazine nitrogen. A 1% suspension in water has pH 4.5 to 6.5. Indications: The primary indications for rifampicin are for treatment of tuberculosis (pulmonary and extrapulmonary lesions) and for leprosy. It is also useful for elimination of Neisseria meningococci in carriers (but not recommended for active meningococcal infection) and for Gram positive (Staphylococcus aureus and epidermidis, Streptococcus pyogenes, viridans and pneumoniae) and gram negative bacteria (Hemophilus influenzae type B). It has some anti-chlamydial activity and in vitro activity against some viruses (poxvirus and adenovirus) at high doses. It has recently been used for brucellosis. HUMAN EXPOSURE: Main risks and target organs: The main target organs are the liver and the gastrointestinal system. Risks of concern are toxic hepatitis with elevation of bile and bilirubin concentrations, anaemia, leukopenia, thrombocytopenia and bleeding. Summary of clinical effects: Some clinical manifestations of overdosage are extension of adverse effects. During therapy, rifampicin is usually well tolerated, however, adverse side-effects are common in intermittent rifampicin intake. These include febrile reaction, eosinophilia, leukopenia, thrombocytopenia, purpura, hemolysis and shock, hepatotoxicity and nephrotoxicity. Gastrointestinal adverse reactions may be severe leading to pseudomembranous colitis. Neurotoxic effects include confusion, ataxia, blurring of vision, dizziness and peripheral neuritis. A common toxic effect is red skin with orange discoloration of body fluids. Fatalities from adverse reactions have been reported. Rifampicin has shown no significant effects on the human fetus. It diffuses into milk and other body fluids. Contraindications: Rifampicin is contraindicated in known cases of hypersensitivity to the drug. It may be contraindicated in pregnancy (because of teratogenicity noted in animal studies and since the effects of drugs on fetus has not been established) except in the presence of a disease such as severe tuberculosis. It is contraindicated in alcoholics with severely impaired liver function and with jaundice. Routes of entry: Oral: This is the common route of entry. Eye: Use for ocular chlamydial infection treatment. Parenteral: Rifampicin may be given intravenously. Kinetics: Absorption by route of exposure: Rifampicin is readily absorbed from the gastrointestinal tract (90%). Peak plasma concentration occurs at 1.5 to 4 hours after an oral dose. Food may reduce and delay absorption. Distribution by route of exposure: Intravenous rifampicin has the same distribution as in oral route. Eighty nine percent of rifampicin in circulation is bound to plasma proteins. It is lipid soluble. It is widely distributed in body tissues and fluids. When the meninges are inflamed, rifampicin enters the cerebrospinal fluid. It reaches therapeutic levels in the lungs, bronchial secretions, pleural fluid, other cavity fluids, liver, bile, and urine. Rifampicin has a high degree of placental transfer with a fetal to maternal serum level ratio of 0.3. It is distributed into breast milk. The apparent volume of distribution (VD) is 0.93 to 1.6 L/kg. Biological half-life by route of exposure: The biological half-life is three hours range (2 to 5 hours). This half-life increases with single high doses or with liver disease. The half-life decreases by 40% during the first two weeks of therapy because of enhanced biliary excretion and induction of its own metabolism. Plasma half-life may decrease after repeated administration. The half-life of rifampicin decreased from 3.5 hours at start of therapy to 2 hours after daily administration for 1 to 2 weeks, and remained constant thereafter. Plasma half-life shortens to 1.8 to 3.1 hours in the presence of anemia. Metabolism: Approximately 85% of rifampicin is metabolised by the liver microsomal enzymes to its main and active metabolite-deacetylrifampicin. Rifampicin undergoes enterohepatic recirculation but not the deacetylated form. Rifampicin increases its own rate of metabolism. Rifampicin may also be inactivated in other parts of the body. Formylrifampicin is a urinary metabolite that spontaneously forms in the urine. Elimination by route of exposure: Rifampicin metabolite deacetylrifampicin is excreted in the bile and also in the urine. Approximately 50% of the rifampicin dose is eliminated within 24 hours and 6 to 30% of the drug is excreted unchanged in the urine, while 15% is excreted as active metabolite. Approximately 43 to 60% of oral dose is excreted in the feces. Intrinsic total body clearance is 3.5 (+/- 1.6) mL/min/kg, reduced in kidney failure. Renal clearance is 8.7 mL/min/kg. Rifampicin levels in the plasma are not significantly affected by haemodialysis or peritoneal dialysis. Rifampicin is excreted in breastmilk (1 to 3 ug/ml). Mode of action: Toxicodynamics: Rifampicin causes cholestasis at both the sinusoids and canaliculi of the liver because of defect in uptake by hepatocytes and defect in excretion, respectively. Rifampicin may produce liver dysfunction. Hepatitis occurs in 1% or less of patients, and usually in the patient with pre-existing liver disease. Hypersensitivity reactions may occur, usually characterized by a "flu" type syndrome. Nephrotoxicity appears to be related to a hypersensitivity reaction and usually occurs after intermittent or interrupted therapy. It has been suggested that some of the adverse effects associated with rifampicin may be attributed to its metabolite desacetylrifampicin. It is lipid soluble, and thus can reach and kill intracellular, as well as extracellular, Mycobacteria. Rifampicin does not bind to mammalian nuclear RNA polymerase and therefore does not affect the RNA synthesis in human beings. Rifampicin, however, may affect mammalian mitochondrial RNA synthesis at a concentration that is 100 times higher than that which affects bacterial RNA synthesis. Pharmacodynamics: Rifampicin has high activity against mycobacterial organisms, including Mycobacterium tuberculosis and M.leprae. It is also active against Staphylococcus aureus, coagulase negative staphylocci, Listeria monocytogenes, Neisseria meningitidis, Haemophilus influenzae, Legionella spp., Brucella, some strains of Escherichia coli, Proteus mirabilis, anaerobic cocci, Clostridium spp., and Bacteroides. Rifampicin is also reported to exhibit an immunosuppressive effect which has been seen in some animal experiments, but this may not be clinically significant in humans. Rifampicin may be bacteriostatic or bactericidal depending on the concentration of drug attained at site of infection. The bactericidal actions are secondary to interfering with the synthesis of nucleic acids by inhibiting bacterial DNA-dependent RNA polymers at the B-subunit thus preventing initiation of RNA transcription, but not chain elongation. Carcinogenicity: One report showed that nasopharyngeal lymphoma may develop after therapy of two years for Pott's disease. This was probably secondary to the immunosuppressive effects of rifampicin. An increase of hepatomas in female mice has been reported in one strain of mice,following one year's administration of rifampicin at a dosage of 2 to 10% of the maximum human dosage. Because of only limited evidence available for the carcinogenicity of rifampicin in mice and the absence of epidemiological studies, no evaluation of the carcinogenicity of rifampicin to humans could be made. Teratogenicity: Malformation and death have been reported in infants born to mothers exposed to rifampicin, although it was the same frequency as in the general population. Interactions: Food lowers peak blood levels because of interference with absorption of rifampicin. Antacids containing aluminium hydroxide reduced the bioavailability of rifampicin. Para-amino salicylic acid granules may delay rifampicin absorption (because of bentonite present as a granule excipient) which leads to an inadequate serum level of rifampicin. These two drugs should be given 8 to 12 hours apart. Isoniazid and rifampicin interaction has led to hepatotoxicity. (Note: slow acetylators of isoniazid have accelerated rifampicin clearance). Alcohol intake with rifampicin increases the risk for hepatotoxicity. Rifampicin induces microsomal enzymes of the liver and therefore accelerates metabolism of some drugs, beta blockers, calciferol, coumadins, cyclosporin, dapsone, diazepam, digitalis, hexobarbital, ketoconazole, methadone, oral contraceptive pills, oral hypoglycaemic agents, phenytoin, sulphasalazine, theophylline, some anti-arrhythmic drugs such as disopyramide, lorcainide, mexiletine, quinidine, and verapamil. Rifampicin induces liver steroid metabolizing enzyme thus lowering the levels of glucocorticoids and mineralocorticoids. Rifampicin lowers chloramphenicol serum levels when the two drugs are used together. When rifampicin and oral contraceptives are used concomitantly, there is decreased effectiveness of oral contraceptives because of the rapid destruction of oestrogen by rifampicin and the latter being a potent inducer of hepatic metabolising enzymes. It was reported that rifampicin may be the cause of some menstrual disorders when used with oral contraceptive pills. When rifampicin and corticosteroids are used, there is a reduction of plasma cortisol half-life and increased urinary excretion of cortisol metabolite. It may be necessary to double or quadruple the dosage of the steroid. When rifampicin and cyclosporin are taken, the serum levels of cycloserine may be lowered. In the therapy of leprosy, rifampicin may induce dapsone metabolism, however, this is of minor significance in the clinical setting. The clinical condition of patients, who are on rifampicin and also taking digoxin for heart failure, may deteriorate because of falling digoxin levels. Hence there may be a need to increase the dosage of digitalis. Another cardiac drug is disopyramide which is used for cardiac dysrhythmias, and when taken with rifampicin, there is a decrease in levels of the antiarrhythmic agent. The clinical importance of this effect has yet to be determined. Patients on methadone maintenance for narcotic detoxification may develop narcotic withdrawal when methadone plasma levels decreased as a consequence of taking rifampicin at the same time. It is also possible that rifampicin alters the distribution of methadone. Rifampicin induces hepatic enzyme metabolism which can decrease metoprolol blood levels, although this may be clinically insignificant. In patients who receive rifampicin and phenytoin together, there is an increase of clearance of phenytoin by twofold, significantly reducing the effects of the anticonvulsant drug. Modification of quinidine dose is necessary when this is used with rifampicin because of the risk of ventricular dysrhythmias. It is recommended that quinidine dosage be always readjusted when one adds or discontinues rifampicin therapy. When verapamil and rifampicin are taken together, rifampicin induces liver enzymes which increases the metabolism of the calcium channel blocker leading to undetectable verapamil levels. Rifampicin can lower the plasma calciferol (Vitamin D) level because of induction of enzyme activity. Barbiturates and salicylates decrease the activity of rifampicin. Effects with clofazimine range from no effect to decrease in the rate of absorption of rifampicin, delay in the time it reaches peak plasma concentrations, decrease in plasma rifampicin concentrations. Rifampicin can decrease the therapeutic levels of ketoconazole when given together. When rifampicin is taken with oral hypoglycemic agents (tolbutamide and chlorpropamide), these latter medications had a decrease in elimination half-lives. Rifampicin enhances antifungal actions of amphotericin B. Probenecid intake diminishes hepatic uptake of rifampicin. ANIMAL/PLANT STUDIES: Carcinogenicity: An increase of hepatomas in female mice has been reported in one strain of mice, following one year's administration of rifampicin at a dosage of 2 to 10% of the maximum human dosage. Teratogenicity: Teratogenic effects noted in rodents treated with high doses 100 to 150 mg/kg bodyweight daily in rodents have been reported to cause cleft palate and spina bifida. Rifampicin is teratogenic for rats and mice. Mutagenicity: The available studies on mutagenicity indicate an absence of mutagenic effect.

Rifampin is usually well tolerated in patients due to its rapid metabolism ability in the liver, even in high concentrations. However, rifampin can cause toxicity either related to dosage, primarily affecting the liver, or treatment duration, involving immunoallergic reactions. Dose-related toxic effects become apparent after ingesting approximately 9 to 15 g of rifampin.

Rifampin acts via the inhibition of DNA-dependent RNA polymerase, leading to a suppression of RNA synthesis and cell death.

/SIGNS AND SYMPTOMS/ Hypersensitivity reactions characterized by a flu-like syndrome with episodes of fever, chills, and sometimes with headache, dizziness, and bone pain have occurred with rifampin. Edema of the face and extremities, decrease in blood pressure, and shock also have been reported. Dyspnea, sometimes accompanied by wheezing, may also occur. Occasionally, pruritus, urticaria, acneiform eruptions, rash, pemphigoid reactions, eosinophilia, sore mouth, sore tongue, anaphylaxis, exfoliative dermatitis, and exudative conjunctivitis have also occurred. Stevens-Johnson syndrome occurred in at least one patient receiving the drug. Some cutaneous reactions, including flushing and pruritus (with or without rash), are mild and self-limiting and do not appear to be hypersensitivity reactions to rifampin. More serious cutaneous reactions occur less frequently and do appear to be hypersensitivity reactions to the drug.

/SIGNS AND SYMPTOMS/ Overdosage of rifampin produces symptoms that are principally extensions of common adverse reactions. These include nausea, vomiting, lethargy, and brownish-red or orange discoloration of skin, urine, sweat, saliva, tears, and feces in proportion to the amount of drug ingested. Following massive overdosage of rifampin, hepatic involvement can develop within a few hours and is manifested by liver enlargement (possibly with tenderness), jaundice, rapid increases in total and direct serum bilirubin and liver enzymes, and loss of consciousness. Hepatotoxicity may be more marked in patients with prior hepatic impairment. An effect upon the hematopoietic system, electrolyte concentrations, or acid-base balance is unlikely.

/SIGNS AND SYMPTOMS/ Thrombocytopenia, leukopenia, purpura, hemolytic anemia, hemolysis, hemoglobinuria, hematuria, and decreased hemoglobin concentrations have occurred with rifampin. Acute hemolytic anemia has generally occurred only with intermittent rifampin therapy. Thrombocytopenia has been reported principally with high-dose intermittent rifampin therapy, but also has been reported rarely after rifampin therapy was discontinued and then resumed; thrombocytopenia occurs only rarely during daily rifampin therapy. Thrombocytopenia generally is reversible if rifampin is discontinued as soon as purpura occurs; cerebral hemorrhage and fatalities have been reported when rifampin therapy was continued or resumed after the appearance of purpura. In addition, disseminated intravascular coagulation has been reported rarely in patients receiving rifampin.

/CASE REPORTS/ A 26-yr-old man died after deliberately ingesting 200 capsules of 300 mg rifampin (60 g total). In 1st few hr, drug and its metabolism products imparted yellow to yellow-orange discoloration to skin, urine, stool, mucous membranes of mouth and nasopharynx.

For more Human Toxicity Excerpts (Complete) data for RIFAMPIN (7 total), please visit the HSDB record page.

Rifampicin

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 24: (1980) Some Pharmaceutical Drugs

1987

1987

3, not classifiable as to its carcinogenicity to humans. (L135)

Drug Induced Liver Injury Rank (DILIrank 2.0)

Rifampin

vMost-DILI-concern

8

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl rifampin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

J04AB02

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

J04AB02

Rifampin works by binding to the beta-subunit of microbial DNA-dependent RNA polymerase (RNAP), thereby inhibiting the enzyme and impeding RNA synthesis. It reduces the affinity of RNAP for short RNA transcripts. It has no activity against the mammalian RNAP enzyme.

Although rifampin is most active during cell multiplication ... /it/ appears to have some effect on resting cells. Electron microscopy has revealed changes in cytoplasm and disappearance of ribosomes in tubercle bacilli exposed to rifampin, indicating inhibition of DNA-dependent RNA polymerase.

Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria and other microorganisms by forming a stable drug-enzyme complex, leading to suppression of initiation of chain formation (but not chain elongation) in RNA synthesis. More specifically, the beta subunit of this complex enzyme is the site of action of the drug, although rifampin binds only to the holoenzyme. Nuclear RNA polymerase from a variety of eukaryotic cells does not bind rifampin, and RNA synthesis is correspondingly unaffected. While rifampin can inhibit RNA synthesis in mammalian mitochondria, considerably higher concentrations of the drug are required than for the inhibition of the bacterial enzyme.

High concentrations of rifamycin antibiotics also inhibit viral DNA-dependent RNA polymerases and reverse transcriptases.

Rifampin is bactericidal for both intracellular and extracellular microorganisms.

Developmental expression of CYPlAl, CYPlA2 and CYP3A6 in the rabbit have been studied. Cytochromes P450IAl, P450IA2 and P450IIIA6 exhibited comparable patterns of developmental expression. Present at low level (less than 0.05 mnol/ng) in the new born animal up to week 3, these proteins sharply accumulated between weeks 3 and 4 to reach a maximum by week 4 (P450IAl, 0.2 nmol/mg; P450IA2, 0.8 nmol/ng; P450IIIA6, 0.12 nmol/mg) and decr in the adult (P450IAl, 0.2 nmol/mg; P450IA2, 0.4 mnol/mg; P450IIIA6, 0.09 nmol/mg). Cytochromes P450IAl and P450IA2 were not expressed in the untreated fetus. Onset of CYP3A6 gene expression occurred at day 30 of gestation and both transcription and mRNA accumulation were transplacentally inducible by rifampicin only shortly before birth, i.e. after treatment of the females between days 28 and 30 of gestation. Both long (1.85 kb) and short (1.7 kb) mRNA transcripts were expressed in untreated or rifampicin treated fetuses. CYP3A6 gene expression was also induced by rifampicin in l week old and 2 week old animals. Developmental expression of CYPlAl and CYPlA2 genes was shown to be closely related to the diet change accompanying weaning which occurs at weeks 3-4. In animals subjected to either delayed (week 6) or early (week 2) weaning, sharp accumulation of messages, proteins and related activities were delayed or anticipated accordingly with respect to normal weaning. Artificially scheduled weaning gave similar results when repeated with biological grade lucern (grown in the absence of chemical fertilizers, pesticides) ... the main constituent of commercial rabbit chow. While CYP3A6 gene expression could be brought forward by early weaning at week 2, both message and protein did not exhibit incr accumulation after delayed weaning at week 6, and remained at the low level of the new born animal. Treatment of l week old and 2 week old animals with triiodothyronine or of 3 week old animals with propylthiouracil, an antithyroid factor, did not modify the normal pattern of developmental expression of genes CYPlAl, CYPlA2 and CYP3A6. ...

In healthy adults, the mean biological half-life of rifampin in serum averages 3.35±0.66 hours after a 600 mg oral dose, with increases up to 5.08±2.45 hours reported after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately two to three hours. The half-life does not differ in patients with renal failure at doses not exceeding 600 mg daily, and, consequently, no dosage adjustment is required. Following a single 900 mg oral dose of rifampin in patients with varying degrees of renal insufficiency, the mean half-life increased from 3.6 hours in healthy adults to 5.0, 7.3, and 11.0 hours in patients with glomerular filtration rates of 30 to 50 mL/min, less than 30 mL/min, and in anuric patients, respectively.

The half-life of rifampin varies from 1.5 to 5 hours and is increased in the presence of hepatic dysfunction; it may be decreased in patients receiving isoniazid concurrently who are slow inactivators of this drug. The half-life of rifampin is progressively shortened by about 40% during the first 14 days of treatment, owing to induction of hepatic microsomal enzymes with acceleration of deacetylation of the drug.

The plasma half-life of rifampin in children 6-58 months of age averages 2.9 hours following oral administration of a single 10 mg/kg dose of the drug. Plasma half-life of the drug in children 3 months to 12.8 years of age following IV doses of the drug was 1.04-3.81 hours during the first few days of therapy and decreased to 1.17-3.19 hours after 5-14 days of therapy.

Rifampin is rapidly eliminated in the bile and undergoes progressive enterohepatic circulation to form its primary metabolite, 25-desacetyl rifampin, which retains about 20% of rifampicin’s antimicrobial activity. It is suggested that arylacetamide deacetylase is the liver esterase involved in the biotransformation of rifampin to 25-desacetyl rifampin. Nearly all the drug in the bile is in its deacetylated form within about six hours of administration. Deacetylation reduces intestinal reabsorption and facilitates elimination.

The effects of rifampicin ... and phenobarbital ... on the metabolic fate of isoniazid ... and hydrazine ... were studied in rats. Male Wistar rats were fasted and injected with rifampicin at 30 mg/kg ip for 6 days, or with phenobarbital at 50 mg/kg for 3 days as pretreatment. After pretreatment, the rats were injected with isoniazid at 40 mg/kg ip. Twenty four hour urine samples were collected, and urinary concentrations of hydrazine and acetylhydrazine ... were determined by gas chromatography/mass spectrometry. The rats were /sacrificed/, livers were immediately perfused in situ and homogenized, and hepatic distribution of metabolites was determined. Separately, blood was sampled and plasma hydrazine concn were determined at 0.5, 1, 2, 3, and 4 hr after a jugular injection of 5 mg/kg hydrazine. Within 1 hr after injection of isoniazid, hydrazine and acetylhydrazine were detected in the liver and plasma. The concn of hydrazine in rifampicin or phenobarbital pretreated groups were significantly lower than those in the control group; the concn of acetylhydrazine were not altered. Pretreatment with rifampicin or phenobarbital resulted in a marked incr in the urinary elimination of hydrazine. ...

In guinea pigs, rabbits and humans, major metabolite of rifampicin in urine and bile is 25-o-deacetyl rifampicin; in body fluids of dogs and rats an unidentified metabolite has been detected.

Rifampin is metabolized in the liver to a deacetylated derivative which also possesses antibacterial activity.

Several fast growing Mycobacterium strains were found to inactivate rifampin. Two inactivated compounds (RIP-Ma and RIP-Mb) produced by these organisms were different from previously reported derivatives, i.e., phosphorylated or glucosylated derivatives, of the antibiotic. The structures of RIP-Ma and RIP-Mb were determined to be those of 3-formyl-23-[O-(alpha-D-ribofuranosyl)]rifamycin SV and 23-[O-(alpha-D-ribofuranosyl)]rifampin, respectively. To our knowledge, this is the first known example of ribosylation as mechanism of antibiotic inactivation.

Primarily hepatic, rapidly deacetylated. Route of Elimination: Less than 30% of the dose is excreted in the urine as rifampin or metabolites. Half Life: 3.35 (+/- 0.66) hours

VJT6J7R4TR

RIFAMPIN

Established Pharmacologic Class [EPC] - Rifamycin Antibacterial

Chemical Structure [CS] - Rifamycins

Rifampin is a Rifamycin Antibacterial.

RIFAMPIN

Substances obtained from various species of microorganisms that are, alone or in combination with other agents, of use in treating various forms of tuberculosis; most of these agents are merely bacteriostatic, induce resistance in the organisms, and may be toxic.

Substances that suppress Mycobacterium leprae, ameliorate the clinical manifestations of leprosy, and/or reduce the incidence and severity of leprous reactions.

Compounds that inhibit cell production of DNA or RNA.

Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP2B6.

Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP2C8.

Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP2C19.

Upon oral administration, rifampin is readily absorbed from the gastrointestinal tract. Peak serum concentrations in healthy adults and pediatric populations vary widely from individual to individual. Following a single 600 mg oral dose of rifampin in healthy adults, the peak serum concentration averages 7 mcg/mL but may vary from 4 to 32 mcg/mL. Absorption of rifampin is reduced by about 30% when the drug is ingested with food. In healthy male volunteers who received a 300 mg dose of rifampin, the mean Cmax was 9 ± 3 mcg/L. The value. increased to 17.5 ± 5 mcg/L for a 600 mg dose.

Less than 30% of the dose is excreted in the urine as rifampin or metabolites. After absorption, rifampin is rapidly eliminated in the bile, and enterohepatic circulation ensues.

Following intravenous administration of a 300 mg and 600 mg dose of rifampin infused over 30 minutes to healthy male volunteers, the volume of distribution at steady state was 0.66 ± 0.14 and 0.64 ± 0.11 L/kg, respectively. Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid.

Following intravenous administration of a 300 mg and 600 mg dose of rifampin infused over 30 minutes to healthy male volunteers, the total body clearance was 0.19 ± 0.06 and 0.14 ± 0.03 L/hr/kg, respectively.

Rifampin is distributed throughout the body and is present in effective concentrations in many organs and body fluids, including the CSF. This is perhaps best exemplified by the fact that the drug may impart an orange-red color to the urine, feces, saliva, sputum, tears, and sweat ... .

Up to 30% of a dose of the drug is excreted in the urine and 60% to 65% in the feces; less than half of this may be unaltered antibiotic.

Antibacterial (tuberculostatic)

MEDICATION

Use (kg; approx.) in Germany (2009): >1000

For the treatment of Tuberculosis and Tuberculosis-related mycobacterial infections.

Rifamycin sv ... is converted to 8-carboxaldehyde derivative, known ... as 3-formylrifamycin sv, and this is condensed with 1-amino-4-methylpiperazine in schiff base reaction to yield rifampin.

Rifamycin SV + dimethylformamide + N-methyl-piperazine (Vilsmeier reaction/diazotisation/reduction/imine formation)

Semisynthetic antibiotic obtained by reacting 3-formylrifamycin SV with 1-amino-4-methylpiperazine in tetrahydrofuran.

Oral: Capsules: 150 mg, Rifadin (Aventis), Rifampin Capsules (Eon); 300 mg, Rifadin (Aventis), Rifampin Capsules (Eon), Rimacetane (with parabens) (Sandoz). Parenteral: For Injection: 600 mg Rifadin IV (with sodium formaldehyde sulfoxylate) (Aventis), Rifampin for Injection (Bedford).