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.
来源:Hazardous Substances Data Bank (HSDB)
代谢
利福平在肝脏中被代谢成为一种去乙酰化衍生物，这种衍生物也具有抗菌活性。
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.
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.
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.
Rifampin is also associated with rare instances of clinically apparent liver injury accompanied by symptoms and jaundice, which can be severe and even fatal. Because rifampin is usually given in combination with isoniazid and/or pyrazinamide, two other known hepatotoxic agents, the cause of the acute liver injury in patients on rifampin may be difficult to relate to a single agent and some evidence suggests that these combinations are more likely to cause injury than the individual drugs would suggest. Typically, the onset of injury due to rifampin is within 1 to 6 weeks (which may help separate it from isoniazid injury which is often later), but cases with longer latency have been reported. The serum enzyme pattern is usually hepatocellular at the onset of injury, but can cholestatic and mixed in contrast to isoniazid. Extrahepatic manifestations such as fever, rash, arthralgias, facial edema and eosinophilia are uncommon as is autoantibody formation.
Likelihood score: A (well established cause of clinically apparent liver injury).
来源:LiverTox
毒理性
致癌性证据
没有关于人类的数据可用。动物致癌性证据有限。总体评估：第3组：该物质对人类致癌性无法分类。
No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
致癌物分类
国际癌症研究机构致癌剂：利福平
IARC Carcinogenic Agent:Rifampicin
来源:International Agency for Research on Cancer (IARC)
毒理性
致癌物分类
国际癌症研究机构（IARC）致癌物分类：第3组：对其对人类的致癌性无法分类
IARC Carcinogenic Classes:Group 3: Not classifiable as to its carcinogenicity to humans
来源:International Agency for Research on Cancer (IARC)
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 ... .
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
药物剂量的多达30%通过尿液排出，60%到65%通过粪便排出；其中不到一半可能是未改变的抗生素。
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.
The oral administration of rifampin produces peak concentrations in plasma in 2 to 4 hours; after ingestion of 600 mg this value is about 7 ug/mL, but there is considerable variability
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
rifampin在胆汁中被迅速排泄，并随后发生肠肝循环。
Following absorption from the gastrointestinal tract, rifampin is eliminated rapidly in the bile, and an enterohepatic circulation ensues.
