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[(7S,9E,12R,13S,16R,17S)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(Z)-(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate

PubChem CID
137286743
Structure
[(7S,9E,12R,13S,16R,17S)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(Z)-(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate_small.png
Molecular Formula
Synonyms
  • rifampin
  • Rifampicin
  • 13292-46-1
  • BCP28502
Molecular Weight
822.9 g/mol
Computed by PubChem 2.1 (PubChem release 2021.05.07)
Dates
  • Create:
    2019-01-26
  • Modify:
    2025-01-18
Description
Rifampin can cause developmental toxicity and female reproductive toxicity according to state or federal government labeling requirements.
Rifampin, also known as rifampicin, is a broad-spectrum antimicrobial that was first discovered in 1965 and clinically used in 1968. Rifampin is used to treat tuberculosis and works by inhibiting the microbial DNA-dependent RNA polymerase (RNAP).
A semisynthetic antibiotic produced from Streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits DNA-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms. (From Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed, p1160)
See also: Rifampin (annotation moved to).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
[(7S,9E,12R,13S,16R,17S)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(Z)-(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate.png

1.2 3D Status

Conformer generation is disallowed since too many atoms, too many undefined stereo centers

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

[(7S,9E,12R,13S,16R,17S)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-[(Z)-(4-methylpiperazin-1-yl)iminomethyl]-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(29),2,4,9,19,21,25,27-octaen-13-yl] acetate
Computed by Lexichem TK 2.7.0 (PubChem release 2021.05.07)

2.1.2 InChI

InChI=1S/C43H58N4O12/c1-21-12-11-13-22(2)42(55)45-33-28(20-44-47-17-15-46(9)16-18-47)37(52)30-31(38(33)53)36(51)26(6)40-32(30)41(54)43(8,59-40)57-19-14-29(56-10)23(3)39(58-27(7)48)25(5)35(50)24(4)34(21)49/h11-14,19-21,23-25,29,34-35,39,49-53H,15-18H2,1-10H3,(H,45,55)/b12-11?,19-14+,22-13?,44-20-/t21?,23-,24-,25?,29?,34+,35?,39-,43+/m1/s1
Computed by InChI 1.0.6 (PubChem release 2021.05.07)

2.1.3 InChIKey

JQXXHWHPUNPDRT-WACSZCHISA-N
Computed by InChI 1.0.6 (PubChem release 2021.05.07)

2.1.4 SMILES

C[C@@H]1[C@H](C(C=CC=C(C(=O)NC2=C(C(=C3C(=C2O)C(=C(C4=C3C(=O)[C@](O4)(O/C=C/C([C@H]([C@H](C(C1O)C)OC(=O)C)C)OC)C)C)O)O)/C=N\N5CCN(CC5)C)C)C)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C43H58N4O12
Computed by PubChem 2.1 (PubChem release 2021.05.07)

2.3 Other Identifiers

2.3.1 CAS

13292-46-1

2.3.2 European Community (EC) Number

2.3.3 DrugBank ID

2.3.4 Metabolomics Workbench ID

2.3.5 Pharos Ligand ID

2.3.6 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Benemycin
  • Rifadin
  • Rifampicin
  • Rifampin
  • Rimactan
  • Rimactane
  • Tubocin

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
822.9 g/mol
Reference
Computed by PubChem 2.1 (PubChem release 2021.05.07)
Property Name
XLogP3-AA
Property Value
4.9
Reference
Computed by XLogP3 3.0 (PubChem release 2021.05.07)
Property Name
Hydrogen Bond Donor Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Hydrogen Bond Acceptor Count
Property Value
15
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Rotatable Bond Count
Property Value
5
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Exact Mass
Property Value
822.40512330 Da
Reference
Computed by PubChem 2.1 (PubChem release 2021.05.07)
Property Name
Monoisotopic Mass
Property Value
822.40512330 Da
Reference
Computed by PubChem 2.1 (PubChem release 2021.05.07)
Property Name
Topological Polar Surface Area
Property Value
220 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Heavy Atom Count
Property Value
59
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
1620
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.05.07)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
5
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
4
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.05.07)

3.2 Experimental Properties

3.2.1 Color / Form

Red to orange platelets from acetone
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1474
Red-brown crystalline powder
Physicians Desk Reference. Montvale, NJ: Thomson PDR. p. 759 (2003)

3.2.2 Odor

ODORLESS
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1124

3.2.3 Melting Point

183
Decomposes 183-188 °C
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1474

3.2.4 Solubility

1400 mg/L (at 25 °C)
YALKOWSKY,SH & DANNENFELSER,RM (1992)
Freely sol in methyl chloride, dimethyl sulfoxide; sol in tetrahydrofuran; slightly sol in water (pH less than 6), acetone, carbon tetrachloride
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1474
Freely soluble in chloroform, soluble in ethyl acetate and in methanol.
Physicians Desk Reference. Montvale, NJ: Thomson PDR. p. 759 (2003)
In water, 1,400 mg/L at 25 °C
Yalkowsky, S.H., He, Yan., Handbook of Aqueous Solubility Data: An Extensive Compilation of Aqueous Solubility Data for Organic Compounds Extracted from the AQUASOL dATAbASE. CRC Press LLC, Boca Raton, FL. 2003., p. 1261

3.2.5 Vapor Pressure

3.1X10-34 mm Hg at 25 °C /Estimated/
US EPA; Estimation Program Interface (EPI) Suite. Ver.3.11. June 10, 2003. Available from, as of Apr 8, 2004: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

3.2.6 LogP

2.7
log Kow = 4.24 /Estimated/
US EPA; Estimation Program Interface (EPI) Suite. Ver.3.11. June 10, 2003. Available from, as of Apr 8, 2004: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

3.2.7 Henry's Law Constant

Henry's Law constant = 2.7X10-42 atm-cu m/mol at 25 °C /Estimated/
US EPA; Estimation Program Interface (EPI) Suite. Ver.3.11. June 10, 2003. Available from, as of Apr 8, 2004: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

3.2.8 Stability / Shelf Life

Very stable in dimethyl sulfoxide; rather stable in water.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1474
Unstable in light, heat, air and moisture
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1124

3.2.9 Dissociation Constants

pKa
1.7
SANGSTER (2004)
Zwitterion with pKa 1.7 related to the 4-hydroxy and pKa 7.9 related to the 3-piperazine nitrogen
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1474

3.2.10 Other Experimental Properties

Very stable in DMSO; rather stable in water.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1474
Hydroxyl radical reaction rate constant = 5.1X10-10 cu cm/molecule-sec at 25 °C /Estimated/
US EPA; Estimation Program Interface (EPI) Suite. Ver.3.11. June 10, 2003. Available from, as of Apr 8, 2004: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

3.3 Chemical Classes

3.3.1 Drugs

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

Antileprosy medicines

Antituberculosis medicines

4 Spectral Information

4.1 UV Spectra

Max absorption (pH 7.38): 237 nm (Epsilon= 33,200); 255 nm (Epsilon= 32,100); 334 nm (Epsilon= 27,000); 475 nm (Epsilon= 15,400)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1474

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Rifampin is indicated for the treatment of tuberculosis and asymptomatic carriers of _Neisseria meningitidis_ to eliminate meningococci from the nasopharynx. In combination with [pyrazinamide] and [isoniazid], it is used in the initial phase of the short-course treatment of pulmonary tuberculosis.

7.2 Drug Classes

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

7.3 WHO Essential Medicines

Drug
Drug Classes
Antileprosy medicines
Formulation
(1) Oral - Liquid: 20 mg per mL; (2) Oral - Solid: 150 mg; 300 mg
Indication
Leprosy
Drug
Drug Classes
Antituberculosis medicines
Formulation
(1) Oral - Liquid: 20 mg per mL; (2) Oral - Solid: 150 mg; 300 mg; (3) Parenteral - General injections - IV: 600 mg in vial powder for injection
Indication
(1) Tuberculosis; (2) Other specified tuberculosis

7.4 Clinical Trials

7.4.1 ClinicalTrials.gov

7.4.2 EU Clinical Trials Register

7.4.3 NIPH Clinical Trials Search of Japan

7.5 Therapeutic Uses

Antibiotics, Antitubercular; Enzyme Inhibitors; Leprostatic Agents; Nucleic Acid Synthesis Inhibitors
National Library of Medicine's Medical Subject Headings online file (MeSH, 1999)
Rifampin is indicated in combination with other antituberculosis medications in the treatment of all forms of tuberculosis, including tuberculous meningitis. /Included in US product labeling/
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2456
Rifampin is indicated in the treatment of close contacts of patients with proved or suspected infection caused by Neisseria meningitidis. These contacts include other household members, children in nurseries, persons in day care centers, and closed populations, such as military recruits. Health care providers who have intimate exposure (e.g., mouth-to-mouth resuscitation) with index cases also should receive prophylactic therapy. /Included in US product labeling/
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2456
Rifampin is used in the treatment of close contacts of patients with proved or suspected infections caused by Hemophilus influenza type b if at least one of the contacts is 4 years of age or younger. A close contact is defined as one who has spent 4 or more hours per day for five of the seven most recent days with the index case. /NOT included in US product labeling/
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2457
For more Therapeutic Uses (Complete) data for RIFAMPIN (7 total), please visit the HSDB record page.

7.6 Drug Warnings

Severe hepatic injuries, including some fatalities, have been reported in patients receiving regimens that contain both rifampin and pyrazinamide for the treatment of latent tuberculosis infection. Between October 2000 and June 2003, the US CDC received a total of 48 reports of severe hepatic injury (i.e., hospitalization or death) in patients with latent tuberculosis infection receiving a rifampin and pyrazinamide regimen; there were 11 fatalities. In many fatal cases, onset of hepatic injury occurred during the second month of the 2 month regimen. Some patients who died were receiving the rifampin and pyrazinamide regimen because they previously experienced isoniazid-associated hepatitis and some had risk factors for chronic liver disease (e.g., serologic evidence of previous hepatitis A or B infection, idiopathic nonalcoholic steatotic hepatitis, alcohol or parenteral drug abuse, concomitant use of other drugs associated with idiosyncratic hepatic injury). Although data are limited, there is no evidence to date that HIV-infected individuals receiving this regimen are at any increased risk for severe hepatitis. There is evidence that the rate of severe liver injury and death related to the use of rifampin and pyrazinamide are higher than the rates reported for isoniazid-associated liver injury in the treatment of latent tuberculosis infection. Based on these reports, rifampin and pyrazinamide regiments should be used for the treatment of latent tuberculosis only when the potential benefits outweigh the risk of liver injury and death.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 574
Rifampin has caused transient increases in serum concentrations of AST (SGOT), ALT (SGPT), bilirubin, and alkaline phosphatase. Asymptomatic jaundice which subsided without discontinuance of the drug has occurred occasionally. However, hepatitis and fatalities associated with jaundice have been reported in patients with preexisting liver disease or in those who received other hepatotoxic agents concomitantly with rifampin. Rarely, hepatitis or a shocklike syndrome with hepatic involvement with abnormal liver function test results (thought to be allergic in nature) have been reported.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 574
Pregnancy risk category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2337
In some animal experiments, an immunosuppressive effect has been observed, but this appears to have no clinical significance..
American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994., p. 2457
For more Drug Warnings (Complete) data for RIFAMPIN (21 total), please visit the HSDB record page.

7.7 Reported Fatal Dose

In humans, acute overdosage with rifampin doses up to 9-12 g in adults and one or two 100 mg/kg doses in children 1-4 years of age have not been fatal; however, fatalities in adults have been reported following ingestion of 14 to 60 g doses of the drug.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 577

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Rifampin is an antimicrobial agent with bactericidal effects and a broad-spectrum activity. It is active against intracellular and extracellular _Mycobacterium tuberculosis_.

8.2 MeSH Pharmacological Classification

Antibiotics, Antitubercular
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. (See all compounds classified as Antibiotics, Antitubercular.)
Cytochrome P-450 CYP2B6 Inducers
Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP2B6. (See all compounds classified as Cytochrome P-450 CYP2B6 Inducers.)
Cytochrome P-450 CYP2C19 Inducers
Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP2C19. (See all compounds classified as Cytochrome P-450 CYP2C19 Inducers.)
Cytochrome P-450 CYP2C8 Inducers
Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP2C8. (See all compounds classified as Cytochrome P-450 CYP2C8 Inducers.)
Cytochrome P-450 CYP2C9 Inducers
Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP2C9. (See all compounds classified as Cytochrome P-450 CYP2C9 Inducers.)
Cytochrome P-450 CYP3A Inducers
Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP3A. (See all compounds classified as Cytochrome P-450 CYP3A Inducers.)
Leprostatic Agents
Substances that suppress Mycobacterium leprae, ameliorate the clinical manifestations of leprosy, and/or reduce the incidence and severity of leprous reactions. (See all compounds classified as Leprostatic Agents.)
Nucleic Acid Synthesis Inhibitors
Compounds that inhibit cell production of DNA or RNA. (See all compounds classified as Nucleic Acid Synthesis Inhibitors.)

8.3 ATC Code

J - Antiinfectives for systemic use

J04 - Antimycobacterials

J04A - Drugs for treatment of tuberculosis

J04AB - Antibiotics

J04AB02 - Rifampicin

J04AB02

8.4 Absorption, Distribution and Excretion

Absorption
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.
Route of Elimination
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.
Volume of Distribution
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.
Clearance
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 ... .
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1278
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.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1278
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
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1278
Following absorption from the gastrointestinal tract, rifampin is eliminated rapidly in the bile, and an enterohepatic circulation ensues.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1278
For more Absorption, Distribution and Excretion (Complete) data for RIFAMPIN (10 total), please visit the HSDB record page.

8.5 Metabolism / Metabolites

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. ...
Noda A, et al; Toxicol Lett 25 (3): 313-17 (1985)
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.
The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 237
Rifampin is metabolized in the liver to a deacetylated derivative which also possesses antibacterial activity.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 578
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.
Dabbs ER, et al; Antimicrob Agents Chemother 39 (4): 1007-9 (1995)

8.6 Biological Half-Life

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.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1278
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.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 538

8.7 Mechanism of Action

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.
American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977., p. 808
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.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1278
High concentrations of rifamycin antibiotics also inhibit viral DNA-dependent RNA polymerases and reverse transcriptases.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1278
Rifampin is bactericidal for both intracellular and extracellular microorganisms.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1278
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. ...
Pineau T, et al; Eur J Biochem 197 (1): 145-53 (1991)

9 Use and Manufacturing

9.1 Uses

Antibacterial (tuberculostatic)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1474
MEDICATION

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

Use (kg) in France (2004): 2383

Consumption (g per capita; approx.) in Germany (2009): 0.0122

Consumption (g per capita) in France (2004): 0.0394

Excretion rate: 0.18

Calculated removal (%): 42.1

9.2 Methods of Manufacturing

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.
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1124
Rifamycin SV + dimethylformamide + N-methyl-piperazine (Vilsmeier reaction/diazotisation/reduction/imine formation)
Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994., p. 791
Semisynthetic antibiotic obtained by reacting 3-formylrifamycin SV with 1-amino-4-methylpiperazine in tetrahydrofuran.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 1474

9.3 Formulations / Preparations

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).
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 578

9.4 General Manufacturing Information

The rifamycins are a group of structurally similar, complex macrocyclic antibiotics produced by Streptomyces mediterranei; rifampin ... is a semisynthetic derivative of one of these -- rifamycin B.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1277

10 Identification

10.1 Analytic Laboratory Methods

... Rifampicin can be determined by a microbiological assay using ... S. aureus 560.
Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present., p. V2 940 (1992)
... Rifampicin can be determined by a microbiological assay using Sarcina lutea ATTC 9341 as the test organism
Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present., p. V2 940 (1992)
HPLC method developed for determination of rifampicin in presence of contaminants and degradation products using p-nitrophenol as internal standard is described. Separation on 1 m column packed zipax pam using mixture of hexane and ethanol (85:15) as eluant.
AWATA N ET AL; PHARM RES CENT, KANEBO LTD, OSAKA 38: 145 (1978)

10.2 Clinical Laboratory Methods

Comparison of disc and cartridge solid phase extraction for the LC determination of rifampin and 25-desacetylrifampin in human serum.
Ye L et al; J Pharm Biomed Anal 13 (9): 1185-8 (1995)

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

Pictogram(s)
Irritant
Signal
Warning
GHS Hazard Statements

H302 (98.3%): Harmful if swallowed [Warning Acute toxicity, oral]

H315 (86.7%): Causes skin irritation [Warning Skin corrosion/irritation]

H319 (86.7%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

H335 (85%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

Precautionary Statement Codes

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

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 60 reports by companies from 16 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 4 (98.3%)

Skin Irrit. 2 (86.7%)

Eye Irrit. 2 (86.7%)

STOT SE 3 (85%)

11.2 Accidental Release Measures

11.2.1 Disposal Methods

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.

11.3 Handling and Storage

11.3.1 Storage Conditions

Rifampin capsules should be stored in tight, light-resistant containers at a temperature of 30 °C or less, preferably between 15-30 °C. The capsules should not be exposed to excessive heat.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 578

11.4 Regulatory Information

California Safe Cosmetics Program (CSCP) Reportable Ingredient

Hazard Traits - Developmental Toxicity; Reproductive Toxicity

Authoritative List - Prop 65

Report - regardless of intended function of ingredient in the product

New Zealand EPA Inventory of Chemical Status
Rifampin: Does not have an individual approval but may be used under an appropriate group standard

11.4.1 FDA Requirements

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.
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of July 1, 2004: https://www.fda.gov/cder/ob/

11.5 Other Safety Information

Chemical Assessment

IMAP assessments - Rifamycin, 3-[[(4-methyl-1-piperazinyl)imino]methyl]-: Environment tier I assessment

IMAP assessments - Rifamycin, 3-[[(4-methyl-1-piperazinyl)imino]methyl]-: Human health tier I assessment

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

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.
International Programme on Chemical Safety; Poisons Information Monograph: Rifampicin (PIM 472) (1991) Available from, as of April 7, 2009: https://www.inchem.org/pages/pims.html

12.1.2 Evidence for Carcinogenicity

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.
IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). Available at: https://monographs.iarc.fr/ENG/Classification/index.php, p. S7 71 (1987)

12.1.3 Carcinogen Classification

IARC Carcinogenic Agent
Rifampicin
IARC Carcinogenic Classes
Group 3: Not classifiable as to its carcinogenicity to humans
IARC Monographs

Volume 24: (1980) Some Pharmaceutical Drugs

Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print)

12.1.4 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Limited information indicates that there are low levels of rifampin in breastmilk that would not be expected to cause any adverse effects in breastfed infants. The amount of rifampin in milk is insufficient to treat tuberculosis in the breastfed infant. The Centers for Disease Control and Prevention and other professional organizations state that breastfeeding should not be discouraged in women taking rifampin. Breastmilk may be stained a yellow, orange, red or brown color.

◉ Effects in Breastfed Infants

One woman taking rifampin 450 mg, isoniazid 300 mg and ethambutol 1200 mg daily during pregnancy and rifampin 450 mg and isoniazid 300 mg for the first 7 months of lactation (extent not stated). The infant was born with mildly elevated serum liver enzymes which persisted for to 1 (alanine transferase) to 2 years (aspartate transaminase), but had no other adverse reactions.

Rifampin was used as part of multi-drug regimens to treat 2 pregnant women with multidrug-resistant tuberculosis throughout pregnancy and postpartum. Their two infants were breastfed (extent and duration not stated). At age 3.9 and 5.1 years, the children were developing normally except for hyperactivity in one.

Two mothers in Türkiye were diagnosed with tuberculosis at the 30th and 34th weeks of pregnancy. They immediately started isoniazid 300 mg, rifampin 600 mg, pyridoxine 50 mg daily for 6 months, plus pyrazinamide 25 mg/kg and ethambutol 25 mg/kg daily for 2 months. Both mothers breastfed their infants (extent not stated). Their infants were given isoniazid 5 mg/kg daily for 3 months prophylactically. Tuberculin skin tests were negative after 3 months and neither infant had tuberculosis at 1 year of age. No adverse effects of the drugs were mentioned.

A woman with leprosy took clofazimine, dapsone and rifampin during pregnancy and breastfeeding. Her infant developed skin discoloration attributed to clofazimine which reversed 3 months after cessation of breastfeeding.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.5 Interactions

Interaction between ethambutol and rifampicin (rifampin) may have caused occurrence of overt Stevens-Johnson syndrome in 40 yr old male tuberculosis patient.
NYIRENDA R, GILL GV; BR MED J 2: 1189 (1977)
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.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2458
Rifampin may increase metabolism of theophylline, oxtriphylline, and aminophylline by induction of hepatic microsomal enzymes, resulting in increased theophylline clearance.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2458
Chronic use of hepatic enzyme-inducing agents prior to anesthesia, except isoflurane, may increase anesthetic metabolism, leading to increased risk of hepatotoxicity.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2458
For more Interactions (Complete) data for RIFAMPIN (40 total), please visit the HSDB record page.

12.1.6 Antidote and Emergency Treatment

Emergency and supportive measures; Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, anaphylaxis, and hemolysis if they occur. Replace fluid losses resulting from gastroenteritis with intravenous crystalloids. ... /Antibacterial Agents/.
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 4th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2004., p. 81
Decontamination; Prehospital. Administer activated charcoal, if available. Hospital. Administer activated charcoal. Gastric emptying is not necessary if activated charcoal can be given promptly /Antibacterial Agents/.
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 4th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2004., p. 81
Enhanced elimination; Most antibiotics are excreted unchanged in the urine, so maintenance of adequate urine flow is important. The role of forced diuresis is unclear. Hemodialysis is not usually indicated, except perhaps in patients with renal dysfunction and high level of a toxic agent. Charcoal hemoperfusion effectively removes chloramphenicol and is indicated after a severe overdose with a high serum level and metabolic acidosis. ... /Antibacterial Agents/.
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 4th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2004., p. 81

12.1.7 Human Toxicity Excerpts

/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.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 574
/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.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 577
/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.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 574
/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.
BROADWELL RO ET AL; J AM MED ASSOC 240: 2283 (1978)
For more Human Toxicity Excerpts (Complete) data for RIFAMPIN (7 total), please visit the HSDB record page.

12.1.8 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Acute Exposure/ Topical testing of rifampin on rabbit eyes as 1% solution in polyethylene glycol, every 15 minutes for 6 hours, produced no damage observable by biomicroscopy.
Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986., p. 793
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Studies in female mice of a strain known to be particularly susceptible to the spontaneous development of hepatomas have shown that rifampin, given in doses of 2 to 10 times the maximum human dose for 1 year, causes a significant increase in the development of hepatomas. However, studies in male mice of the same strain, in other strains of male or female mice, or in rats have not shown that rifampin is tumorigenic.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2457
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Imperfect osteogenesis and embryotoxicity were reported in rabbits given up to 20 times the usual daily human dose. Studies in rodents have shown that rifampin given in dose of 150 to 250 mg/kg of body weight daily causes congenital malformations, primarily cleft palate and spina bifida.
Thomson.Micromedex. Drug Information for the Health Care Professional. 24th ed. Volume 1. Plus Updates. Content Reviewed by the United States Pharmacopeial Convention, Inc. Greenwood Village, CO. 2004., p. 2457
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ An increased incidence of congenital malformations (principally spina bifida and cleft palate) has been reported in the offspring of mice and rats given rifampin in a dosage of 150-250 mg/kg daily during pregnancy. The incidence of these anomalies was dose dependent. In addition, imperfect osteogenesis and embryotoxicity occurred when rifampin doses up to 20 times the usual daily human dose were used in pregnant rabbits.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 575
For more Non-Human Toxicity Excerpts (Complete) data for RIFAMPIN (8 total), please visit the HSDB record page.

12.1.9 Human Toxicity Values

Fatalities in adults have been reported following ingestion of 14 to 60 g doses of the drug.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 577

12.1.10 Non-Human Toxicity Values

LD50 Rabbit oral 2.12 g/kg
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 577
LD50 Rat oral 1.72 g/kg
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 577
LD50 Mouse oral 0.885 g/kg
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2004. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2004 (Plus Supplements)., p. 577

12.1.11 Protein Binding

Rifampin is about 80% protein bound. It may bind to serum albumin. Most of the unbound fraction is not ionized and, therefore, diffuses freely into tissues.

12.2 Ecological Information

12.2.1 Natural Pollution Sources

The rifamycins are a group of structurally similar, complex macrocyclic antibiotics produced by Streptomyces mediterranei; rifampin ... is a semisynthetic derivative of one of these -- rifamycin B.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 1277

13 Literature

13.1 Consolidated References

13.2 NLM Curated PubMed Citations

13.3 Chemical Co-Occurrences in Literature

13.4 Chemical-Gene Co-Occurrences in Literature

13.5 Chemical-Disease Co-Occurrences in Literature

14 Interactions and Pathways

14.1 Chemical-Target Interactions

14.2 Drug-Drug Interactions

14.3 Drug-Food Interactions

  • Avoid alcohol. Alcohol may lead to an increased risk of severe hepatocellular toxicity.
  • Take on an empty stomach. Absorption of rifampin is reduced by about 30% when the drug is ingested with food.
  • Take with a full glass of water. Oral capsules should be taken with a glass of water.

15 Classification

15.1 MeSH Tree

15.2 WHO ATC Classification System

15.3 UN GHS Classification

15.4 International Agency for Research on Cancer (IARC) Classification

15.5 FDA Drug Type and Pharmacologic Classification

16 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    Rifamycin, 3-[[(4-methyl-1-piperazinyl)imino]methyl]-
    https://services.industrialchemicals.gov.au/search-assessments/
  2. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  3. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  4. Hazardous Substances Data Bank (HSDB)
  5. New Zealand Environmental Protection Authority (EPA)
    LICENSE
    This work is licensed under the Creative Commons Attribution-ShareAlike 4.0 International licence.
    https://www.epa.govt.nz/about-this-site/general-copyright-statement/
  6. California Office of Environmental Health Hazard Assessment (OEHHA)
  7. California Safe Cosmetics Program (CSCP) Product Database
  8. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  9. Drugs and Lactation Database (LactMed)
  10. WHO Model Lists of Essential Medicines
    LICENSE
    Permission from WHO is not required for the use of WHO materials issued under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license.
    https://www.who.int/about/policies/publishing/copyright
  11. EU Clinical Trials Register
  12. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    RIFAMPICIN
  13. International Agency for Research on Cancer (IARC)
    LICENSE
    Materials made available by IARC/WHO enjoy copyright protection under the Berne Convention for the Protection of Literature and Artistic Works, under other international conventions, and under national laws on copyright and neighbouring rights. IARC exercises copyright over its Materials to make sure that they are used in accordance with the Agency's principles. All rights are reserved.
    https://publications.iarc.fr/Terms-Of-Use
    IARC Classification
    https://www.iarc.fr/
  14. Metabolomics Workbench
  15. NIPH Clinical Trials Search of Japan
  16. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  17. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  18. Wikipedia
  19. Medical Subject Headings (MeSH)
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    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
    Cytochrome P-450 CYP2B6 Inducers
    https://www.ncbi.nlm.nih.gov/mesh/68065695
    Cytochrome P-450 CYP2C19 Inducers
    https://www.ncbi.nlm.nih.gov/mesh/68065697
    Cytochrome P-450 CYP2C8 Inducers
    https://www.ncbi.nlm.nih.gov/mesh/68065696
    Cytochrome P-450 CYP2C9 Inducers
    https://www.ncbi.nlm.nih.gov/mesh/68065698
    Cytochrome P-450 CYP3A Inducers
    https://www.ncbi.nlm.nih.gov/mesh/68065701
    Nucleic Acid Synthesis Inhibitors
    https://www.ncbi.nlm.nih.gov/mesh/68019384
  20. PubChem
  21. GHS Classification (UNECE)
  22. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
CONTENTS