rifampin

Rifampicin

Systematic (IUPAC) name
(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-{(E)-[(4-methylpiperazin-1-yl)imino]methyl}-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25(29),26-octaen-13-yl acetate
Clinical data
Trade names	Rifadin
AHFS/Drugs.com	International Drug Names
MedlinePlus	a682403
Pregnancy cat.	C(AU)
Legal status	Prescription Only (S4) (AU) POM (UK)
Routes	Oral, IV
Pharmacokinetic data
Bioavailability	90 to 95%
Metabolism	Hepatic and intestinal wall
Half-life	1.5 to 5 hours
Excretion	15 to 30% renal 60% faecal
Identifiers
CAS number	13292-46-1 Y
ATC code	J04AB02 QJ54AB02
PubChem	CID 5360416
DrugBank	APRD00207
ChemSpider	4529237 Y
UNII	VJT6J7R4TR N
KEGG	D00211 N
ChEMBL	CHEMBL180 N
NIAID ChemDB	AIDSNO:007228
Synonyms	5,6,9,17,19,21-Hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-methyl-1-piperazinyl)formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)-naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate
Chemical data
Formula	C43H58N4O12
Mol. mass	822.94 g/mol
SMILES	eMolecules & PubChem
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/h11-14,19-21,23-25,29,34-35,39,44,49-51,53H,15-18H2,1-10H3,(H,45,55)/b12-11-,19-14+,22-13+,28-20+/t21-,23-,24-,25-,29-,34+,35+,39-,43-/m0/s1 Y Key:FZYOVNIOYYPUPY-KMBRGFCMSA-N Y
Physical data
Melt. point	183–188 °C (361–370 °F)
N(what is this?)  (verify)

Rifampicin (INN) ( /rɪˈfæmpəsɪn/) or rifampin (USAN) is a bactericidal antibiotic drug of the rifamycin group.^[1] It is a semisynthetic compound derived from Amycolatopsis rifamycinica (formerly known as Amycolatopsis mediterranei and Streptomyces mediterranei).^[2] Rifampicin may be abbreviated R, RMP, RA, RF, or RIF (US).

In 1957, a soil sample from a pine forest on the French Riviera was brought for analysis to the Lepetit Pharmaceuticals research lab in Milan, Italy. There, a research group headed by Prof. Piero Sensi (1920-) and Dr. Maria Teresa Timbal (1925 - 1969) discovered a new bacterium. This new species appeared immediately of great scientific interest since it was producing a new class of molecules with antibiotic activity. Because Sensi, Timbal and the researchers were particularly fond of the French crime story Rififi (about a jewel heist and rival gangs),^[3] they decided to call these compounds "rifamycins". After two years of attempts to obtain more stable semi-synthetic products, a new molecule with high efficacy and good tolerability was produced in 1959 and was named "rifampicin".

Rifampicin is also known as rifaldazine, R/AMP, rofact (in Canada), and rifampin in the United States. There are various types of rifamycins from which this is derived, but the rifampicin form, with a 4-methyl-1-piperazinaminyl group, is by far the most clinically effective.

Rifampicin is an intensely red solid, and the small fraction which reaches body fluids is known for imparting a harmless red-orange color to the urine (and to a lesser extent, also sweat and tears) of users, for a few hours after a dose. Maximal concentrations in the blood are decreased by about a third when the antibiotic is taken with food.^[4]

Rifampicin is used in the treatment of a number of bacteria, but best known for activity against Mycobacterium strains, such as cause tuberculosis and Hansen's Disease. Rifampicin can be used as monotherapy for a few days as prophylaxis against meningitis, but resistance develops quickly during long treatment of active infections, so the drug is always used against active infections in combination with other antibiotics.

Indications

Rifampicin was introduced in 1967,^[5] as a major addition to the cocktail-drug treatment of tuberculosis and inactive meningitis, along with isoniazid, ethambutol, pyrazinamide and streptomycin. It requires a prescription in North America. It must be administered regularly daily for several months without break; otherwise, the risk of drug-resistant tuberculosis is greatly increased.^[5] In fact, this is the primary reason that it is used in tandem with the three aforementioned drugs, particularly isoniazid.^[6] This is also the primary motivation behind directly observed therapy for tuberculosis.

Rifampicin resistance develops quickly during treatment and rifampicin monotherapy should not be used to treat these infections — it should be used in combination with other antibiotics.

Rifampicin is also used in the treatment of cholestatic pruritus.^[7]

Mycobacteria

Rifampicin is typically used to treat Mycobacterium infections, including tuberculosis and Hansen's Disease. It can be used to treat BCG-oma, which follows as an uncommon complication of BCG vaccination for tuberculosis.

With multidrug therapy used as the standard treatment of Hansen's Disease, rifampicin is always used in combination with dapsone and clofazimine to avoid eliciting drug resistance.

Other bacteria

Rifampicin also has a role in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) in combination with fusidic acid, although recent inquiries have raised questions over the lack of studies into the efficacy of this treatment.^[8] It is used in prophylactic therapy against Neisseria meningitidis (meningococcal) infection.

It is also used to treat infection by Listeria species, Neisseria gonorrhoeae, Haemophilus influenzae and Legionella pneumophila. For these non-standard indications, sensitivity testing should be done (if possible) before starting rifampicin therapy.

The Enterobacteriaceae, Acinetobacter, and Pseudomonas species are intrinsically resistant to rifampicin.

Further, it has been used with amphotericin B in largely unsuccessful attempts to treat primary amoebic meningoencephalitis caused by Naegleria fowleri.

Virus

Rifampicin has some effectiveness against vaccinia virus.^[9][10]

Mechanism of action

Rifampicin inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation to proteins.^[11] Its lipophilic nature makes it a good candidate to treat the meningitis form of tuberculosis, which requires distribution to the central nervous system and penetration through the blood-brain barrier.

Rifampicin acts directly on messenger RNA synthesis. It inhibits only prokaryotic DNA-primed RNA polymerase, especially those that are Gram-stain-positive and Mycobacterium tuberculosis. Much of this acid-fast positive bacteria's membrane is mycolic acid complexed with peptidoglycan, which allows easy movement of the drug into the cell. Evidence shows that in vitro DNA treated with concentrations 5000 times higher than normal dosage remained unaffected; in vivo eukaryotic specimens' RNA and DNA polymerases suffered few problems as well.^[6][12] Rifampicin interacts with the β subunit of RNA polymerase when it is in an α2β trimer. This halts mRNA transcription, therefore preventing translation of polypeptides.^[6] It should be made clear, however, that it cannot stop the elongation of mRNA once binding to the template-strand of DNA has been initiated.^[13] The Rifampin-RNA polymerase complex is extremely stable and yet experiments have shown that this is not due to any form of covalent linkage. It is hypothesized that hydrogen bonds and π-π bond interactions between naphthoquinone and the aromatic amino acids are the major stabilizers, though this requires the oxidation of naphthohydroquinone which is found most commonly in rifampicin. It is this last hypothesis that explains the explosion of multi-drug-resistant bacteria: mutations in the rpoB gene that replace phenylalanine, tryptophan, and tyrosine with non-aromatic amino acids result in poor bonding between rifampicin and the RNA polymerase.^[6]

Rifampicin-resistant bacteria produce RNA Polymerases with subtly different β subunit structures which are not readily inhibited by the drug.^[14] In molecular biology research, plasmids containing rifampicin-resistant genes are often used for colony screening. Many plasmids containing these resistant genes are commercially available to researchers.

Adverse effects

The most serious adverse effect is related to rifampicin's hepatotoxicity, and patients receiving rifampicin often undergo baseline and frequent liver function tests to detect liver damage.

Rifampicin is an effective liver enzyme-inducer, promoting the upregulation of hepatic cytochrome P450 enzymes (such as CYP2C9 and CYP3A4), increasing the rate of metabolism of many other drugs that are cleared by the liver through these enzymes. As a consequence, rifampicin can cause a range of adverse reactions when taken concurrently with other drugs.^[15] For instance, patients undergoing long term anticoagulation therapy with warfarin have to be especially cautious and increase their dosage of warfarin accordingly.^[16] Failure to do so could lead to under-treating with anticoagulation resulting in serious consequences of thromboembolism.

Upregulation of hepatic metabolism of hormones decreases their levels, and rifampicin can also in similar fashion reduce the efficacy of hormonal contraception, to the extent the unintended pregnancies have been reported among users of oral contraceptives taking rifampicin in even short courses (for example, as prophylaxis against exposure to bacterial meningitis).

The more common unwanted effects include fever, gastrointestinal disturbances, rashes, and immunological reactions.

Taking rifampicin can cause certain bodily fluids, such as urine and tears, to become orange-red in color, a benign side effect which can be frightening if it is not expected and prepared for. This effect may also be used to monitor effective absorption of the drug (if drug color is not seen in the urine, the patient may wish to move the drug dose farther in time from food or milk intake). The discolorizion of sweat and tears is not directly noticeable, but sweat may stain light clothing orange, and tears may permanently stain soft contact lenses.

Since rifampicin may be excreted in breast milk, breast feeding should be avoided while it is being taken.

Adverse effects include:

• Hepatotoxic - Hepatitis, jaundice, liver failure in severe cases
• Respiratory - breathlessness
• Cutaneous - flushing, pruritus, rash, redness and watering of eyes
• Abdominal - nausea, vomiting, abdominal cramps with or without diarrhea
• Flu-like symptoms - with chills, fever, headache, arthralgia, and malaise. Rifampin has good penetration into the brain, and this may directly explain some malaise and dysphoria in a minority of users.

Pharmacokinetics

Orally-administered rifampicin results in peak plasma concentrations in about 2 to 4 hours. 4-Aminosalicylic acid (another anti-tuberculosis drug) significantly reduces absorption of rifampicin,^[17] and peak concentrations may not be reached. If these two drugs must be used concurrently (which happens often in treatment of TB), they must be given separately with an interval of 8 to 12 hours between administrations.

Rifampicin is easily absorbed from the gastrointestinal tract; its ester functional group is quickly hydrolyzed in the bile; and it is catalyzed by a high pH and substrate-specific enzymes called esterases. After about 6 hours, almost all of the drug is deacetylated. Even in this deacetylated form, rifampin is still a potent antibiotic; however, it can no longer be reabsorbed by the intestines and it is subsequently eliminated from the body. Only about 7% of the administered drug will be excreted unchanged through the urine, though urinary elimination accounts for only about 30% of the dose of the drug that is excreted. About 60% to 65% is excreted through the feces.

The half-life of rifampicin ranges from 1.5 to 5 hours, though hepatic impairment will significantly increase it. Food consumption, on the other hand, inhibits absorption from the GI tract, and the drug is more quickly eliminated. When rifampicin is taken with a meal peak blood concentration fall by 36%. Antacids do not affect absorption, however.^[4] The decrease in rifampin absorption with food is sometimes enough to noticeably affect urine color, which can be used as a marker for whether or not a dose of the drug has been effectively absorbed.

Distribution of the drug is high throughout the body, and reaches effective concentrations in many organs and body fluids, including the CSF. Since the substance itself is red, this high distribution is the reason for the orange-red color of the saliva, tears, sweat, urine, and feces. About 60% to 90% of the drug is bound to plasma proteins.^[13]

rifampicin is considered as liver microsomal enzyme inducer lead to "high metabolic rate"

Interactions

Rifampicin is an inducer of many enzymes of the cytochrome P450 superfamily, including CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and CYP3A7.^[18] Thus it will speed up the metabolism of any drug that is metabolized by any of these enzymes in the body. A complete list of drugs metabolized by each of these enzymes can be found here [1].

Other possible interactions which may not be listed include antiretroviral agents, everolimus, atorvastatin, rosiglitazone/pioglitazone, celecoxib, clarithromycin, caspofungin, and lorazepam.^[19]

Preparations

Rifampicin is available in:

• Bulgaria as Tubocin (by Actavis/Balkanpharma)
• Romania as Sinerdol (Sicomed)
• UK as Rifadin (Aventis), Rimactan (Sandoz), Rifater a combination with isoniazid and pyrazinamide (Aventis), Rifinah a combination with isoniazid (Aventis), and Rimactazid a combination with isoniazid (Sandoz)
• U.S. as Rifadin (Aventis), Rifater combination with isoniazid and pyrazinamide (Aventis), Rimactane (Novartis)
• France as Rifadine (Aventis)
• India R-Cinex 600 (Lupin Ltd)/Micox, a combination of rifampicin and isoniazid
• Australia as Rimycin (Alphapharm)
• Egypt as Rimactan (Sandoz)
• Germany as Eremfat (Riemser)

References

External links

• PubPK - Rifampicin pharmacokinetics
• Prescribing Information for RIFADIN by Sanofi-Aventis
• U.S. National Library of Medicine: Drug Information Portal - Rifampicin
• PDR.net Concise Monograph - Rifadin