RIFABUTIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C46H62N4O11
Molecular Weight	847.0047
Optical Activity	UNSPECIFIED
Defined Stereocenters	9 / 9
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CO[C@H]1\C=C\O[C@@]2(C)OC3=C(C2=O)C4=C(C(=O)C(NC(=O)C(C)=C\C=C\[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)=C5NC6(CCN(CC(C)C)CC6)N=C45)C(O)=C3C

InChI

InChIKey=ATEBXHFBFRCZMA-VXTBVIBXSA-N

InChI=1S/C46H62N4O11/c1-22(2)21-50-18-16-46(17-19-50)48-34-31-32-39(54)28(8)42-33(31)43(56)45(10,61-42)59-20-15-30(58-11)25(5)41(60-29(9)51)27(7)38(53)26(6)37(52)23(3)13-12-14-24(4)44(57)47-36(40(32)55)35(34)49-46/h12-15,20,22-23,25-27,30,37-38,41,49,52-54H,16-19,21H2,1-11H3,(H,47,57)/b13-12+,20-15+,24-14-/t23-,25+,26+,27+,30-,37-,38+,41+,45-/m0/s1

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/050689s022lbl.pdf
Curator's Comment: description was created based on several sources, including: https://www.drugs.com/cdi/rifabutin.html http://www.rxlist.com/mycobutin-drug.htm http://www.wikidoc.org/index.php/Rifabutin

Rifabutin is an antibiotic that inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. It is bactericidal and has a very broad spectrum of activity against most gram-positive and gram-negative organisms (including Pseudomonas aeruginosa) and specifically Mycobacterium tuberculosis. It is FDA approved for the prophylaxis of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Multiple dosing of rifabutin has been associated with induction of hepatic metabolic enzymes of the CYP3A subfamily. Rifabutin’s predominant metabolite (25-desacetyl rifabutin: LM565), may also contribute to this effect. Similarly, concomitant medications that competitively inhibit the CYP3A activity may increase plasma concentrations of rifabutin. Common adverse reactions include discoloration of skin, rash, diarrhea, disorder of taste, indigestion, loss of appetite, nausea, vomiting, increased liver aminotransferase level (mild), ocular discoloration, uveitis, abnormal color of body fluid.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Cytochrome P450 3A4 126 Target ID: CHEMBL340 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18713760	Substrate 656
DNA-directed RNA polymerase subunit beta 5 Target ID: P0A8V2 Gene ID: 948488.0 Gene Symbol: rpoB Target Organism: Escherichia coli (strain K12) Sources: https://www.ncbi.nlm.nih.gov/pubmed/15805525 \| https://www.ncbi.nlm.nih.gov/pubmed/7849340	Inhibitor 8228

Conditions

Condition	Modality	Targets	Highest Phase	Product
Disseminated Mycobacterium avium complex (MAC) disease 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/050689s022lbl.pdf	Preventing		Approved 8360	MYCOBUTIN Approved Use MYCOBUTIN Capsules are indicated for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Launch Date 7.2506881E11

C_max

Value	Dose	Co-administered	Analyte	Population
613 ng/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/8785251/	450 mg 1 times / day multiple, oral dose: 450 mg route of administration: Oral experiment type: MULTIPLE co-administered:		RIFABUTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
691 ng/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/8785251/	450 mg single, oral dose: 450 mg route of administration: Oral experiment type: SINGLE co-administered:		RIFABUTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
5803 ng × h/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/8785251/	450 mg 1 times / day multiple, oral dose: 450 mg route of administration: Oral experiment type: MULTIPLE co-administered:		RIFABUTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
9287 ng × h/mL REVIEW https://pubmed.ncbi.nlm.nih.gov/8785251/	450 mg single, oral dose: 450 mg route of administration: Oral experiment type: SINGLE co-administered:		RIFABUTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
58 h REVIEW https://pubmed.ncbi.nlm.nih.gov/8785251/	450 mg 1 times / day multiple, oral dose: 450 mg route of administration: Oral experiment type: MULTIPLE co-administered:		RIFABUTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN
45 h REVIEW https://pubmed.ncbi.nlm.nih.gov/8785251/	450 mg single, oral dose: 450 mg route of administration: Oral experiment type: SINGLE co-administered:		RIFABUTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
21.5% REVIEW https://pubmed.ncbi.nlm.nih.gov/8785251/	450 mg single, oral dose: 450 mg route of administration: Oral experiment type: SINGLE co-administered:		RIFABUTIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
300 mg 1 times / day multiple, oral Recommended Dose: 300 mg, 1 times / day Route: oral Route: multiple Dose: 300 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/050689Orig1s018lbl.pdf	unhealthy, adult n = 566 Health Status: unhealthy Condition: Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection Age Group: adult Population Size: 566 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/050689Orig1s018lbl.pdf	Other AEs: Abdominal pain, Asthenia... Other AEs: Abdominal pain (4%) Asthenia (1%) Chest pain (1%) Fever (2%) Headache (3%) Pain (1%) Anorexia (2%) Diarrhea (3%) Dyspepsia (3%) Eructation (3%) Flatulence (2%) Nausea (6%) Nausea and vomiting (3%) Vomiting (1%) Myalgia (2%) Insomnia (1%) Rash (11%) Taste perversion (3%) Urine discoloration (30%) Alkaline phosphatase increased (<1%) SGOT increased (7%) SGPT increased (9%) Anemia (6%) Eosinophilia (1%) Leukopenia (17%) Neutropenia (25%) Thrombocytopenia (5%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/050689Orig1s018lbl.pdf

AEs

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
activator 77 inducer 768 substrate 1709	inhibitor 1752	inhibitor 1837

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1509 CYP3A 211 CYP2B6 799 CYP2C8 901 CYP2C19 1463 CYP2E1 876 UGT1A1 204 UGT1A4 77 UGT1A6 108 UGT1A9 116 UGT2B7 146 UGT2B15 64	AADAC 1	P-gp 257 OATP1B1 26 OATP1B3 6 MRP2 111

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
UGT1A4 80	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	likely
CYP1A2 1673	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
CYP2C19 1537	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
CYP2E1 964	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
MRP2 459	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	no
OATP1B1 796	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	no
UGT1A6 141	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
UGT1A9 121	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
CYP3A 295	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely [IC50 31.5 uM]
CYP2B6 985	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
CYP2C8 955	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
CYP2C9 1803	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
CYP2D6 1875	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
UGT1A1 254	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
UGT2B15 64	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
UGT2B7 157	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
CYP3A4 1909	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	yes
OATP1B3 709	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	yes
P-gp 1626	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	yes
CYP3A4 1909	activator 210 Sources: https://pubmed.ncbi.nlm.nih.gov/10418969/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050689s016lbl.pdf	yes	yes (co-administration study) Comment: many DDIs: see https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050689s016lbl.pdf#page=3 Sources: https://pubmed.ncbi.nlm.nih.gov/10418969/ \| https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050689s016lbl.pdf

Drug as victim

Target	Modality	Activity	Metabolite
CYP3A4 1709	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/9145845/	no
AADAC 1	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/21856291/	yes
CYP3A4 1709	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/9145845/	yes	25-O-DEACETYLRIFABUTIN 1

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:45367	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:45367
ChemicalBook	CB0702764	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB0702764
Selleck Chemicals	Rifabutin(Mycobutin)	http://www.selleckchem.com/products/Rifabutin(Mycobutin).html
ZINC	ZINC000169621215	http://zinc15.docking.org/substances/ZINC000169621215
eMolecules	29541954	https://www.emolecules.com/cgi-bin/more?vid=29541954
eMolecules	3717994	https://www.emolecules.com/cgi-bin/more?vid=3717994

PubMed

Title	Date	PubMed
LM 427, a new spiropiperidylrifamycin: in vitro and in vivo studies.	1983 Nov	6317622
Determination of in vitro susceptibility of mycobacteria to ansamycin.	1985 Sep	3929660
Determination of MICs of conventional and experimental drugs in liquid medium by the radiometric method against Mycobacterium avium complex.	1987	3428133
In vitro susceptibility of Mycobacterium avium complex to antibacterial agents.	1987 Nov	3440370
Qualitative and quantitative drug-susceptibility tests in mycobacteriology.	1988 May	3195815
In vitro effectiveness of a combination of zidovudine and ansamycin against human immunodeficiency virus.	1988 Oct	3171233
Comparative in-vitro activity of fleroxacin and other 6-fluoroquinolones against mycobacteria.	1988 Oct	3144550
In vitro activities against mycobacteria of two long-acting rifamycins, FCE22807 and CGP40/469A (SPA-S-565).	1990 Jun	2120827
Bactericidal activity in vitro of various rifamycins against Mycobacterium avium and Mycobacterium tuberculosis.	1990 Mar	2155555
Oxazolidinones, a new class of synthetic antituberculosis agent. In vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis.	1991 Nov-Dec	1802533
In vivo activities of newer rifamycin analogs against Mycobacterium avium infection.	1991 Oct	1662021
Treatment of experimental pneumocystosis: review of 7 years of experience and development of a new system for classifying antimicrobial drugs.	1992 Sep	1416885
In vitro antimicrobial activity of benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex, determined by the radiometric method.	1993 Jan	8431020
Azithromycin, rifabutin, and rifapentine for treatment and prophylaxis of Mycobacterium avium complex in rats treated with cyclosporine.	1993 Mar	8384809
Rifabutin is active in murine models of toxoplasmosis.	1994 Mar	8203856
Effectiveness of various antimicrobial agents against Mycobacterium avium complex in the beige mouse model.	1994 Nov	7872741
Comparison of activities of fluoroquinolones in murine macrophages infected with Mycobacterium tuberculosis.	1995 Mar	7793885
Activity of seven antimicrobial agents, alone and in combination, against AIDS-associated isolates of Mycobacterium avium complex.	1995 Sep	8830013
Chemotherapeutic activity of benzoxazinorifamycin, KRM-1648, against Mycobacterium tuberculosis in C57BL/6 mice.	1996 Apr	8762850
Low-dose aerosol infection model for testing drugs for efficacy against Mycobacterium tuberculosis.	1996 Dec	9124846
How effective is KRM-1648 in treatment of disseminated Mycobacterium avium complex infections in beige mice?	1996 Feb	8834894
Rifamycin resistance in mycobacteria.	1996 Jan-Feb	8761722
Use of rifabutin in combination with atovaquone, clindamycin, pyrimethamine, or sulfadiazine for treatment of toxoplasmic encephalitis in mice.	1996 May	8793398
Evaluation of the activities of rifabutin combined with atovaquone or low-dose of cotrimoxazole for prevention of pneumocystosis and toxoplasmosis in a dual infection rat model.	1996 Sep-Oct	8822822
New ophthalmic manifestations of presumed rifabutin-related uveitis.	1997 Apr	9101573
In-vitro activity of rifabutin and albendazole singly and in combination with other clinically used antimicrobial agents against Pneumocystis carinii.	1999 Nov	10552982
Activity of nitazoxanide alone and in combination with azithromycin and rifabutin against Cryptosporidium parvum in cell culture.	2000 Apr	10747821
Activity of rifapentine and its metabolite 25-O-desacetylrifapentine compared with rifampicin and rifabutin against Mycobacterium tuberculosis, Mycobacterium africanum, Mycobacterium bovis and M. bovis BCG.	2000 Oct	11020253
Idiosyncratic rifabutin-induced leukopenia and SIADH: case report and review.	2001 Apr	11310523
CYP3A inductive potential of the rifamycins, rifabutin and rifampin, in the rabbit.	2001 May	11745918
In vitro effect of short-term exposure to two synthetic peptides, alone or in combination with clarithromycin or rifabutin, on Cryptosporidium parvum infectivity.	2002 May	12084535
Activities of moxifloxacin alone and in combination with other antimicrobial agents against multidrug-resistant Mycobacterium tuberculosis infection in BALB/c mice.	2003 Jan	12499213
Human arylacetamide deacetylase is responsible for deacetylation of rifamycins: rifampicin, rifabutin, and rifapentine.	2011 Dec 1	21856291
The pharmacokinetics and pharmacodynamics of pulmonary Mycobacterium avium complex disease treatment.	2012 Sep 15	22744719

Patents

Sample Use Guides

In Vivo Use Guide

It is recommended that Rifabutin Capsules be administered at a dose of 300 mg once daily. For those patients with propensity to nausea, vomiting, or other gastrointestinal upset, administration of Rifabutin at doses of 150 mg twice daily taken with food may be useful.

Route of Administration: Oral

In Vitro Use Guide

The IC50 of rifabutin was 26.5 mg/L in a different series of experiments using an enzyme-linked immunoassay and the T. gondii high virulence strain.

Name

Type

Language

RIFABUTIN

Official Name

English

LM-427

Code

English

RIFABUTIN [VANDF]

Common Name

English

LM 427

Code

English

RIFABUTIN [ORANGE BOOK]

Common Name

English

MYCOBUTIN

Code

English

RIFABUTIN [USP-RS]

Common Name

English

ANSAMYCIN

Common Name

English

RIFABUTIN [JAN]

Common Name

English

RIFABUTIN [EP MONOGRAPH]

Common Name

English

RIFABUTIN COMPONENT OF TALICIA

Brand Name

English

RIFABUTIN [MI]

Common Name

English

1',4-DIDEHYDRO-1-DEOXY-1,4-DIHYDRO-5'-(2-METHYLPROPYL)-1-OXORIFAMYCIN XIV

Common Name

English

rifabutin [INN]

Common Name

English

Rifabutin [WHO-DD]

Common Name

English

4-DEOXO-3,4-(2-SPIRO-(N-ISOBUTYL-4-PIPERIDYL))-(1H)-IMIDAZO-(2,5-DIHYDRO)RIFAMYCIN S

Common Name

English

RIFABUTIN [USAN]

Common Name

English

TALICIA COMPONENT RIFABUTIN

Brand Name

English

4-N-ISOBUTYLSPIROPIPERIDYLRIFAMYCIN S

Common Name

English

RIFABUTIN [HSDB]

Common Name

English

RIFABUTIN [USP MONOGRAPH]

Common Name

English

RIFABUTIN [MART.]

Common Name

English

Classification Tree Code System Code

WHO-VATC

QJ04AB04