RIFABUTIN

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C46H62N4O11
Molecular Weight	847.0064
Optical Activity	UNSPECIFIED
Defined Stereocenters	9 / 9
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC(C)CN1CCC2(CC1)N=C3c4c5c(c(C)c6c4C(=O)[C@@](C)(O/C(/[H])=C(\[H])/[C@@]([H])([C@@]([H])(C)[C@]([H])([C@]([H])(C)[C@@]([H])([C@]([H])(C)[C@]([H])([C@@]([H])(C)/C(/[H])=C(\[H])/C(/[H])=C(/C)\C(=NC(=C3N2)C5=O)O)O)O)OC(=O)C)OC)O6)O

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

Molecular Formula	C46H62N4O11
Molecular Weight	847.0064
Charge	0
Count

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	9 / 9
E/Z Centers	0
Optical Activity	UNSPECIFIED

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 116 Target ID: CHEMBL340 Sources: https://www.ncbi.nlm.nih.gov/pubmed/18713760	Substrate 609
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 7728

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 8043	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 74 inducer 707 substrate 1601	inhibitor 1604	inhibitor 1702

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
CYP1A2 1383 CYP3A 191 CYP2B6 717 CYP2C8 818 CYP2C19 1325 CYP2E1 790 UGT1A1 192 UGT1A4 74 UGT1A6 104 UGT1A9 113 UGT2B7 141 UGT2B15 61	AADAC 1	P-gp 248 OATP1B1 26 OATP1B3 6 MRP2 107

Drug as perpetrator

Target	Modality	Activity	Clinical evidence
UGT1A4 77	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	likely
CYP1A2 1532	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
CYP2C19 1392	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
CYP2E1 871	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
MRP2 434	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	no
OATP1B1 748	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	no
UGT1A6 136	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
UGT1A9 118	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	no
CYP3A 271	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely [IC50 31.5 uM]
CYP2B6 884	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
CYP2C8 865	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
CYP2C9 1648	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
CYP2D6 1738	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
UGT1A1 240	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
UGT2B15 61	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
UGT2B7 152	inhibitor 3045 Sources: https://pubmed.ncbi.nlm.nih.gov/28663285/	unlikely
CYP3A4 1772	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	yes
OATP1B3 666	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	yes
P-gp 1514	inducer 1440 Sources: https://pubmed.ncbi.nlm.nih.gov/24060875/	yes
CYP3A4 1772	activator 202 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 1601	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/9145845/	no
AADAC 1	substrate 3113 Sources: https://pubmed.ncbi.nlm.nih.gov/21856291/	yes
CYP3A4 1601	substrate 3113 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
Biological activity of a new class of rifamycins. Spiro-piperidyl-rifamycins.	1980 Oct	6256335
In vitro susceptibility of Mycobacterium avium complex and Mycobacterium tuberculosis strains to a spiro-piperidyl rifamycin.	1982 Sep	6289711
Activity of the spiropiperidyl rifamycin LM 427 on rifampicin resistant Mycobacterium tuberculosis.	1984 Sep-Dec	6100178
Determination of ansamycin MICs for Mycobacterium avium complex in liquid medium by radiometric and conventional methods.	1985 Oct	4073881
Comparative in vitro activities of MDL 473, rifampin, and ansamycin against Mycobacterium intracellulare.	1985 Sep	4073865
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
Activity of rifabutin alone or in combination with clofazimine or ethambutol or both against acute and chronic experimental Mycobacterium intracellulare infections.	1987 Aug	3039879
In vitro susceptibility of Mycobacterium avium complex to antibacterial agents.	1987 Nov	3440370
Action of antituberculous and beta-lactam drugs (including imipenem) against extra- and intra-cellularly growing Mycobacterium avium-intracellulare.	1988 Mar-Apr	3165640
Interaction between rifabutin and human immunodeficiency virus type 1: inhibition of replication, cytopathic effect, and reverse transcriptase in vitro.	1988 May	2456033
Comparative in vitro and in vivo activity of rifabutin and rifampicin against Mycobacterium avium complex.	1988 Sep	2855458
In vitro activities against mycobacteria of two long-acting rifamycins, FCE22807 and CGP40/469A (SPA-S-565).	1990 Jun	2120827
Effect of rifabutin on disseminated Mycobacterium avium infections in thymectomized, CD4 T-cell-deficient mice.	1990 Sep	2178333
[In vivo activities of new rifamycin derivatives against mycobacteria].	1991 Jan	2013969
In vitro antimycobacterial activities of newly synthesized benzoxazinorifamycins.	1991 Mar	2039206
Oxazolidinones, a new class of synthetic antituberculosis agent. In vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis.	1991 Nov-Dec	1802533
Effectiveness of rifampin, rifabutin, and rifapentine for preventive therapy of tuberculosis in mice.	1993 Dec	8256897
Azithromycin, rifabutin, and rifapentine for treatment and prophylaxis of Mycobacterium avium complex in rats treated with cyclosporine.	1993 Mar	8384809
Anti-Mycobacterium avium activity of quinolones: in vitro activities.	1993 Sep	8239587
Rifabutin is active in murine models of toxoplasmosis.	1994 Mar	8203856
In vitro and in vivo antibacterial activities of KRM-1648 and KRM-1657, new rifamycin derivatives.	1994 May	8067748
A bone marrow-derived murine macrophage model for evaluating efficacy of antimycobacterial drugs under relevant physiological conditions.	1994 Nov	7872747
Effectiveness of various antimicrobial agents against Mycobacterium avium complex in the beige mouse model.	1994 Nov	7872741
Clinical experience with rifabutin in the treatment of mycobacterial infections.	1995	8867175
[Extra and intracellular activity of dirithromycin against Mycobacterium avium].	1995 Apr	7567116
In-vitro and intracellular activity of rifabutin on drug-susceptible and multiple drug-resistant (MDR) tubercle bacilli.	1995 Aug	8522465
Mutation position and type of substitution in the beta-subunit of the RNA polymerase influence in-vitro activity of rifamycins in rifampicin-resistant Mycobacterium tuberculosis.	1995 Feb	7759399
Activities of rifabutin, clarithromycin, and ethambutol against two virulent strains of Mycobacterium avium in a mouse model.	1995 Mar	7793895
Comparison of activities of fluoroquinolones in murine macrophages infected with Mycobacterium tuberculosis.	1995 Mar	7793885
In vitro and in vivo activities of the benzoxazinorifamycin KRM-1648 against Mycobacterium tuberculosis.	1995 Oct	8619585
Activity of seven antimicrobial agents, alone and in combination, against AIDS-associated isolates of Mycobacterium avium complex.	1995 Sep	8830013
New drugs for tuberculosis.	1995 Sep	8590571
Chemotherapeutic activity of benzoxazinorifamycin, KRM-1648, against Mycobacterium tuberculosis in C57BL/6 mice.	1996 Apr	8762850
Susceptibility testing of Mycobacterium avium complex isolates.	1996 Aug	8843278
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
Rifapentine is active in vitro and in vivo against Toxoplasma gondii.	1996 Jun	8725996
Activity of rifabutin, clarithromycin, ethambutol, sparfloxacin and amikacin, alone and in combination, against Mycobacterium avium complex in human macrophages.	1996 Mar	9182107
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
Rapid drug susceptibility of Mycobacterium avium complex using a fluorescence quenching method.	1997 Aug	9269603
Clinically used antimicrobial drugs against experimental pneumocystosis, singly and in combination: analysis of drug interactions and efficacies.	1997 Feb	9021174
[Therapeutic efficacy of benzoxazinorifamycin KRM-1648 against experimental murine tuberculosis: (1). A study on the efficacy of short course treatment with the intratracheal and intravenous infection model].	1998 Feb	9545697
Contribution of rpoB mutations to development of rifamycin cross-resistance in Mycobacterium tuberculosis.	1998 Jul	9661035
Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction.	2006 Oct	16837568
Efficacy of rifabutin-loaded microspheres for treatment of Mycobacterium avium-infected macrophages and mice.	2007 Mar	17454031
Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development.	2010 Dec	20829430
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.

Substance Class	Chemical Created by `admin` on `Fri Jun 25 21:05:16 UTC 2021` Edited by `admin` on `Fri Jun 25 21:05:16 UTC 2021`
Record UNII	1W306TDA6S
Record Status	`Validated (UNII)`
Record Version

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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

RIFABUTIN [WHO-DD]

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

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