Rifampicin

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Rifampicin
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Executive Summary Information

Compound Rifampicin
Toxicities Steatosis, MOA standard for PXR agonists.
Mechanisms PXR agonist.
Comments PXR is a highly promiscuous nuclear hormone receptor that up-regulates uptake of fatty acids into the liver via the transporter CD36. Rifampicin is, therefore, pro-steatotic in the presence of high circulating fatty acid levels. PXR agonists also induce a wide profile of xenobiotic-metabolizing enzymes. This induction is the source of major drug-drug interactions in the clinic but is important for in vitro studies only to the extent that it may affect compound levels in repeated dose experiments. Care should be taken to avoid exposure to air to minimize the formation of the reactive quinone form of the compound.
Feedback Contact Gold Compound Working Group (GCWG)
Rifampicin
Rifampicin.png
Identifiers
Leadscope Id LS-7689
CAS 13292-46-1
DrugBank DB01045
ChemSpider 10468813
UNII VJT6J7R4TR
Pathway DBs
KEGG D00211
Assay DBs
PubChem CID 5381226
ChEMBL CHEMBL374478
Omics DBs
Open TG-Gate 00008
Properties
ToxCast Accepted yes
Toxic Effect Steatosis
ToxBank Accepted yes
Target PXR receptor
Toxicities Steatosis


In Vivo Data ? Compound Assessment
Adverse Events ? Rifampicin is an antibiotic used in the treatment of tuberculosis and as such is often used in drug combinations. As a PXR agonist rifampicin up-regulates a wide range of drug-metabolizing enzymes and can cause serious drug-drug interactions, resulting in increased clearance of other drugs and increased concentrations of reactive metabolites.

References:

-Chen & Raymond, 2006; Yew & Leung, 2006; Peters, 2005

Rifampicin itself, i.e. not in combination, has a major adverse event frequency of 0.4 per 100 person-months of dosing. 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, leucopenia, thrombocytopenia, and bleeding. The nervous system may be affected, manifesting as confusion, lethargy, ataxia, dizziness, blurring of vision, and peripheral neuritis. A different profile of adverse side-effects is observed with intermittent rifampicin intake. These include febrile reaction, eosinophilia, leucopenia, thrombocytopenia, purpura, haemolysis and shock, hepatotoxicity, and nephrotoxicity. This is assumed to be a hypersensitivity reaction. Other reported indications of hypersensitivity are polyarthritis, the presence of anti-native DNA antibodies, and pehphigus foliaceous.

References:

-InChem data sheet; Yew & Leung, 2006; Maalej, et al., 2003

Prolonged use of rifampicin causes a reduction of 25-hydroxycholecalciferol levels. It also causes increased deiodination and biliary clearance of thyroxine [InChem data sheet].

References:

-Jiezhong Chen and Kenneth Raymond (2006) “Roles of rifampicin in drug-drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor”, Annals of Clinical Microbiology and Antimicrobials 5:3.
-InChem data sheet: http://www.inchem.org/documents/pims/pharm/rifam.htm#SubSectionTitle:7.2.1
-Fenniche S, Maalej S, Fekih L, Hassene H, Belhabib D, Megdiche ML. (2003) “Manifestations of rifampicin-induced hypersensitivity”, Presse Med. 32:1167-1169.
-Terry Peters (2005) “Do Preclinical Testing Strategies Help Predict Human Hepatotoxic Potentials”, Toxicologic Pathology, 33:146–154.
-Yew WW, Leung CC. (2006) “Antituberculosis drugs and hepatotoxicity,” Respirology 11:699–707.
Toxicity Mechanisms ? Rifampicin is widely used as a selective agonist for the PXR nuclear receptor. PXR has one of the largest binding pockets of all the NHR’s and thus is a highly promiscuous receptor [Watkins et al., 2001]. For example, 75% of the compounds in a ToxCast screen were ligands for this receptor [Marin et al., 2010]. It is highly likely, therefore, that an unknown compound in a toxicity screen may be a ligand for this receptor. Since activation of PXR modulates expression of a wide range of genes (see “Gene Expression Profiles”), it is important to have available the gene expression profile of a PXR agonist such as rifampicin available as a control gene expression profile to distinguish cellular effects on PXR from other activities in building predictive toxicity profiles.

PXR has a well-characterized role in modulating the metabolism of xenobiotics [Goodwin et al., 2001; Smirlis et al., 2001; Ma et al., 2008]. These effects have major implications for drug-drug interactions (see “Adverse events”) in the clinic but are likely to be relevant in in vitro screens only to the extent they affect compound levels over the course of a repeated dose experiment.

Steatosis has not been reported as a significant adverse event for rifampicin [AERS database, accessed 16 May 2011; Ma et al., 2008]. However PXR is centrally implicated in the control of lipid metabolism, especially with respect to induction of the high affinity fatty acid transporter, CD36 [He et al., 2011]. This transporter is present in macrophages, where it is implicated in atherosclerosis, and in heart, skeletal muscle, adipose tissues, and liver, where it modulates lipid utilization for energy vs. storage. The transporter is strongly implicated in steatosis and is regulated in the liver jointly by LXR, PXR, and PPARγ. Activation of hLXR or hPXR in transgenic mice will induce CD36 and cause steatosis, including activation of PXR by rifampicin (Zhou et al., 2006; Moreau et al., 2009).

However, induction of CD36 is not always observed for hLXR and hPXR transgenics [Mitro, et al. 2007], so that the level of receptor expression may be a factor in determining the biology observed. This variability and the fact that joint activation of LXR and PXR consistently increases the steatotic response (Zhou et al., 2006; Mitro et al., 2007] is consistent with the fact that rifampicin (i.e. PXR activation alone) does not routinely induce steatosis in the clinic. The ToxBank wiki pages on TO901317 provide more discussion on this topic. Moya et al. [2010] have designed a screening assay well-suited to detecting induction of CD36 and steatosis by nuclear hormone ligands in the presence of high exogenous levels of fatty acids.

PXR is also a member of a nuclear hormone receptor system for cholesterol and bile acid homeostasis. LXR agonists increase the synthesis of bile acids and FXR, PXR, CAR, and VDR coordinately act to suppress bile acid levels [Eloranta and Kullak-Ublick, 2005; Li and Chang, 2005; Makishima, 2005; Ma et al., 2008]. Activation of PXR modulates, in particular, the P450 enzymes involved in synthesis and degradation of bile acids to reduce bile acid levels. However, rifampicin also inhibits the bile acid export pump, BSEP, with Ki = 30 uM [Byrne et al., 2002]. Since cholestasis is a statistically significant adverse event for rifampicin [AERS database, accessed 16 May 2011], the net effect of rifampicin itself is to increase the risk of cholestasis in some patients. Rifampicin is, therefore, suitable for studying PXR-mediated gene expression but not the effects of PXR activation on cholestasis per se [Ma et al., 2008].

In addition to its activity as a PXR ligand, rifampicin has an intrinsic chemical reactivity that has been associated with toxicities observed in the clinical. Because rifampicin is a poor ligand for rat and mouse PXR [Jones et al., 2000], it is probable that toxicities observed for these species [Shen et al., 2009], either invitro or in vivo, are due to this intrinsic toxicity, for example. We are primarily interested in the effects of rifampicin on PXR-mediated effects but provide a synopsis of its intrinsic toxicity for completeness:

Rifampicin has a fully substituted (reduced) naphthoquinone moiety that is expected to have a reduction potential similar to DMNQ (also a Gold Compound) but will not be a site of alkylation [Song and Buettner, 2010]. Redox cycling similar to DMNQ is expected,and enzyme-catalyzed oxidation and reduction have been demonstrated [dos Santos et al., 20050; Bolt and Remmer, 1976]. The quinone form is thought to be the primary source of intrinsic toxicity [Bolt and Remmer, 1976; Konrad and Stenberg, 1988]; and air-oxidation of stock solution should be avoided in handling rifampicin. The oxidized form alkylates amino groups at low levels [Bolt and Remmer, 1976], possibly via transamination at the aminal moiety; and alkylation may be the source of hypersensitivity on repeated dosing (see “Adverse events” section). Lipid peroxidation is also observed as might be expected for a redox cycling agent [Upadhyay, et al., 2007; Shen et al., 2009], although the levels observed are relatively low in comparison to other toxicants [Xu et al, 2008].

References:

-Bolt HM, Remmer H. (1976) “Implication of rifampicin-quinone in the irreversible binding of rifampicin to macromolecules.” Xenobiotica 6:21-32.
-Jane A. Byrne, Sandra S. Strautnieks, Giorgina Mieli–Vergani, Christopher F. Higgins, Kenneth J. Linton, and Richard J. Thompson, (2002) “The Human Bile Salt Export Pump: Characterization of Substrate Specificity and Identification of Inhibitors”, Gastroenterology 123:1649 –1658.
-Jyrki J. Eloranta and Gerd A. Kullak-Ublick (2005) “Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism”, Archives of Biochemistry and Biophysics 433:397–412.
-Bryan Goodwin, Linda B. Moore, Catherine M. Stoltz, David D. Mckee, and Steven A. Kliewer (2001) “Regulation of the Human CYP2B6 Gene by the Nuclear Pregnane X Receptor”, Mol Pharmacol 60:427–431.
-Jinhan He, Jung Hoon Lee, Maria Febbraio and Wen Xie (2011) “The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease”, Experimental Biology and Medicine 236: 1116–1121.
-S.A. Jones, L.B. Moore, J.L. Shenk, G.B. Wisely, G.A. Hamilton, D.D. McKee, N.C. Tomkinson, E.L. LeCluyse, M.H. Lambert, T.M. Willson, S.A. Kliewer, J.T. Moore (2000) “The pregnane x receptor: A promiscuous xenobiotic receptor that has diverged during evolution”, Mol. Endocrinol. 14:27–39.
-P. Konrad and P. Stenberg (1988) “Rifampicin Quinone Is an Immunosuppressant, but Not Rifampicin Itself”, Clinical Immunology and Immunopathology 46, 162-166.
-Tiangang Li and John Y. L. Chiang (2005) “Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7-hydroxylase gene transcription” Am J Physiol Gastrointest Liver Physiol 288: G74–G84.
-Xiaochao Ma, Jeffrey R. Idle, and Frank J. Gonzalez (2008) “The Pregnane X Receptor: From Bench to Bedside”, Expert Opin Drug Metab Toxicol. 4: 895–908.
-Makoto Makishima (2005) “Nuclear Receptors as Targets for Drug Development: Regulation of Cholesterol and Bile Acid Metabolism by Nuclear Receptors”, J Pharmacol Sci 97, 177 – 183.
-Matthew T. Martin, David J. Dix, Richard S. Judson, Robert J. Kavlock, David M. Reif, Ann M. Richard, Daniel M. Rotroff, Sergei Romanov, Alexander Medvedev, Natalia Poltoratskaya, Maria Gambarian, Matt Moeser, Sergei S. Makarov,§ and Keith A. Houck (2010) “Impact of Environmental Chemicals on Key Transcription Regulators and Correlation to Toxicity End Points within EPA’s ToxCast Program”, Chem. Res. Toxicol. 23:578–590.
-Xiaochao Ma, Jeffrey R. Idle, and Frank J. Gonzalez (2008) “The Pregnane X Receptor: From Bench to Bedside”, Expert Opin Drug Metab Toxicol. 4: 895–908.
-Nico Mitro, Leo Vargas, Russell Romeo, Alan Koder, Enrique Saez, (2007) “T0901317 is a potent PXR ligand: Implications for the biology ascribed to LXR”, FEBS Letters 581:1721–1726.
-Am´elie Moreau, Christelle T´eruel, Michel Beylot, Val´erie Albalea, Viola Tamasi, Thierry Umbdenstock, Yannick Parmentier, Antonio Sa-Cunha, Bertrand Suc, Jean-Michel Fabre, Francis Navarro, Jeanne Ramos, Urs Meyer, Patrick Maurel, Marie-Jos´e Vilarem, and Jean-Marc Pascussi (2009) “A Novel Pregnane X Receptor and S14-Mediated Lipogenic Pathway in Human Hepatocyte”, Hepatology 49:2068-2079.
-Marta Moya, M. José Gómez-Lechóna, José V. Castell, Ramiro Jovera (2010) “Enhanced steatosis by nuclear receptor ligands: A study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile”, Chemico-Biological Interactions 184 376–387.
-Chong Shen, Xiangdong Cheng, Donghui Li, and Qin Meng (2009) “Investigation of rifampicin-induced hepatotoxicity in rat hepatocytes maintained in gel entrapment culture”, Cell Biol Toxicol 25:265–274.
-Fernanda de Jesus Notário dos Santos, Valdecir Farias Ximenes, Luiz Marcos da Fonseca, Olga Maria Mascarenhas de Faria Oliveira, and Iguatemy Lourenço Brunetti (2005) “Horseradish Peroxidase-Catalyzed Oxidation of Rifampicin: Reaction Rate Enhancement by Co-oxidation with Anti-inflammatory Drugs”, Biol. Pharm. Bull. 28:1822—1826.
-Chong Shen, Xiangdong Cheng, Donghui Li, and Qin Meng, “Investigation of rifampicin-induced hepatotoxicity in rat hepatocytes maintained in gel entrapment culture”, Cell Biol Toxicol 25:265–274.
-Despina Smirlis, Roongsiri Muangmoonchai, Mina Edwards, Ian R. Phillipsi, and Elizabeth A. Shephard (2001) “Orphan Receptor Promiscuity in the Induction of Cytochromes P450 by Xenobiotics”, J. Biol. Chem. 276:12822–12826.
-Yang Song, Garry R. Buettner, “Thermodynamic and kinetic considerations for the reaction of semiquinone radicals to form superoxide and hydrogen peroxide”, Free Radical Biology & Medicine 49 (2010) 919–962.
-Ghanshyam Upadhyay, Abhai Kumar, Mahendra Pratap Singh (2007) “Effect of silymarin on pyrogallol- and rifampicin-induced hepatotoxicity in mouse”, European Journal of Pharmacology 565:190–201.
-Watkins RE, Wisely GB, Moore LB, Collins JL, Lambert MH, Williams SP, Willson TM, Kliewer SA, and Redinbo MR (2001) "The Human Nuclear Xenobiotic Receptor PXR: Structural Determinants of Directed Promiscuity", Science 292:2329-2333.
-Jinghai J. Xu, Peter V. Henstock, Margaret C. Dunn, Arthur R. Smith, Jeffrey R. Chabot, and David de Graaf (2008) “Cellular Imaging Predictions of Clinical Drug-Induced Liver Injury”, Toxicological Sciences 105: 97–105.
-Zhou J, Zhai Y, Mu Y, Gong H, Uppal H, Toma D, Ren S, Evans RM, Xie W. “A novel pregnane X receptor-mediated and sterol regulatory element-binding protein-independent lipogenic pathway”, J Biol Chem 2006;281:15013–20.
Therapeutic Target ? Rifampicin, discovered in 1966, is anti-bacterial by virtue of inhibiting bacterial RNA-polymerase. Because of a high frequency of resistance it is generally reserved for the treatment of tuberculosis. Inhibitors of bacterial RNA or DNA synthesis may be expected to inhibit mitochondrial RNA/DNA synthesis, however, rifampicin inhibits mammalian mitochondrial RNA synthesis only weakly at a concentration that is 100 times higher than for bacterial RNA synthesis.

References:

-Maggi N, Pasqualucci CR, Ballotta R, and Sensi P. (1966) “Rifampicin: a new orally active rifamycin”, Chemotherapy. 11:285-92.
-Molavi A (1990) “Antimicrobials III: Sulfonamides, Trimethoprim and Anti-Mycobacterial Agents”, in Joseph di Palma & John Di Gregorio's Basic Pharmacology in Medicine, 3rd ed. McGraw-Hill.
-Walter Wehrli (1983) “Rifampin: Mechanisms of Action and Resistanc”, Reviews of Infectious Diseases, 5( Supplement 3):S407-S411.
-Christopher J. Chetsanga, Jay I. Novetsky and Michael J. Dimino (1974) “Some Properties of Rat Liver Mitochondrial RNA Polymerase”, Molecular and Cellular Biochemistry 13:147-156.

FDA and Label Information

The following link will display all of the currently approved FDA drug products on the market. The web page will contain a table listing all current products by their respective Tradenames and primary active ingredients. The list is navigable by simply clicking on the product of interest, which will in turn list all of the NDA's and ANDA's associated with that product. From here users can click on a specific NDA or ANDA and see documents that have been submitted for the product that the FDA has made available via their website. The types of documents include approval history, letters, reviews and labels.
FDA Approved Products

This next url will perform a search in the FDA's system for all labels for products that contain "Rifampin" as an active ingredient.
FDA Label Search

PubMed references

The following resource link will perform a PubMed query for the terms "Rifampin" and "liver toxicity".
Rifampin Search

The table listed below contains a summarized listing of toxic effect information leveraged from the 6th European Framework Programme project LIINTOP. For a complete listing of the Gold Compound evaluation criteria please see the Gold Compound Evaluation and Comments immediately following the summary table below.

SMILES CC1C=CC=C(C(=O)NC2=C(C3=C(C(=C4C(=C3C(=O)C2=CNN5CCN(CC5)C)C(=O)C(O4)(OC=CC(C(C(C(C(C(C1O)C)O)C)OC(=O)C)C)OC)C)C)O)O)C
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}}
InChI-Key

FZYOVNIOYYPUPY-ZTWDQPHTSA-N

Summary Hepatotoxic Effects from the LIINTOP FP6 Program
Hepatocellular necrosis.gif Apoptosis.gif Transporter inhibition.gif Cholestatic.gif Steatotic.gif Phospholipidosis.gif Hepatocyte function.gif Mithochondria impairment.gif Oxidative stress.gif DNA synthesis genotoxicity.gif Covalent binding.gif Idiosyncrasia metabolic.gif Idiosyncrasia immune.gif Bioactivation required.gif LIINTOP severity.gif References
+ + + + 2

[1] [2] [3]

References

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PK-ADME ? Compound Assessment
PK parameters ?
  • Recommended Dose: 10 mg/kg (max 600 mg) uid
  • Cmax: 4-32 micro-g/mL (9 micro-M)
  • Vd: 0.9 - 1.6 L/kg
  • t1/2: 2-5 hour; shortens by a factor of 2 on repeated dosing due to enhanced excretion

References:

-INCHEM
Therapeutic window ?
  • LD50 (acute oral) mouse 830 mg/kg
  • LD50 (acute oral) rat 1300 mg/kg
  • LD50 (acute oral) rabbit 2100 mg/kg

Acute toxicity is observed in humans who have intentionally overdosed on 10 g of rifampicin and deaths from ingestion of 60g have been described. Toxicity is observed at the therapeutic dose of 0.6 g/day on intermittent exposure.

References:

-INCHEM
Metabolically activated ? We are primarily interested in the effects of the parent compound as a PXR activator and not interested in metabolites.

Approximately 85% of rifampicin is metabolised by the liver microsomal enzymes to its main metabolite,deacetylrifampicin, which is also active as an anti-bacterial.

References:

-INCHEM

At least 21 metabolites have been identified, but the relevance of these metabolites to toxicity is not well understood.

References:

-Bhagwat Prasad, Saranjit Singh (2009) “In vitro and in vivo investigation of metabolic fate of rifampicin using an optimized sample preparation approach and modern tools of liquid chromatography–mass spectrometry”, Journal of Pharmaceutical and Biomedical Analysis 50:475–490.

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? Included in the metabolic genes up-regulated by PXR activation are: CYP2B6, CYP2C9, CYP3A4 and in less extent CYP2C8, CYP2C19, CYP2D6, CYP3A5, CYP3A7, CYP2A13, CYP2C18, CYP2E1, CYP2F1, Epoxide hydrolase 1 (s1), Epoxide hydrolase 1 (s2), Heme oxygenase (decycling) 1. As the P450 responsible for degradation of approximately half of the marketed drugs, CYP3A4 is highly relevant to the association of rifampicin with drug-drug interactions. Induction of CYP3A genes, particularly CYP3A4, is a marker for PXR activation; however, these markers are not unique to PXR and are also induced by CAR agonists. [Goodwin et al., 2001; Smirlis et al., 2001; Ma et al., 2008]

The PXR and CAR mammalian genes arose by divergence from a single avian gene and have highly overlapping functionality. In addition, PXR stimulates expression of CAR, making it difficult to ascribe a unique pattern of gene expression to PXR alone. Where unique gene induction patterns have been identified for PXR, they are found primarily in the intestine, whereas unique CAR gene induction is found primarily in the liver. PXR also stimulates expression of PPARγ and AHR [Tien and Negishi, 2006; Handschin and Meyer, 2003; Maglich et al., 2002; Makishima, 2005; Ma et al., 2008]

Effective removal of bilirubin from the circulation requires organic anion transporters (OATP2) to transport bilirubin into liver from the blood, glucuronidation (UGT1A1), and efflux transporters to transport the bilirubin glucuronide into bile duct (MRP2). This bilirubin disposal system is upregulated by PXR (and CAR) agonists. [Tien and Negishi, 2006; Ito et al., 2005]

PXR in conjunction with FXR and CAR is part of the system for bile acid homeostasis. PXR is activated by bile acids, e.g. the highly toxic lithocholic acid, to down-regulate CYP7A1 for the synthesis of bile acids, up-regulate CYP3A4 to catalyze degradation of bile acids, and up-regulate MRP2 for the export of conjugated degradation products (among other effects better characterized in mice). [Eloranta and Kullak-Ublick, 2005; Li and Chiang, 2005; Pavek, et al. 2012; Makishima, 2005; Ma et al., 2008]

PXR, in conjunction with LXR, AhR, and PPARγ is part of a nuclear hormone system for control of fatty acid metabolism. Current focus is on the upregulation of CD36, which is a high affinity fatty acid uptake receptor found cardiac and skeletal muscle, adipocytes, and liver. PXR up-regulation of CD36 is specific to liver in hPXR transgenic mice and has been linked to steatosis. Other lipid-related proteins that are up-regulated are acyl-CoA synthase,enoyl-CoA hydratase in beta oxidation, E1A binding protein, and lipase [reviewed in Ma et al., 2008; He et al. 2011; Moreau et al. 2009].

Entries in DrugMatrix:

-Cd36: fatty acid translocase [RGD], 5d, 99mg/kg, Rat, Male, CD-IGS, Sprague Dawley, RU1 BIOCHIP
-Cd36: fatty acid translocase [RGD], 1d, 125uM,Primary Rat Hepatocytes, RG230-2, GENECHIP
-ADRP: adipose differentiation related protein (1390850_at, rc_AA874941_at) [RGD], 1d, 125 uM, Primrary Rat Hepatocytes, RG230-2 GENECHIP
-Lipc: lipase, hepatic (NM_012597_PROBE1) [RGD], 5d, 99 mg/kg Rat, Male, CD-IGS, Sprague Dawley, RU1, BIOCHIP
-Ep300: E1A binding protein p300 (1373916_at,AA996888_PROBE1) [RGD], 5d, 9mg/kg, Rat, Male, CD-IGS, Sprague Dawley, RU1 BIOCHIP
-Echdc2_predicted enoyl Coenzyme A hydratase domain containing 2 (DBSS) (1374527_at,AI172274_PROBE1) [RGD], 5d, 99 mg/kg, Rat, Male, CD-IGS, Sprague Dawley RU1 BIOCHIP
-LOC498962: acyl-CoA synthase enzyme [RGD], 5d, 99mg/kg, Rat, Male, CD-IGS, Sprague Dawley RU1 BIOCHIP

References:

-Jyrki J. Eloranta and Gerd A. Kullak-Ublick (2005) “Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism”, Archives of Biochemistry and Biophysics 433:397–412.
-Bryan Goodwin, Linda B. Moore, Catherine M. Stoltz, David D. Mckee, and Steven A. Kliewer (2001) “Regulation of the Human CYP2B6 Gene by the Nuclear Pregnane X Receptor”, Mol Pharmacol 60:427–431.
-C. Handschin, U.A. Meyer (2003) “Induction of drug metabolism: the role of nuclear receptors”, Pharmacol. Rev. 55:649–673.
-Jinhan He, Jung Hoon Lee, Maria Febbraio and Wen Xie (2011) “The emerging roles of fatty acid translocase/CD36 and the aryl hydrocarbon receptor in fatty liver disease”, Experimental Biology and Medicine 236: 1116–1121.
-Ito K, Suzuki H, Horie T, and Sugiyama Y. (2005) "Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport.". Pharm Res 22:1559–1577.
-Tiangang Li and John Y. L. Chiang (2005) “Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7-hydroxylase gene transcription” Am J Physiol Gastrointest Liver Physiol 288: G74–G84.
-Xiaochao Ma, Jeffrey R. Idle, and Frank J. Gonzalez (2008) “The Pregnane X Receptor: From Bench to Bedside”, Expert Opin Drug Metab Toxicol. 4: 895–908.
-Jodi M. Maglich, Catherine M. Stoltz, Bryan Goodwin, Diane Hawkins-Brown, John T. Moore, and Steven A. Kliewer (2002) “Nuclear Pregnane X Receptor and Constitutive Androstane Receptor Regulate Overlapping but Distinct Sets of Genes Involved in Xenobiotic Detoxification”, Mol Pharmacol 62:638–646.
-Makoto Makishima (2005) “Nuclear Receptors as Targets for Drug Development: Regulation of Cholesterol and Bile Acid Metabolism by Nuclear Receptors”, J Pharmacol Sci 97, 177 – 183.
-Am´elie Moreau, Christelle T´eruel, Michel Beylot, Val´erie Albalea, Viola Tamasi, Thierry Umbdenstock, Yannick Parmentier, Antonio Sa-Cunha, Bertrand Suc, Jean-Michel Fabre, Francis Navarro, Jeanne Ramos, Urs Meyer, Patrick Maurel, Marie-Jos´e Vilarem, and Jean-Marc Pascussi (2009) “A Novel Pregnane X Receptor and S14-Mediated Lipogenic Pathway in Human Hepatocyte”, Hepatology 49:2068-2079.
-Despina Smirlis, Roongsiri Muangmoonchai, Mina Edwards, Ian R. Phillipsi, and Elizabeth A. Shephard (2001) “Orphan Receptor Promiscuity in the Induction of Cytochromes P450 by Xenobiotics”, J. Biol. Chem. 276:12822–12826.
-Eric S. Tien and Masahiko Negishi (2006) “Nuclear receptors CAR and PXR in the regulation of hepatic metabolism”, Xenobiotica 36:1152–1163
-Petr Pavek , Lucie Stejskalova, Lucie Krausova, Michal Bitman, Radim Vrzal and Zdenek Dvorak (2012) “Rifampicin does not significantly affect the expression of small heterodimer partner in primary human hepatocytes”, Frontiers in Pharmacology vol 3, article1:1-5.
Proteomics profiles known. ? Not found.
Metabonomics profiles known. ?
-Kim B, Moon JY, Choi MH, Yang HH, Lee S, Lim KS, Yoon SH, Yu KS, Jang IJ, Cho JY (2013) “Global Metabolomics and Targeted Steroid Profiling Reveal That Rifampin, a Strong Human PXR Activator, Alters Endogenous Urinary Steroid Markers”, J Proteome Res. 2013 Jan 28. doi:10.1021/pr301021p
Fluxomics profiles known. ?
Epigenomics profiles known. ?
-Ramamoorthy A, Skaar TC. “In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes”, Drug Metab. Lett.5(2),126–131 (2011)
-Ying Xie, Sui Ke, Nengtai Ouyang, Jinhan He, Wen Xie, Mark T. Bedford, and Yanan Tian (2009) “Epigenetic Regulation of Transcriptional Activity of Pregnane X Receptor by Protein Arginine Methyltransferase 1”, J Biol Chem 284:9199 –9205.
Observed IC50 for in vitro cellular efficacy. ? Rifampin specifically inhibits bacterial RNA polymerase, the enzyme

responsible for DNA transcription, by forming a stable drug-enzyme complex with a binding constant of 1 nM.

References:

-Walter Wehrli (1983) “Rifampin: Mechanisms of Action and Resistance”, Reviews of Infectious Diseases, Vol. 5, Suppl. 3:S407-S411.
Observed IC50 for in vitro cellular toxicity studies. ? Note that there is species variability for PXR ligand affinity.

Rifampicin is a potent activator of human and rabbit PXR, but not mouse or rat. The EC50 for activation of the human receptor is 1.3 uM.

References:

-S.A. Jones, L.B. Moore, J.L. Shenk, G.B. Wisely, G.A. Hamilton, D.D. McKee, N.C. Tomkinson, E.L. LeCluyse, M.H. Lambert, T.M. Willson, S.A. Kliewer, J.T. Moore (2000) “The pregnane x receptor: A promiscuous xenobiotic receptor that has diverged during evolution”, Mol. Endocrinol. 14:27–39.

The studies of Moya, et al. are recommended as a model for experimental design of assays to evaluate the role of nuclear hormone receptors in steatosis.

References:

-Marta Moya, M. José Gómez-Lechón, José V. Castell, Ramiro Jovera (2010) “Enhanced steatosis by nuclear receptor ligands: A study in cultured human hepatocytes and hepatoma cells with a characterized nuclear receptor expression profile”, Chemico-Biological Interactions 184 376–387.

Rifampicin inhibits the bile acid export pump, BSEP, with Ki = 30 uM.

References:

-Jane A. Byrne, Sandra S. Strautnieks, Giorgina Mieli–Vergani, Christopher F. Higgins, Kenneth J. Linton, and Richard J. Thompson, (2002) “The Human Bile Salt Export Pump: Characterization of Substrate Specificity and Identification of Inhibitors”, Gastroenterology 123:1649 –1658.

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? Yes - Included in ToxCast Phase I and II Chemicals List.
Substance stability. ? Rifampicin solid should be stable for at least two years when stored desiccated at -20°C and protected from light.

Solution stabilities : DMSO, 10 mg/ml, about 8 months at 15°C; water-ethanol (8:2), 1 mg/ml, 8 weeks at 4°C or 20°C. In mildly basic aqueous solutions (pH 8.2, 20-22°C) in the presence of air, it is converted to rifampin quinone. Addition of sodium ascorbate can prevent its oxidation. Under basic conditions it undergoes desacetylation at 22°C forming the 25-desacetylrifampin (most of antibacterial activity is maintained). Rifampicin decomposes rapidly in acidic or alkaline conditions at 25°C but slowly in neutral conditions, i.e. at 200 μg/ml, at pH 2.3 it is hydrolyzed to 3-formylrifampicin. Due to the toxicity associated with the chemical reactivity of the quinone, it is best to prepare aqueous solutions with oxygen-free solvent and at neutral pH.

-Sigma Aldrich R3501 Product Information Sheet

Very stable in dimethyl sulfoxide; rather stable in water. Unstable in light, heat, air and moisture.

-Pubchem Rifampicin-Substance Summary
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Rifampicin is a zwitterions with pKa 1.7 related to the 4-hydroxy and pKa 7.9 related to the 3-piperazine nitrogen. A 1% suspension in water has pH 4.5 to 6.5.
-Merck Index, 1989

1400 mg/L (25°C)

-ChemIDplus Advanced

Solubility in water at 25°C: 2.5 mg/ml, pH 7.3; 1.3 mg/ml, pH 4.3

-Sigma Aldrich R3501 Product Information Sheet


estimated intrinsic solubility : 0.563 mg/ml
estimated solubility in pure water at pH 6.28: 1.736X-2 mg/ml
estimated solubility in water at pH 7.4: 3.49E-2 mg/ml
(Calculations performed using ACD/PhysChem v 12.02)

Solubility in DMSO 100 times buffer solubility. ? Soluble
-Sigma Aldrich R3501 Product Information Sheet
-Tocris Bioscience (4121) Product Information Sheet
Vessel binding properties. ? Reported loss of rifampicin after successive transfers of aqueous solutions between polypropylene tubes.
-Zientek KD, Nelson MD, Payne L. Difficulties in Developing a Sensitive Assay for the Quantification of Rifampin in Multiple Biological Matrices by LC-MS/MS. Bioanalytical Systems, Inc. McMinnville, OR.
Vapor pressure. (Non-volatile) ? Estimated vapor pressure (25°C): 3.07E-034 mmHg (Calculation performed using EPI Suite v4.10)

Calculated/Predicted Properties

Water Solubility Results
pH Sol,mg/ml Flags  % Graph
0 894.13 B 100 Rifampicin solubility.png
0.1 786.15 B 100
0.2 686.71 B 100
0.3 595.29 B 100
0.4 511.73 B 100
0.5 436.07 B 100
0.6 368.36 B 100
0.7 308.56 B 100
0.8 256.44 B 100
Summary Solubility Data
Intrinsic Solubility,mg/ml 0.563
Intrinsic Solubility,log(S,mol/l) -3.1649
Solubility in Pure Water at pH = 6.28,mg/ml 1.736E-2
Calculations performed using ACD/PhysChem v 12.02
LogD Results
pH LogD pH LogD Graph
0 -0.99 0.9 -0.91 Rifampicin logd.png
0.1 -0.97 1.0 -0.91
0.2 -0.96 1.1 -0.91
0.3 -0.95 1.2 -0.9
0.4 -0.94 1.3 -0.9
0.5 -0.93 1.4 -0.9
0.6 -0.92 1.5 -0.9
0.7 -0.92 1.6 -0.9
0.8 -0.91 1.7 -0.9
Calculations performed using ACD/PhysChem v 12.02
Single-valued Properties
Property Value Units Error
LogP 2.39 1.74
MW 822.94 -
PSA 220.15 -
FRB 10 -
HDonors 6 -
HAcceptors 16 -
Rule Of 5 3 -
Molar Refractivity 213.06 cm3 0.5
Molar Volume 611.74 cm3 7
Parachor 1610.13 cm3 8
Index of Refraction 1.61 4.67E-02
Surface Tension 47.99 dyne/cm 7
Density 1.35 g/cm3 0.14
Polarizability 84.46 10E-24 cm3 0.5
Boiling Point 941.64 °C 65
Calculations performed using ACD/PhysChem v 12.02
Property Name Value Units Source
Estimated VP 1.41E-035 mm Hg EPI Suite v4.11
Estimated VP 1.87E-033 Pa EPI Suite v4.11
Estimated Water Solubility 0.3337 mg/L EPI Suite v4.11
WATERNT Frag Water Solubility Estimate 9.0111E005 mg/L EPI Suite v4.11
pKa Results
Acidic/Basic Acidic/Basic Aparrent pKa Value Error
45 A 18.71 0.7
31 A 14.95 0.7
35 A 14.51 0.7
48 A 9.92 0.7
A = Acidic
B = Basic
MA = Most Acidic
MB = Most Basic
Calculations performed using ACD/PhysChem v 12.02

Authors of this ToxBank wiki page

David Bower
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