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targets (1) enzymes (5)
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Identification
Name Telithromycin
Accession Number DB00976 (APRD00483)
Type small molecule
Groups approved
Description

Telithromycin, a semi-synthetic erythromycin derivative, belongs to a new chemical class of antibiotics called ketolides. Ketolides have been recently added to the macrolide-lincosamide-streptogramin class of antibiotics. Similar to the macrolide antibiotics, telithromycin prevents bacterial growth by interfering with bacterial protein synthesis. Telithromycin binds to the 50S subunit of the 70S bacterial ribosome and blocks further peptide elongation. Binding occurs simultaneously at to two domains of 23S RNA of the 50S ribosomal subunit, domain II and V, where older macrolides bind only to one. It is used to treat mild to moderate respiratory infections.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • telithromycin
Brand names
  • Ketek
Brand name mixtures Not Available
Categories
  • Anti-Bacterial Agents
  • Ketolides
CAS number 191114-48-4
Weight Average: 812.0037
Monoisotopic: 811.473143325
Chemical Formula C43H65N5O10
InChI Key InChIKey=LJVAJPDWBABPEJ-RMNISARHSA-N
InChI
InChI=1S/C43H65N5O10/c1-12-33-43(8)37(48(41(53)58-43)19-14-13-18-47-23-31(45-24-47)30-16-15-17-44-22-30)27(4)34(49)25(2)21-42(7,54-11)38(28(5)35(50)29(6)39(52)56-33)57-40-36(51)32(46(9)10)20-26(3)55-40/h15-17,22-29,32-33,36-38,40,51H,12-14,18-21H2,1-11H3/t25-,26-,27+,28+,29-,32+,33+,36-,37-,38-,40+,42-,43+/m1/s1
Plain Text
IUPAC Name
(3aR,4S,7R,9R,10R,11R,13R,15R,15aR)-10-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-4-ethyl-11-methoxy-3a,7,9,11,13,15-hexamethyl-1-{4-[4-(pyridin-3-yl)-1H-imidazol-1-yl]butyl}-tetradecahydro-1H-oxacyclotetradeca[4,3-d][1,3]oxazole-2,6,8,14-tetrone
SMILES
CC[C@@H]1OC(=O)[C@H](C)C(=O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@@H]([C@H]2O)N(C)C)[C@@](C)(C[C@@H](C)C(=O)[C@H](C)[C@H]2N(CCCCN3C=NC(=C3)C3=CC=CN=C3)C(=O)O[C@@]12C)OC
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For the treatment of Pneumococcal infection, acute sinusitis, acute bacterial tonsillitis, acute bronchitis and bronchiolitis, lower respiratory tract infection and lobar (pneumococcal) pneumonia.
Pharmacodynamics Telithromycin is a ketolide antibiotic which has an antimicrobial spectrum similar or slightly broader than that of penicillin. It is often used as an alternative in patients who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma. Telithromycin prevents bacterial growth by binding to bacterial 50S ribosomal subunits and interfering with bacterial peptide translocation and elongation.
Mechanism of action Telithromycin acts by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding at domain II, telithromycin retains activity against gram-positive cocci (e.g. Streptococcus pneumoniae) in the presence of resistance mediated by methylases (erm genes) that alter the binding site at domain V. Telithromycin may also inhibit the assembly of nascent ribosomal units. Compared to erythromycin A, telithromycin binds to the 23S rRNA with 10 times greater affinity in erythromycin-susceptible organisms and 25 times greater affinity in macrolide-resistant strains. This increased binding affinity may be conferred by the C11-12 carbamate side chain of telithromycin. The side chain appears to maintain binding at domain II in the presence of resistance mediated by alterations in domain V.
Absorption Absolute bioavailability is approximately 57%. Maximal concentrations are reached 0.5 - 4 hours following oral administration. Food intake does not affected absorption.
Volume of distribution
  • 2.9 L/kg
Protein binding 60 - 70% bound primarily to human serum albumin
Metabolism

Hepatic - estimated 50% metabolized by CYP3A4 and 50% metabolized independent of cytochrome P450
Route of elimination The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver.
Half life Main elimination half-life is 2-3 hours; terminal elimination half-life is 10 hours
Clearance Not Available
Toxicity LD50>2000 mg/kg (PO in rats). Adverse effects are similar to those of clarithormycin and erithromycin and include diarrhea, nausea, vomiting, loose stools, abdominal pain, flatulence and dyspepsia. It may also cause dizziness, headache and taste disturbances.
Affected organisms
  • Enteric bacteria and other eubacteria
Pathways
Pathway Name SMPDB ID
Smp00252 Telithromycin Pathway SMP00252
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Ketek pak 400 mg tablet 6.12 USD tablet
Ketek 400 mg tablet 5.87 USD tablet
Ketek 300 mg tablet 5.76 USD tablet
Patents
Country Patent Number Approved Expires
United States 5635485 1998-04-01 2018-04-01
United States D459798 1995-09-24 2015-09-24
Canada 2189271 2005-12-27 2015-05-02
Canada 2102457 2002-01-22 2013-11-04
Properties
State solid
Melting point 176-188 oC
Experimental Properties
Property Value Source
water solubility 300 mg/L PhysProp
logP 3 PhysProp
Predicted Properties
Property Value Source
water solubility 2.83e-02 g/l ALOGPS
logP 4.00 ALOGPS
logP 5.37 ChemAxon Molconvert
logS -4.46 ALOGPS
pKa 12.83 ChemAxon Molconvert
hydrogen acceptor count 11 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 171.85 ChemAxon Molconvert
rotatable bond count 11 ChemAxon Molconvert
refractivity 214.68 ChemAxon Molconvert
polarizability 89.27 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Clay KD, Hanson JS, Pope SD, Rissmiller RW, Purdum PP 3rd, Banks PM: Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med. 2006 Mar 21;144(6):415-20. Epub 2006 Feb 15. Pubmed
External Links
Resource Link
KEGG Drug D01078 Link_out
KEGG Compound C12009 Link_out
Therapeutic Targets Database DAP000109 Link_out
PharmGKB PA10202 Link_out
HET TEL Link_out
Drug Product Database 2247520 Link_out
RxList http://www.rxlist.com/cgi/generic3/ketek.htm Link_out
Drugs.com http://www.drugs.com/cdi/telithromycin.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/ket1695.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Telithromycin Link_out
ATC Codes
  • J01FA15
AHFS Codes
  • 08:12.12.12
PDB Entries Not Available
FDA label show (1.6 MB)
MSDS show (200.9 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. 23S rRNA

Pharmacological action: yes
Actions: inhibitor

In prokaryotes, the 23S rRNA is part of the large subunit (the 50S) that joins with the 30S small subunit to create the functional 70S ribosome. The ribosome is comprised of 3 RNAs: the 23S, the 16S and the 5S ribosomal RNAs. The 23S and the 5S associate with their respective proteins to make up the large subunit of the ribosome, while the 16S RNA associates with its proteins to make up the small subunit.

Gene Sequence: FASTA

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Reinert RR, Al-Lahham A: Time-kill study of the activity of telithromycin against macrolide-resistant Streptococcus pneumoniae Isolates with 23S rRNA mutations and changes in ribosomal proteins L4 and L22. Antimicrob Agents Chemother. 2005 Jul;49(7):3011-3. Pubmed
  4. Farrell DJ, Shackcloth J, Barbadora KA, Green MD: Streptococcus pyogenes isolates with high-level macrolide resistance and reduced susceptibility to telithromycin associated with 23S rRNA mutations. Antimicrob Agents Chemother. 2006 Feb;50(2):817-8. Pubmed
  5. Hirakata Y, Mizuta Y, Wada A, Kondoh A, Kurihara S, Izumikawa K, Seki M, Yanagihara K, Miyazaki Y, Tomono K, Kohno S: The first telithromycin-resistant Streptococcus pneumoniae isolate in Japan associated with erm(B) and mutations in 23S rRNA and riboprotein L4. Jpn J Infect Dis. 2007 Feb;60(1):48-50. Pubmed
  6. Champney WS, Mentens N, Zurawick K: An examination of the differential sensitivity to ketolide antibiotics in ermB strains of Streptococcus pyogenes and Streptococcus pneumoniae. Curr Microbiol. 2004 Oct;49(4):239-47. Pubmed
Enzymes

1. Cytochrome P450 3A7

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

2. Cytochrome P450 1A2

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 3A4

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Bearden DT, Neuhauser MM, Garey KW: Telithromycin: an oral ketolide for respiratory infections. Pharmacotherapy. 2001 Oct;21(10):1204-22. Pubmed
  3. Zhanel GG, Walters M, Noreddin A, Vercaigne LM, Wierzbowski A, Embil JM, Gin AS, Douthwaite S, Hoban DJ: The ketolides: a critical review. Drugs. 2002;62(12):1771-804. Pubmed
  4. Reed M, Wall GC, Shah NP, Heun JM, Hicklin GA: Verapamil toxicity resulting from a probable interaction with telithromycin. Ann Pharmacother. 2005 Feb;39(2):357-60. Epub 2004 Dec 14. Pubmed
  5. Shi J, Chapel S, Montay G, Hardy P, Barrett JS, Sica D, Swan SK, Noveck R, Leroy B, Bhargava VO: Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment. Int J Clin Pharmacol Ther. 2005 Mar;43(3):123-33. Pubmed
  6. Nguyen M, Chung EP: Telithromycin: the first ketolide antimicrobial. Clin Ther. 2005 Aug;27(8):1144-63. Pubmed
  7. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

4. Cytochrome P450 3A5

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

5. Cytochrome P450 2D6

Actions: inhibitor

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on November 19, 2010 15:29

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.