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
Synonyms
  • Telithromycin
  • telitromicina
External IDs
HMR 3647
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
KetekTablet400 mgOralSanofi Aventis2003-05-292011-08-15Canada
KetekTablet, film coated400 mg/1OralSanofi Aventis2010-06-012016-06-30Us
KetekTablet, film coated400 mg/1OralPhysicians Total Care, Inc.2004-10-27Not applicableUs
KetekTablet, film coated300 mg/1OralSanofi Aventis2010-06-012016-06-30Us
Categories
UNII
KI8H7H19WL
CAS number
191114-48-4
Weight
Average: 812.018
Monoisotopic: 811.473143313
Chemical Formula
C43H65N5O10
InChI Key
LJVAJPDWBABPEJ-PNUFFHFMSA-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
IUPAC Name
(3aS,4R,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
[H][C@@]12[C@@H](C)C(=O)[C@H](C)C[C@@](C)(OC)[C@H](O[C@@H]3O[C@H](C)C[C@@H]([C@H]3O)N(C)C)[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@H](CC)[C@@]1(C)OC(=O)N2CCCCN1C=NC(=C1)C1=CC=CN=C1

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.

Associated Conditions
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.

TargetActionsOrganism
A23S rRNA
inhibitor
Enteric bacteria and other eubacteria
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
PathwayCategory
Telithromycin Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Interacting Gene/EnzymeAllele nameGenotype(s)Defining Change(s)Type(s)DescriptionDetails
Cytochrome P450 3A4CYP3A4*20Not Available1461_1462insAEffect InferredPoor drug metabolizer.Details
Cytochrome P450 3A4CYP3A4*26Not Available802C>TEffect InferredPoor drug metabolizer.Details

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Telithromycin.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Telithromycin.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Telithromycin.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Telithromycin.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Telithromycin.
6-Deoxyerythronolide BThe metabolism of Telithromycin can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Telithromycin.
7-ethyl-10-hydroxycamptothecinThe metabolism of 7-ethyl-10-hydroxycamptothecin can be decreased when combined with Telithromycin.
9-aminocamptothecinThe metabolism of 9-aminocamptothecin can be decreased when combined with Telithromycin.
AbataceptThe metabolism of Telithromycin can be increased when combined with Abatacept.
Food Interactions
  • Take without regard to meals.

References

Synthesis Reference

Suhas Sohani, Mandar Deodhar, Nishant Patel, Manish Patel, Mahesh Davadra, Vinodhamar Kansal, "Process for the Preparation of Telithromycin." U.S. Patent US20070260066, issued November 08, 2007.

US20070260066
General References
  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:16481451]
External Links
KEGG Drug
D01078
KEGG Compound
C12009
PubChem Compound
3002190
PubChem Substance
46504510
ChemSpider
2273373
BindingDB
50378137
ChEMBL
CHEMBL1136
Therapeutic Targets Database
DAP000109
PharmGKB
PA10202
HET
TEL
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Telithromycin
ATC Codes
J01FA15 — Telithromycin
FDA label
Download (1.6 MB)
MSDS
Download (201 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAsthma Bronchial1
3CompletedTreatmentChildren / Infection NOS1
3CompletedTreatmentMaxillary Sinusitis1
3CompletedTreatmentOtitis Media (OM)1
3CompletedTreatmentPneumonia1
3TerminatedTreatmentOtitis Media (OM)1
3TerminatedTreatmentOtitis Media, Purulent / Otitis Media, Suppurative1
3TerminatedTreatmentPharyngitis / Tonsillitis2
3Unknown StatusTreatmentScrub Typhus1
4CompletedTreatmentAcute Exacerbation of Chronic Bronchitis (AECB) / Community Acquired Pneumonia (CAP)1
4CompletedTreatmentChronic Bronchitis2
4CompletedTreatmentPneumonia1
4CompletedTreatmentRespiratory Tract Infections (RTI)1
4CompletedTreatmentSinusitis1
4TerminatedNot AvailableHealthy Volunteers1
4TerminatedDiagnosticMaxillary Sinusitis1
4TerminatedTreatmentChronic Bronchitis1
4TerminatedTreatmentChronic Bronchitis / Pneumonia / Respiratory Tract Infections (RTI)1
4TerminatedTreatmentPneumonia1
4WithdrawnTreatmentChronic Bronchitis / Pneumonia, Bacterial1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • A-S Medication Solutions LLC
  • Murfreesboro Pharmaceutical Nursing Supply
  • Physicians Total Care Inc.
  • Sanofi-Aventis Inc.
  • Southwood Pharmaceuticals
Dosage forms
FormRouteStrength
TabletOral400 mg
Tablet, film coatedOral300 mg/1
Tablet, film coatedOral400 mg/1
Prices
Unit descriptionCostUnit
Ketek pak 400 mg tablet6.12USD tablet
Ketek 400 mg tablet5.87USD tablet
Ketek 300 mg tablet5.76USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2189271No2005-12-272015-05-02Canada
CA2102457No2002-01-222013-11-04Canada
US5635485No1997-06-032018-04-01Us
USD459798No2002-07-022015-09-24Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)176-188 °CNot Available
water solubility300 mg/LNot Available
logP3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0283 mg/mLALOGPS
logP4.21ALOGPS
logP5.13ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)8.84ChemAxon
pKa (Strongest Basic)7.65ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area171.85 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity214.68 m3·mol-1ChemAxon
Polarizability90.44 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9904
Blood Brain Barrier-0.8608
Caco-2 permeable-0.8958
P-glycoprotein substrateSubstrate0.8472
P-glycoprotein inhibitor IInhibitor0.8737
P-glycoprotein inhibitor IIInhibitor0.7653
Renal organic cation transporterNon-inhibitor0.8479
CYP450 2C9 substrateNon-substrate0.7872
CYP450 2D6 substrateNon-substrate0.8617
CYP450 3A4 substrateSubstrate0.7538
CYP450 1A2 substrateNon-inhibitor0.8288
CYP450 2C9 inhibitorNon-inhibitor0.7157
CYP450 2D6 inhibitorNon-inhibitor0.8675
CYP450 2C19 inhibitorNon-inhibitor0.6476
CYP450 3A4 inhibitorNon-inhibitor0.8407
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7749
Ames testNon AMES toxic0.7687
CarcinogenicityNon-carcinogens0.8998
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.7843 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9399
hERG inhibition (predictor II)Non-inhibitor0.6053
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as aminoglycosides. These are molecules or a portion of a molecule composed of amino-modified sugars.
Kingdom
Organic compounds
Super Class
Organic oxygen compounds
Class
Organooxygen compounds
Sub Class
Carbohydrates and carbohydrate conjugates
Direct Parent
Aminoglycosides
Alternative Parents
Pyridines and derivatives / Oxazolidinones / Oxanes / 1,3-dicarbonyl compounds / N-substituted imidazoles / Carbamate esters / Heteroaromatic compounds / Trialkylamines / Secondary alcohols / 1,2-aminoalcohols
show 12 more
Substituents
Aminoglycoside core / N-substituted imidazole / Oxane / Oxazolidinone / Pyridine / 1,3-dicarbonyl compound / Oxazolidine / Azole / Heteroaromatic compound / Carbamic acid ester
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Targets

1. 23S rRNA
Kind
Nucleotide
Organism
Enteric bacteria and other eubacteria
Pharmacological action
Yes
Actions
Inhibitor
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:17139284]
  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:17016423]
  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:15980387]
  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:16436755]
  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:17314426]
  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:15386111]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Oxygen binding
Specific Function
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 un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Bearden DT, Neuhauser MM, Garey KW: Telithromycin: an oral ketolide for respiratory infections. Pharmacotherapy. 2001 Oct;21(10):1204-22. [PubMed:11601667]
  2. 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:12149046]
  3. 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:15598962]
  4. 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:15792396]
  5. Nguyen M, Chung EP: Telithromycin: the first ketolide antimicrobial. Clin Ther. 2005 Aug;27(8):1144-63. [PubMed:16199242]
  6. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]
  7. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Oxygen binding
Specific Function
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 un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
References
  1. Kalliokoski A, Niemi M: Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009 Oct;158(3):693-705. doi: 10.1111/j.1476-5381.2009.00430.x. Epub 2009 Sep 25. [PubMed:19785645]
  2. Konig J: Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms. Handb Exp Pharmacol. 2011;(201):1-28. doi: 10.1007/978-3-642-14541-4_1. [PubMed:21103967]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as 17-beta-glucuronosyl estradiol, taurocholate, triiodothyronine (T3), leukotriene C4, dehydroepiandrosterone sulfate (DHEAS), methotre...
Gene Name
SLCO1B3
Uniprot ID
Q9NPD5
Uniprot Name
Solute carrier organic anion transporter family member 1B3
Molecular Weight
77402.175 Da
References
  1. Kalliokoski A, Niemi M: Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009 Oct;158(3):693-705. doi: 10.1111/j.1476-5381.2009.00430.x. Epub 2009 Sep 25. [PubMed:19785645]
  2. Konig J: Uptake transporters of the human OATP family: molecular characteristics, substrates, their role in drug-drug interactions, and functional consequences of polymorphisms. Handb Exp Pharmacol. 2011;(201):1-28. doi: 10.1007/978-3-642-14541-4_1. [PubMed:21103967]

Drug created on June 13, 2005 07:24 / Updated on December 16, 2018 06:45