Identification

Name
Dirithromycin
Accession Number
DB00954  (APRD00931)
Type
Small Molecule
Groups
Experimental
Description

Dirithromycin is a macrolide glycopeptide antibiotic. It is used to treat many different types of bacterial infections, such as bronchitis, pneumonia, tonsillitis, and even skin infections.

Structure
Thumb
Synonyms
  • diritromicina
External IDs
LY 237216 / LY-237216
International/Other Brands
Dynabac
Categories
UNII
1801D76STL
CAS number
62013-04-1
Weight
Average: 835.086
Monoisotopic: 834.5453052
Chemical Formula
C42H78N2O14
InChI Key
WLOHNSSYAXHWNR-DWIOZXRMSA-N
InChI
InChI=1S/C42H78N2O14/c1-15-29-42(10,49)37-24(4)32(43-30(56-37)21-52-17-16-50-13)22(2)19-40(8,48)36(58-39-33(45)28(44(11)12)18-23(3)53-39)25(5)34(26(6)38(47)55-29)57-31-20-41(9,51-14)35(46)27(7)54-31/h22-37,39,43,45-46,48-49H,15-21H2,1-14H3/t22-,23-,24+,25+,26-,27+,28+,29-,30-,31+,32+,33-,34+,35+,36-,37-,39+,40-,41-,42-/m1/s1
IUPAC Name
(1R,2R,3R,6R,7S,8S,9R,10R,12R,13S,15R,17S)-9-{[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy}-3-ethyl-2,10-dihydroxy-7-{[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy}-15-[(2-methoxyethoxy)methyl]-2,6,8,10,12,17-hexamethyl-4,16-dioxa-14-azabicyclo[11.3.1]heptadecan-5-one
SMILES
CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@@H]([C@H]2O)N(C)C)[C@](C)(O)C[C@@H](C)[C@@H]2N[C@@H](COCCOC)O[C@H]([C@H]2C)[C@]1(C)O

Pharmacology

Indication

For the treatment of the following mild-to-moderate infections caused by susceptible strains of microorganisms: acute bacterial exacerbations of chronic bronchitis, secondary bacterial infection of acute bronchitis, community-acquired pneumonia, pharyngitis/tonsilitis, and uncomplicated skin and skin structure infections.

Pharmacodynamics

Dirithromycin is a pro-drug which is converted non-enzymatically during intestinal absorption into the microbiologically active moiety erythromycylamine. Erythromycylamine exerts its activity by binding to the 50S ribosomal subunits of susceptible mircoorganisms resulting in inhibition of protein synthesis. Dirithromycin/erythromycylamine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections: Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, and Mycoplasma pneumoniae.

Mechanism of action

Dirithromycin prevents bacteria from growing, by interfering with their protein synthesis. Dirithromycin binds to the 50S subunit of the 70S bacterial ribosome, and thus inhibits the translocation of peptides. Dirithromycin has over 10 times higher affinity to the subunit 50S than erythromycin. In addition, dirithromycin binds simultaneously in to two domains of 23S RNA of the ribosomal subunit 50S, where older macrolides bind only in one. Dirithromycin can also inhibit the formation of ribosomal subunits 50S and 30S.

TargetActionsOrganism
A23S rRNA
inhibitor
Enteric bacteria and other eubacteria
Absorption

Oral dirithromycin is rapidly absorbed, with an absolute bioavailability of approximately 10%. Dietary fat has little or no effect on the bioavailability of dirithromycin.

Volume of distribution
Not Available
Protein binding

15 to 30% for erythromycylamine, the active compound.

Metabolism

Dirithromycin is converted by nonenzymatic hydrolysis during absorption to the active compound, erythromycylamine. Sixty to 90% of a dose is hydrolyzed to erythromycylamine within 35 minutes after dosing, and conversion is nearly complete after 1.5 hours. Erythromycylamine undergoes little or no hepatic biotransformation. No other metabolites of dirithromycin have been detected in the serum.

Route of elimination
Not Available
Half life

The mean plasma half-life of erythromycylamine was estimated to be about 8 h (2 to 36 h), with a mean urinary terminal elimination half-life of about 44 h (16 to 65 h) in patients with normal renal function.

Clearance
Not Available
Toxicity

The toxic symptoms following an overdose of a macrolide antibiotic may include nausea, vomiting, epigastric distress, and diarrhea.

Affected organisms
  • Enteric bacteria and other eubacteria
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe serum concentration of (R)-warfarin can be increased when it is combined with Dirithromycin.
(S)-WarfarinThe serum concentration of (S)-Warfarin can be increased when it is combined with Dirithromycin.
3-isobutyl-1-methyl-7H-xanthineThe metabolism of 3-isobutyl-1-methyl-7H-xanthine can be decreased when combined with Dirithromycin.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Dirithromycin.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Dirithromycin.
5-androstenedioneThe metabolism of 5-androstenedione can be decreased when combined with Dirithromycin.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Dirithromycin.
7-DeazaguanineThe metabolism of 7-Deazaguanine can be decreased when combined with Dirithromycin.
7,9-DimethylguanineThe metabolism of 7,9-Dimethylguanine can be decreased when combined with Dirithromycin.
8-azaguanineThe metabolism of 8-azaguanine can be decreased when combined with Dirithromycin.
Food Interactions
Not Available

References

Synthesis Reference

Counter FT, Ensminger PW, Preston DA, Wu CY, Greene JM, Felty-Duckworth AM, Paschal JW, Kirst HA: Synthesis and antimicrobial evaluation of dirithromycin (AS-E 136; LY237216), a new macrolide antibiotic derived from erythromycin. Antimicrob Agents Chemother. 1991 Jun;35(6):1116-26. Pubmed.

General References
  1. Brogden RN, Peters DH: Dirithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1994 Oct;48(4):599-616. [PubMed:7528132]
  2. Wintermeyer SM, Abdel-Rahman SM, Nahata MC: Dirithromycin: a new macrolide. Ann Pharmacother. 1996 Oct;30(10):1141-9. [PubMed:8893122]
  3. Sides GD, Cerimele BJ, Black HR, Busch U, DeSante KA: Pharmacokinetics of dirithromycin. J Antimicrob Chemother. 1993 Mar;31 Suppl C:65-75. [PubMed:8478313]
External Links
KEGG Drug
D03865
PubChem Compound
6473883
PubChem Substance
46509156
ChemSpider
4976073
BindingDB
59397
ChEBI
474014
ChEMBL
CHEMBL1237072
Therapeutic Targets Database
DAP000888
PharmGKB
PA449368
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Dirithromycin
ATC Codes
J01FA13 — Dirithromycin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentOsteomyelitis1

Pharmacoeconomics

Manufacturers
  • Lilly research laboratories
Packagers
Not Available
Dosage forms
Not Available
Prices
Unit descriptionCostUnit
Dynabac D5-Pak 10 250 mg Enteric Coated Tabs Box43.54USD box
Dynabac D5-Pak 250 mg Enteric Coated Tabs4.35USD tab
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityPoorNot Available
logP1.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.23 mg/mLALOGPS
logP2.9ALOGPS
logP2.95ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)12.49ChemAxon
pKa (Strongest Basic)9.13ChemAxon
Physiological Charge2ChemAxon
Hydrogen Acceptor Count15ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area196.33 Å2ChemAxon
Rotatable Bond Count12ChemAxon
Refractivity212.95 m3·mol-1ChemAxon
Polarizability91.38 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.6028
Blood Brain Barrier-0.9704
Caco-2 permeable-0.7573
P-glycoprotein substrateSubstrate0.8808
P-glycoprotein inhibitor IInhibitor0.7564
P-glycoprotein inhibitor IINon-inhibitor0.6712
Renal organic cation transporterNon-inhibitor0.8978
CYP450 2C9 substrateNon-substrate0.8537
CYP450 2D6 substrateNon-substrate0.9117
CYP450 3A4 substrateSubstrate0.7329
CYP450 1A2 substrateNon-inhibitor0.9305
CYP450 2C9 inhibitorNon-inhibitor0.907
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.9051
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9141
Ames testNon AMES toxic0.7677
CarcinogenicityNon-carcinogens0.9345
BiodegradationNot ready biodegradable0.9961
Rat acute toxicity2.7997 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9944
hERG inhibition (predictor II)Non-inhibitor0.5956
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
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-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
Macrolides and analogues / O-glycosyl compounds / Oxanes / 1,3-oxazinanes / Monosaccharides / Tertiary alcohols / Trialkylamines / Secondary alcohols / Amino acids and derivatives / 1,2-aminoalcohols
show 13 more
Substituents
Aminoglycoside core / Macrolide / O-glycosyl compound / Glycosyl compound / Monosaccharide / 1,3-oxazinane / Oxane / Oxazinane / Tertiary alcohol / Tertiary amine
show 26 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
macrolide antibiotic (CHEBI:474014)

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. Zhanel GG, Dueck M, Hoban DJ, Vercaigne LM, Embil JM, Gin AS, Karlowsky JA: Review of macrolides and ketolides: focus on respiratory tract infections. Drugs. 2001;61(4):443-98. [PubMed:11324679]
  4. Parsad D, Pandhi R, Dogra S: A guide to selection and appropriate use of macrolides in skin infections. Am J Clin Dermatol. 2003;4(6):389-97. [PubMed:12762831]
  5. Williams JD, Sefton AM: Comparison of macrolide antibiotics. J Antimicrob Chemother. 1993 Mar;31 Suppl C:11-26. [PubMed:8478301]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
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. Kuper JI, D'Aprile M: Drug-Drug interactions of clinical significance in the treatment of patients with Mycobacterium avium complex disease. Clin Pharmacokinet. 2000 Sep;39(3):203-14. [PubMed:11020135]

Drug created on June 13, 2005 07:24 / Updated on November 02, 2018 04:53