Identification

Name
Loracarbef
Accession Number
DB00447  (APRD01077)
Type
Small Molecule
Groups
Investigational, Withdrawn
Description

Loracarbef is a carbacephem antibiotic sometimes grouped together with the second-generation cephalosporin antibiotics. It is marketed under the trade name Lorabid.

Structure
Thumb
Synonyms
  • Anhydrous loracarbef
  • Loracarbef
  • Loracarbef, anhydrous
  • Loracarbefum
External IDs
LY 163892
Product Ingredients
IngredientUNIICASInChI Key
Loracarbef monohydrate3X11EVM5SU121961-22-6GPYKKBAAPVOCIW-HSASPSRMSA-N
International/Other Brands
Lorabid (Actavis) / Lorafem (Pierre Fabre) / Lorbef (Lilly)
Categories
UNII
W72I5ZT78Z
CAS number
76470-66-1
Weight
Average: 349.769
Monoisotopic: 349.082933722
Chemical Formula
C16H16ClN3O4
InChI Key
JAPHQRWPEGVNBT-UTUOFQBUSA-N
InChI
InChI=1S/C16H16ClN3O4/c17-9-6-7-10-12(15(22)20(10)13(9)16(23)24)19-14(21)11(18)8-4-2-1-3-5-8/h1-5,10-12H,6-7,18H2,(H,19,21)(H,23,24)/t10-,11-,12+/m1/s1
IUPAC Name
(6R,7S)-7-[(2R)-2-amino-2-phenylacetamido]-3-chloro-8-oxo-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
SMILES
N[[email protected]@H](C(=O)N[[email protected]]1[[email protected]]2CCC(Cl)=C(N2C1=O)C(O)=O)C1=CC=CC=C1

Pharmacology

Indication

Used to treat upper respiratory tract bacterial infections, chronic bronchitis, pneumonia, sinusitis, pharyntitis and tonsillitis, skin absceses, urinary tract infections and pyelonephritis caused by E. coli, S. pyogenes, S. aureus, S. saprphyticus, S. penumoniae, H. influenzae and M. catarrhalis.

Structured Indications
Not Available
Pharmacodynamics

Loracarbef is considered a second generation cephalosporin antibiotic. The advantages of cephalosporin antibiotics include a broad range of activity, a safe record in children with almost no dose-related toxicity, and the lack of need to monitor levels. Adverse reactions are rare and consist primarily of hypersensitivity reactions with urticaria, nonspecific rash, and pruritus. Loracarbef can be used to treat a large number of bacterial infections caused by gram-negative and gram-positive bacteria, including upper respiratory tract bacterial infections, chronic bronchitis, pneumonia, sinusitis, pharyntitis and tonsillitis, skin absceses, urinary tract infections and pyelonephritis caused by E. coli, S. pyogenes, S. aureus, S. saprphyticus, S. penumoniae, H. influenzae and M. catarrhalis.

Mechanism of action

Loracarbef is an oral, synthetic beta-lactam antibiotic of the carbacephem class. Chemically, carbacephems differ from cephalosporin-class antibiotics in the dihydrothiazine ring where a methylene group has been substituted for a sulfur atom. Loracarbef has a spectrum of activity similar to that of the second generation cephalosporins. It is structurally identical to cefaclor except for a sulfur atom that has been replaced by a methylene group. This change gives greater chemical stability in solution and allows storage at room temperature. Loracarbef, like all b-lactams and cephalosporins, inhibits penicillin binding proteins, enzymes that create the cross-linkage of the peptidoglycan polymer. This binding leads to interference with the formation and remodeling of the cell wall structure.

TargetActionsOrganism
APenicillin-binding protein 3
inhibitor
Streptococcus pneumoniae
APenicillin-binding protein 1A
inhibitor
Clostridium perfringens (strain 13 / Type A)
Absorption

Well absorbed with approximately 90% absorbed from the gastrointestinal tract after oral ingestion.

Volume of distribution
Not Available
Protein binding

25%

Metabolism

There is no evidence of metabolism in humans.

Route of elimination
Not Available
Half life

1 hour. In subjects with moderate impairment of renal function the plasma half-life was prolonged to approximately 5.6 hours.

Clearance
Not Available
Toxicity

Adverse effects include diarrhea, nausea, stomach upset, vomiting, headache, dizziness, rash, bone marrow depression.

Affected organisms
  • Various gram-negative and gram-positive eubacteria
  • Streptococcus pyogenes
  • Streptococcus pneumoniae
  • Haemophilus influenzae
  • Escherichia coli
  • Staphylococcus aureus
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Loracarbef.Investigational
Picosulfuric acidThe therapeutic efficacy of Picosulfuric acid can be decreased when used in combination with Loracarbef.Approved
Food Interactions
  • Take on an empty stomach. Food reduces Cmax by 50 to 60%.

References

Synthesis Reference

William C. Henning, Theodore R. Stout, "Process for preparing loracarbef monohydrate." U.S. Patent US5580977, issued May, 1990.

US5580977
General References
  1. Dantzig AH, Duckworth DC, Tabas LB: Transport mechanisms responsible for the absorption of loracarbef, cefixime, and cefuroxime axetil into human intestinal Caco-2 cells. Biochim Biophys Acta. 1994 Apr 20;1191(1):7-13. [PubMed:8155686]
  2. Brogden RN, McTavish D: Loracarbef. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1993 May;45(5):716-36. [PubMed:7686466]
  3. Force RW, Nahata MC: Loracarbef: a new orally administered carbacephem antibiotic. Ann Pharmacother. 1993 Mar;27(3):321-9. [PubMed:8453172]
  4. Copper RD: The carbacephems: a new beta-lactam antibiotic class. Am J Med. 1992 Jun 22;92(6A):2S-6S. [PubMed:1621741]
External Links
Human Metabolome Database
HMDB14590
KEGG Drug
D00916
KEGG Compound
C08109
PubChem Compound
5284585
PubChem Substance
46506369
ChemSpider
4447635
ChEBI
47544
ChEMBL
CHEMBL1013
Therapeutic Targets Database
DAP000434
PharmGKB
PA164754806
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Loracarbef
ATC Codes
J01DC08 — Loracarbef
MSDS
Download (44.1 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingTreatmentOsteomyelitis1

Pharmacoeconomics

Manufacturers
  • King pharmaceuticals inc
Packagers
Dosage forms
Not Available
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2034592No2001-06-052011-01-18Canada
CA1334970No1995-03-282012-03-28Canada

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP0.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.325 mg/mLALOGPS
logP0.55ALOGPS
logP-2.4ChemAxon
logS-3ALOGPS
pKa (Strongest Acidic)3.13ChemAxon
pKa (Strongest Basic)7.44ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area112.73 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity86.64 m3·mol-1ChemAxon
Polarizability32.61 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.6242
Blood Brain Barrier-0.9659
Caco-2 permeable-0.8958
P-glycoprotein substrateSubstrate0.7255
P-glycoprotein inhibitor INon-inhibitor0.89
P-glycoprotein inhibitor IINon-inhibitor0.9848
Renal organic cation transporterNon-inhibitor0.8905
CYP450 2C9 substrateNon-substrate0.8338
CYP450 2D6 substrateNon-substrate0.8339
CYP450 3A4 substrateSubstrate0.5199
CYP450 1A2 substrateNon-inhibitor0.82
CYP450 2C9 inhibitorNon-inhibitor0.8491
CYP450 2D6 inhibitorNon-inhibitor0.888
CYP450 2C19 inhibitorNon-inhibitor0.7748
CYP450 3A4 inhibitorNon-inhibitor0.6813
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9341
Ames testNon AMES toxic0.6788
CarcinogenicityNon-carcinogens0.929
BiodegradationNot ready biodegradable0.9959
Rat acute toxicity2.1829 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9752
hERG inhibition (predictor II)Non-inhibitor0.8654
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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 carbacephems. These are a new class of beta-lactam antibiotics similar in structure to the cephalosporins. They differ from cephalosporins, however, in the substitution of a sulfur atom in the dihydrothiazine ring with a methylene group to form a tetrahydropyridine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Lactams
Sub Class
Beta lactams
Direct Parent
Carbacephems
Alternative Parents
N-acyl-alpha amino acids and derivatives / Alpha amino acid amides / Phenylacetamides / Tetrahydropyridines / Aralkylamines / Vinylogous halides / Tertiary carboxylic acid amides / Secondary carboxylic acid amides / Amino acids / Azetidines
show 11 more
Substituents
Carbacephem / N-acyl-alpha amino acid or derivatives / Alpha-amino acid amide / Alpha-amino acid or derivatives / Phenylacetamide / Tetrahydropyridine / Aralkylamine / Monocyclic benzene moiety / Benzenoid / Tertiary carboxylic acid amide
show 28 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
zwitterion, carbacephem (CHEBI:214480)

Targets

Kind
Protein
Organism
Streptococcus pneumoniae
Pharmacological action
Yes
Actions
Inhibitor
General Function
Serine-type d-ala-d-ala carboxypeptidase activity
Specific Function
Not Available
Gene Name
pbp3
Uniprot ID
Q75Y35
Uniprot Name
Penicillin-binding protein 3
Molecular Weight
45209.84 Da
References
  1. Chambers HF, Miick C: Characterization of penicillin-binding protein 2 of Staphylococcus aureus: deacylation reaction and identification of two penicillin-binding peptides. Antimicrob Agents Chemother. 1992 Mar;36(3):656-61. [PubMed:1622180]
  2. Sato K, Okachi R, Matsukuma I, Mochida K, Hirata T: In vitro and in vivo antibacterial activity of KT3777, a new orally active carbacephem. J Antibiot (Tokyo). 1989 Dec;42(12):1844-53. [PubMed:2621166]
Kind
Protein
Organism
Clostridium perfringens (strain 13 / Type A)
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transferase activity, transferring glycosyl groups
Specific Function
Cell wall formation. Synthesis of cross-linked peptidoglycan from the lipid intermediates. The enzyme has a penicillin-insensitive transglycosylase N-terminal domain (formation of linear glycan str...
Gene Name
pbpA
Uniprot ID
Q8XJ01
Uniprot Name
Penicillin-binding protein 1A
Molecular Weight
75176.35 Da
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. Sato K, Okachi R, Matsukuma I, Mochida K, Hirata T: In vitro and in vivo antibacterial activity of KT3777, a new orally active carbacephem. J Antibiot (Tokyo). 1989 Dec;42(12):1844-53. [PubMed:2621166]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Proton-dependent oligopeptide secondary active transmembrane transporter activity
Specific Function
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products.
Gene Name
SLC15A1
Uniprot ID
P46059
Uniprot Name
Solute carrier family 15 member 1
Molecular Weight
78805.265 Da
References
  1. Wenzel U, Gebert I, Weintraut H, Weber WM, Clauss W, Daniel H: Transport characteristics of differently charged cephalosporin antibiotics in oocytes expressing the cloned intestinal peptide transporter PepT1 and in human intestinal Caco-2 cells. J Pharmacol Exp Ther. 1996 May;277(2):831-9. [PubMed:8627565]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Peptide:proton symporter activity
Specific Function
Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides.
Gene Name
SLC15A2
Uniprot ID
Q16348
Uniprot Name
Solute carrier family 15 member 2
Molecular Weight
81782.77 Da
References
  1. Boll M, Herget M, Wagener M, Weber WM, Markovich D, Biber J, Clauss W, Murer H, Daniel H: Expression cloning and functional characterization of the kidney cortex high-affinity proton-coupled peptide transporter. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):284-9. [PubMed:8552623]

Drug created on June 13, 2005 07:24 / Updated on November 07, 2017 01:38