Bicisate

Identification

Name
Bicisate
Accession Number
DB11164
Type
Small Molecule
Groups
Approved, Investigational
Description

Bicisate, also known as ethyl cysteinate dimer (ECD), presents a molecular formula os N,N'-1,2-ethylene-di-yl-bis-L-cysteinate diethyl ester. It is usually complex with technetium Tc99m for its usage as a tracer to measure cerebral blood flow with single-photon emission computed tomography (SPECT).[1] The complex of bicisate and technetium Tc99m as a kit was developed by Lantheus Medcl and FDA-approved on November 23, 1994.[8]

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Bicisate dihydrochlorideB005P07V0714344-58-2HKASNZKRIQURIX-BZDVOYDHSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NeuroliteKit0.9 mg/1IntravenousLantheus Medical Imaging1994-11-23Not applicableUs
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
BicisateBicisate (1.35 mg/1)Injection, powder, lyophilized, for solutionIntravenousAnazao Health Corporation2012-05-23Not applicableUs
Categories
Not Available
UNII
3JXF0Z0XOI
CAS number
121251-02-3
Weight
Average: 324.45
Monoisotopic: 324.117749609
Chemical Formula
C12H24N2O4S2
InChI Key
RZQNBTMGBODDSK-UWVGGRQHSA-N
InChI
InChI=1S/C12H24N2O4S2/c1-3-17-11(15)9(7-19)13-5-6-14-10(8-20)12(16)18-4-2/h9-10,13-14,19-20H,3-8H2,1-2H3/t9-,10-/m0/s1
IUPAC Name
ethyl (2R)-2-[(2-{[(2R)-1-ethoxy-1-oxo-3-sulfanylpropan-2-yl]amino}ethyl)amino]-3-sulfanylpropanoate
SMILES
CCOC(=O)[C@H](CS)NCCN[C@@H](CS)C(=O)OCC

Pharmacology

Indication

Bicisate as a complex with technetium Tc-99m is used in single photon emission computerized tomography (SPECT) as an adjunct to conventional CT or MRI in the localization of stroke in patients whom the presence of a stroke has already been diagnosed. It is not indicated to assess the functional viability of brain tissue or to distinguish between a stroke and other brain lesions.[10]

A stroke is defined as a condition in which the blood stops flowing to any part of the brain causing a damage to brain cells. The potential effect of a stroke depends on the part of the brain that was affected by it as well as the extension of the damage.[11]

Pharmacodynamics

The neutral and lipophilic nature of bicisate provides it with high stability. This property is given by its N2S2 core. This characteristic has been proven to allow bicisate to be used even several hours after preparation and to present an easy passage through the blood-brain barrier.[4]

Mechanism of action

Bicisate is rapidly uptaken by the brain. The retention of bicisate in the brain is associated with stereospecific de-esterification to hydrophilic acid derivatives.[1] Even though both DD and LL isomers demonstrate brain uptake, only the LL presents brain retention.[5] Bicisate brain localization is performed by passive diffusion and the presence of slow hydrolysis in the blood and rapid hydrolysis in the brain. The hydrolysis of bicisate forms the monoacid and diacid bicisate derivatives. The formation of these derivatives results in high brain uptake and retention.[4, 5] The uptake of bicisate depends on the blood flow directed to the brain and thus the presence of a stroke will be translated into specific zones in the brain that would not include the complex of bicisate and technetium Tc-99m.

Absorption

After intravenous administration, bicisate presents a very large brain extraction.[1] About 5% of the administered dose remains in the blood one hour after administration. The highest concentration of radioactivity in blood was attained 0.5 minutes after intravenous injection and it represented 13.9% of the injected dose.[10] After intravenous administration of bicisate, the permeability surface area was 0.48 ml.g/min.[3]

Volume of distribution

After intravenous administration of bicisate, the distribution volume was 0.74 L.[3]

Protein binding

Bicisate and its major metabolites are not protein-bound.[10]

Metabolism

Bicisate is metabolized to form mono- and di-acids by the action of esterases. The exact metabolic transformation has not been elucidated.[10, 6]

Route of elimination

Bicisate is primarily excreted by the kidneys. It has been reported that 50% of the dose is excreted in urine two hours after initial administration and even 74% of the administered dose is excreted in urine after 24 hours. Fecal excretion just accounts for 12.5% of the administered dose 48 hours after initial administration.[10]

Half life

The stability of bicisate is superior when compared to other brain radiopharmaceuticals.[4] Thus, the reported half-life of bicisate is of 6.02 hours.[9] When broadly studied in clinical trials, the pharmacokinetic profile fits a three-compartment model with half-lives of 43 seconds, 49.5 minutes and 533 minutes.[2]

Clearance

The clearance of bicisate from 1 to 24 hours, studied as a loss of hydrophilic tracer, is of approximate 3.5% per hour.[2]

Toxicity

In vitro, the complex of bicisate and technetium Tc-99m has been shown to cause unscheduled DNA synthesis and caused an increased frequency of chromatid exchange. Bicisate as a unique compound increased the apparent rate of gene mutation but it did not demonstrate clastogenic activity. Studies related to clastogenic potential or effects in fertility have not been performed.[10]

Affected organisms
  • Humans
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Bicisate which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Bicisate which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Bicisate which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Bicisate which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Bicisate which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Bicisate which could result in a higher serum level.
AclidiniumAclidinium may decrease the excretion rate of Bicisate which could result in a higher serum level.
AcrivastineAcrivastine may decrease the excretion rate of Bicisate which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Bicisate which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Bicisate which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Dormehl IC, Oliver DW, Langen KJ, Hugo N, Croft SA: Technetium-99m-HMPAO, technetium-99m-ECD and iodine-123-IMP cerebral blood flow measurements with pharmacological interventions in primates. J Nucl Med. 1997 Dec;38(12):1897-901. [PubMed:9430465]
  2. Friberg L, Andersen AR, Lassen NA, Holm S, Dam M: Retention of 99mTc-bicisate in the human brain after intracarotid injection. J Cereb Blood Flow Metab. 1994 Jan;14 Suppl 1:S19-27. [PubMed:8263067]
  3. Knudsen GM, Andersen AR, Somnier FE, Videbaek C, Hasselbalch S, Paulson OB: Brain extraction and distribution of 99mTc-bicisate in humans and in rats. J Cereb Blood Flow Metab. 1994 Jan;14 Suppl 1:S12-8. [PubMed:8263066]
  4. International Atomic Energy Agency (2008). Technetium-99m radiopharmaceuticals: Manufacture of kits. IAEA.
  5. Kowalsky R. (2006). Technetium radiopharmaceutical chemistry. University of New Mexico Health Sciences Center.
  6. Grunwald F., Kasper S., Biersack J. and Moller J. (1995). Brain SPECT Imaging in psychiatry. Walter de Gruyter.
  7. Dailymed [Link]
  8. FDA approved drugs [Link]
  9. WHO [Link]
  10. Dailymed [Link]
  11. Heart and stroke foundation [Link]
External Links
PubChem Compound
72048
PubChem Substance
347827929
ChemSpider
65035
MSDS
Download (84.6 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionIntravenous1.35 mg/1
KitIntravenous0.9 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)196-198ºCInternational Atomic Energy Agency. (2008)
water solubilityInsolubleKowalsky RJ. Technetium Radiopharmaceutical Chemistry.
Predicted Properties
PropertyValueSource
Water Solubility0.0867 mg/mLALOGPS
logP1.28ALOGPS
logP0.64ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)9.65ChemAxon
pKa (Strongest Basic)5.76ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area76.66 Å2ChemAxon
Rotatable Bond Count13ChemAxon
Refractivity83.06 m3·mol-1ChemAxon
Polarizability34.5 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

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 alpha amino acid esters. These are ester derivatives of alpha amino acids.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Carboxylic acids and derivatives
Sub Class
Amino acids, peptides, and analogues
Direct Parent
Alpha amino acid esters
Alternative Parents
Cysteine and derivatives / Dicarboxylic acids and derivatives / Carboxylic acid esters / Dialkylamines / Alkylthiols / Organopnictogen compounds / Organic oxides / Hydrocarbon derivatives / Carbonyl compounds
Substituents
Alpha-amino acid ester / Cysteine or derivatives / Dicarboxylic acid or derivatives / Carboxylic acid ester / Alkylthiol / Secondary aliphatic amine / Secondary amine / Organic nitrogen compound / Organosulfur compound / Organooxygen compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
Not Available

Drug created on December 03, 2015 09:51 / Updated on November 02, 2018 08:53