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Identification
NameIsoflurophate
Accession NumberDB00677  (APRD00763)
TypeSmall Molecule
GroupsApproved, Withdrawn
Description

An irreversible cholinesterase inhibitor with actions similar to those of echothiophate. It is a powerful miotic used mainly in the treatment of glaucoma. Its vapor is highly toxic and it is recommended that only solutions in arachis oil be used therapeutically. (From Martindale, The Extra Pharmacopoeia, 29th ed, p1330)

Structure
Thumb
Synonyms
SynonymLanguageCode
DFPNot AvailableNot Available
Diisopropoxyphosphoryl FluorideNot AvailableNot Available
Diisopropyl fluorophosphateNot AvailableNot Available
Diisopropyl FluorophosphonateNot AvailableNot Available
Diisopropyl PhosphofluoridateNot AvailableNot Available
Diisopropyl PhosphorofluoridateNot AvailableNot Available
DiisopropylfluorophosphateNot AvailableNot Available
Diisopropylfluorophosphoric acid esterNot AvailableNot Available
DiisopropylphosphofluoridateNot AvailableNot Available
DiisopropylphosphorofluoridateNot AvailableNot Available
Fluorodiisopropyl PhosphateNot AvailableNot Available
FluorostigmineNot AvailableNot Available
IsofluorphateNot AvailableNot Available
IsoflurophateNot AvailableNot Available
IsoflurophosphateNot AvailableNot Available
Isopropyl fluophosphateNot AvailableNot Available
Isopropyl PhosphorofluoridateNot AvailableNot Available
NeoglaucitNot AvailableNot Available
O,O'-diisopropyl phosphoryl fluorideNot AvailableNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
DiflupylNot Available
FloroprylMerck
FluoprylMerck
Brand mixturesNot Available
SaltsNot Available
Categories
CAS number55-91-4
WeightAverage: 184.1457
Monoisotopic: 184.066459031
Chemical FormulaC6H14FO3P
InChI KeyMUCZHBLJLSDCSD-UHFFFAOYSA-N
InChI
InChI=1S/C6H14FO3P/c1-5(2)9-11(7,8)10-6(3)4/h5-6H,1-4H3
IUPAC Name
bis(propan-2-yl) fluorophosphonate
SMILES
CC(C)OP(F)(=O)OC(C)C
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phosphate esters. These are organic compounds containing phosphoric acid ester functional group, with the general structure R1P(=O)(R2)OR3. R1,R2 = O,N, or halogen atom; R3 = organyl group.
KingdomOrganic compounds
Super ClassOrganophosphorus compounds
ClassOrganic phosphoric acids and derivatives
Sub ClassPhosphate esters
Direct ParentPhosphate esters
Alternative Parents
Substituents
  • Phosphoric acid ester
  • Hydrocarbon derivative
  • Organooxygen compound
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
Pharmacology
IndicationFor use in the eye to treat certain types of glaucoma and other eye conditions, such as accommodative esotropia.
PharmacodynamicsIsoflurophate is used as ocular drops in the treatment of chronic glaucoma. Isoflurophate is an organophosphorus compound that acts as an irreversible cholinesterase inhibitor. As such, it displays parasympathomimetic effects. Isoflurophate is used in the eye to treat certain types of glaucoma and other eye conditions, such as accommodative esotropia. They may also be used in the diagnosis of certain eye conditions, such as accommodative esotropia. Isoflurophate damages the acetylcholinesterase enzyme and is therefore irreversible, however, pralidoxime can displace organophosphates such as isoflurophate from acetylcholinesterase, but only if administered before isoflurophate damages (alkylates) the enzyme.
Mechanism of actionThe mechanism of isoflurophate's action involves the irreversible inhibition of cholinesterase.
AbsorptionNot Available
Volume of distributionNot Available
Protein bindingNot Available
MetabolismNot Available
Route of eliminationNot Available
Half lifeNot Available
ClearanceNot Available
ToxicitySigns of overdose include increased sweating, loss of bladder control, muscle weakness, nausea, vomiting, diarrhea, or stomach cramps or pain, shortness of breath, tightness in chest, or wheezing, slow or irregular heartbeat, unusual tiredness or weakness, watering of mouth.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9971
Blood Brain Barrier+0.9803
Caco-2 permeable-0.5386
P-glycoprotein substrateNon-substrate0.8483
P-glycoprotein inhibitor INon-inhibitor0.7683
P-glycoprotein inhibitor IINon-inhibitor0.9518
Renal organic cation transporterNon-inhibitor0.9541
CYP450 2C9 substrateNon-substrate0.8393
CYP450 2D6 substrateNon-substrate0.8447
CYP450 3A4 substrateNon-substrate0.5232
CYP450 1A2 substrateNon-inhibitor0.8174
CYP450 2C9 substrateNon-inhibitor0.8396
CYP450 2D6 substrateNon-inhibitor0.9132
CYP450 2C19 substrateNon-inhibitor0.7248
CYP450 3A4 substrateNon-inhibitor0.8834
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9185
Ames testNon AMES toxic0.8082
CarcinogenicityCarcinogens 0.8124
BiodegradationNot ready biodegradable0.8938
Rat acute toxicity4.5346 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9572
hERG inhibition (predictor II)Non-inhibitor0.8508
Pharmacoeconomics
Manufacturers
  • Merck and co inc
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateLiquid
Experimental Properties
PropertyValueSource
boiling point62 @ 9mm, 46 @ 5mmU.S. Patent 2,409,039.
water solubility1.54E+004 mg/L (at 25 °C)MERCK INDEX (1996)
logP1.17CZERWINSKI,SE ET AL. (1998)
Predicted Properties
PropertyValueSource
Water Solubility6.78 mg/mLALOGPS
logP1.1ALOGPS
logP1.76ChemAxon
logS-1.4ALOGPS
pKa (Strongest Basic)-9.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area35.53 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity40.89 m3·mol-1ChemAxon
Polarizability16.75 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

U.S. Patent 2,409,039.

General ReferenceNot Available
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (57.7 KB)
Interactions
Drug Interactions
Drug
AbacavirMay decrease the serum concentration of Abacavir.
AlfuzosinMay increase the serum concentration of Alfuzosin.
AlprazolamMay increase the serum concentration of ALPRAZolam.
AminophyllineMay decrease the serum concentration of Theophylline Derivatives. Exceptions: Fosamprenavir.
AmitriptylineMay increase the serum concentration of Tricyclic Antidepressants.
AmlodipineMay decrease the metabolism of Calcium Channel Blockers (Dihydropyridine).
AmoxapineMay increase the serum concentration of Tricyclic Antidepressants.
AtazanavirMay increase the serum concentration of other Protease Inhibitors.
AtorvastatinMay increase the serum concentration of AtorvaSTATin.
BoceprevirBoceprevir may decrease the serum concentration of Protease Inhibitors. Protease Inhibitors may decrease the serum concentration of Boceprevir.
BromocriptineMay increase the serum concentration of Ergot Derivatives.
CarbamazepineCarBAMazepine may increase the metabolism of Protease Inhibitors. Protease Inhibitors may decrease the metabolism of CarBAMazepine.
CisaprideMay increase the serum concentration of Cisapride. This may result in QTc prolongation and malignant cardiac arrhythmias.
ClarithromycinMay diminish the therapeutic effect of Clarithromycin. Specifically, certain protease inhibitors may decrease formation of the active 14-hydroxy-clarithromycin metabolite, which may negatively impact clarithromycin effectiveness vs. H. influenzae and other non-MAC infections. Clarithromycin may increase the serum concentration of Protease Inhibitors. Protease Inhibitors may increase the serum concentration of Clarithromycin. Clarithromycin dose adjustment in renally impaired patients may be needed.
ClomipramineMay increase the serum concentration of Tricyclic Antidepressants.
CyclophosphamideMay enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased.
DarunavirMay increase the serum concentration of other Protease Inhibitors.
DelavirdineDelavirdine may increase the serum concentration of Protease Inhibitors. Protease Inhibitors may decrease the serum concentration of Delavirdine.
DesipramineMay increase the serum concentration of Tricyclic Antidepressants.
DesogestrelMay decrease the serum concentration of Contraceptives (Estrogens).
DigoxinMay increase the serum concentration of Digoxin. Increased serum concentrations of digoxin may increase risk of AV nodal blockade.
DihydroergotamineMay increase the serum concentration of Ergot Derivatives.
DiltiazemMay decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Increased serum concentrations of the calcium channel blocker may increase risk of AV nodal blockade.
EnfuvirtideEnfuvirtide may increase the serum concentration of Protease Inhibitors. Protease Inhibitors may increase the serum concentration of Enfuvirtide.
Ergoloid mesylateMay increase the serum concentration of Ergot Derivatives.
ErgonovineMay increase the serum concentration of Ergot Derivatives.
ErgotamineMay increase the serum concentration of Ergot Derivatives.
Ethinyl EstradiolMay decrease the serum concentration of Contraceptives (Estrogens).
EthynodiolMay decrease the serum concentration of Contraceptives (Estrogens).
EtravirineEtravirine may increase the serum concentration of Protease Inhibitors. This effect is anticipated with nelfinavir. Protease Inhibitors may decrease the serum concentration of Etravirine. This effect is anticipated with darunavir, saquinavir, and lopinavir (with low-dose ritonavir).
FelodipineMay decrease the metabolism of Calcium Channel Blockers (Dihydropyridine).
FosamprenavirMay increase the serum concentration of other Protease Inhibitors.
ImipramineMay increase the serum concentration of Tricyclic Antidepressants.
IndinavirMay increase the serum concentration of other Protease Inhibitors.
IsradipineMay decrease the metabolism of Calcium Channel Blockers (Dihydropyridine).
LopinavirMay increase the serum concentration of other Protease Inhibitors.
LovastatinMay increase the serum concentration of Lovastatin.
MestranolMay decrease the serum concentration of Contraceptives (Estrogens).
MethylergometrineMay increase the serum concentration of Ergot Derivatives.
MidazolamMay increase the serum concentration of Midazolam.
NefazodoneMay increase the serum concentration of Nefazodone.
NelfinavirMay increase the serum concentration of other Protease Inhibitors.
NifedipineMay decrease the metabolism of Calcium Channel Blockers (Dihydropyridine).
NimodipineMay decrease the metabolism of Calcium Channel Blockers (Dihydropyridine).
NisoldipineMay decrease the metabolism of Calcium Channel Blockers (Dihydropyridine).
NorelgestrominMay decrease the serum concentration of Contraceptives (Estrogens).
NortriptylineMay increase the serum concentration of Tricyclic Antidepressants.
PethidineMay enhance the adverse/toxic effect of Meperidine. Protease Inhibitors may decrease the serum concentration of Meperidine. Concentrations of the toxic Normeperidine metabolite may be increased.
PimozideMay increase the serum concentration of Pimozide.
ProtriptylineMay increase the serum concentration of Tricyclic Antidepressants.
RiociguatMay increase the serum concentration of Riociguat.
RitonavirMay increase the serum concentration of other Protease Inhibitors.
RosuvastatinMay increase the serum concentration of Rosuvastatin.
SaquinavirMay increase the serum concentration of other Protease Inhibitors.
SildenafilMay increase the serum concentration of Sildenafil.
SimeprevirSimeprevir may increase the serum concentration of Protease Inhibitors. Protease Inhibitors may increase the serum concentration of Simeprevir.
SimvastatinMay increase the serum concentration of Simvastatin.
TemsirolimusMay enhance the adverse/toxic effect of Temsirolimus. Levels of sirolimus, the active metabolite, may be increased, likely due to inhibition of CYP-mediated metabolism.
TheophyllineMay decrease the serum concentration of Theophylline Derivatives. Exceptions: Fosamprenavir.
TipranavirTipranavir may decrease the serum concentration of Protease Inhibitors. Exceptions: Ritonavir.
TriazolamMay increase the serum concentration of Triazolam.
Valproic AcidMay decrease the serum concentration of Valproic Acid and Derivatives.
ZidovudineMay decrease the serum concentration of Zidovudine.
Food InteractionsNot Available

Targets

1. Acetylcholinesterase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Acetylcholinesterase P22303 Details

References:

  1. Malatova Z, Gottlieb M, Marsala J: Depression of acetylcholinesterase synthesis following transient cerebral ischemia in rat: pharmacohistochemical and biochemical investigation. Gen Physiol Biophys. 1999 Mar;18(1):57-71. Pubmed
  2. Quistad GB, Zhang N, Sparks SE, Casida JE: Phosphoacetylcholinesterase: toxicity of phosphorus oxychloride to mammals and insects that can be attributed to selective phosphorylation of acetylcholinesterase by phosphorodichloridic acid. Chem Res Toxicol. 2000 Jul;13(7):652-7. Pubmed
  3. da Costa VL Jr, Lapa AJ, Godinho RO: Short- and long-term influences of calcitonin gene-related peptide on the synthesis of acetylcholinesterase in mammalian myotubes. Br J Pharmacol. 2001 May;133(2):229-36. Pubmed
  4. Pang YP, Kollmeyer TM, Hong F, Lee JC, Hammond PI, Haugabouk SP, Brimijoin S: Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators. Chem Biol. 2003 Jun;10(6):491-502. Pubmed
  5. Ashani Y, Gentry MK, Doctor BP: Differences in conformational stability between native and phosphorylated acetylcholinesterase as evidenced by a monoclonal antibody. Biochemistry. 1990 Mar 13;29(10):2456-63. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Cholinesterase

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Cholinesterase P06276 Details

References:

  1. Kamata R, Saito S, Suzuki T, Takewaki T, Kobayashi H: Correlation of binding sites for diisopropyl phosphorofluoridate with cholinesterase and neuropathy target esterase in membrane and cytosol preparations from hen. Neurotoxicology. 2001 Apr;22(2):203-14. Pubmed
  2. Acey RA, Bailey S, Healy P, Jo C, Unger TF, Hudson RA: A butyrylcholinesterase in the early development of the brine shrimp (Artemia salina) larvae: a target for phthalate ester embryotoxicity? Biochem Biophys Res Commun. 2002 Dec 13;299(4):659-62. Pubmed
  3. Pittel Z, Cohen S, Fisher A, Heldman E: Differential long-term effect of AF64A on [3H]ACh synthesis and release in rat hippocampal synaptosomes. Brain Res. 1992 Jul 17;586(1):148-51. Pubmed
  4. Miller RB, Blank CL: Determination of serum cholinesterase activity by liquid chromatography with electrochemical detection. Anal Biochem. 1991 Aug 1;196(2):377-84. Pubmed
  5. Kelly SS, Ferry CB, Bamforth JP: The effects of anticholinesterases on the latencies of action potentials in mouse skeletal muscles. Br J Pharmacol. 1990 Apr;99(4):721-6. Pubmed

Enzymes

1. Cholinesterase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cholinesterase P06276 Details

References:

  1. Kamata R, Saito S, Suzuki T, Takewaki T, Kobayashi H: Correlation of binding sites for diisopropyl phosphorofluoridate with cholinesterase and neuropathy target esterase in membrane and cytosol preparations from hen. Neurotoxicology. 2001 Apr;22(2):203-14. Pubmed
  2. Acey RA, Bailey S, Healy P, Jo C, Unger TF, Hudson RA: A butyrylcholinesterase in the early development of the brine shrimp (Artemia salina) larvae: a target for phthalate ester embryotoxicity? Biochem Biophys Res Commun. 2002 Dec 13;299(4):659-62. Pubmed
  3. Pittel Z, Cohen S, Fisher A, Heldman E: Differential long-term effect of AF64A on [3H]ACh synthesis and release in rat hippocampal synaptosomes. Brain Res. 1992 Jul 17;586(1):148-51. Pubmed
  4. Miller RB, Blank CL: Determination of serum cholinesterase activity by liquid chromatography with electrochemical detection. Anal Biochem. 1991 Aug 1;196(2):377-84. Pubmed
  5. Kelly SS, Ferry CB, Bamforth JP: The effects of anticholinesterases on the latencies of action potentials in mouse skeletal muscles. Br J Pharmacol. 1990 Apr;99(4):721-6. Pubmed
  6. Masson P, Fortier PL, Albaret C, Froment MT, Bartels CF, Lockridge O: Aging of di-isopropyl-phosphorylated human butyrylcholinesterase. Biochem J. 1997 Oct 15;327 ( Pt 2):601-7. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on May 02, 2014 15:42