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Identification
NameFospropofol
Accession NumberDB06716  (DB05279)
Typesmall molecule
Groupsapproved, illicit
Description

Fospropofol is a water soluble prodrug and is converted to propofol in the liver. Fospropofol is a short acting hypnotic/sedative/anesthetic agent. Unlike propofol, does not cause injection-site pain as it is unable to activate TRPA1. FDA approved in December 2008.
Fospropofol is classified as a Schedule IV controlled substance in the United States’ Controlled Substances Act.

Structure
Thumb
Synonyms
SynonymLanguageCode
FospropofolNot AvailableNot Available
Salts
Name/CAS Structure Properties
Fospropofol disodium
Thumb
  • InChI Key: LWYLQNWMSGFCOZ-UHFFFAOYSA-L
  • Monoisotopic Mass: 332.07654958
  • Average Mass: 332.2403
DBSALT000090
Brand names
NameCompany
AquavanNot Available
LusedraEisai Inc.
Brand mixturesNot Available
Categories
CAS number258516-87-9
WeightAverage: 288.2766
Monoisotopic: 288.112660294
Chemical FormulaC13H21O5P
InChI KeyQVNNONOFASOXQV-UHFFFAOYSA-N
InChI
InChI=1S/C13H21O5P/c1-9(2)11-6-5-7-12(10(3)4)13(11)17-8-18-19(14,15)16/h5-7,9-10H,8H2,1-4H3,(H2,14,15,16)
IUPAC Name
[2,6-bis(propan-2-yl)phenoxymethoxy]phosphonic acid
SMILES
CC(C)C1=CC=CC(C(C)C)=C1OCOP(O)(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassBenzene and Substituted Derivatives
SubclassCumenes
Direct parentCumenes
Alternative parentsPhenol Ethers; Alkyl Aryl Ethers; Organophosphate Esters; Organic Phosphoric Acids; Polyamines
Substituentsphenol ether; alkyl aryl ether; phosphoric acid ester; organic phosphate; ether; polyamine
Classification descriptionThis compound belongs to the cumenes. These are aromatic compounds containing a prop-2-ylbenzene moiety.
Pharmacology
IndicationFor monitored anaesthesia care sedation in patients undergoing diagnostic procedures like bronchoscopy and colonscopy or minor surgical procedures like arthroscopy and bunionectomy.
PharmacodynamicsFospropofol is a prodrug of propofol, a sedative hypnotic drug. Unlike propofol, fospropofol is water soluble and can be administered in an aqueous solution. 1.86 mg of fospropofol is the molar equivalent for 1mg of propofol.
Mechanism of actionAfter in-vivo conversion of fospropofol into propofol by endothelial alkaline phosphatase, propofol crosses the blood-brain barrier, binds to GABA-A receptors and acts as an agonist. By binding to GABA-A receptor, it will cause an increase in chloride conductance, thus inhibiting the firing of new action potentials in the post-synaptic neuron.
AbsorptionAdequate sedation achieved after 7 minutes with a IV bolus dose of 10mg/kg. It takes 21-45 minutes for patients to recover for fospropopol-induced sedation. Following an intravenous bolus administration of 6 mg/kg in a healthy subject, the pharmacokinetic parameters of fospropofol are as follows: Cmax = 78.7 μg/mL; Tmax = 4 minutes; AUC(0-∞) = 19.0 μg ⋅ h/mL;
Volume of distribution

Fospropofol = 0.33±0.069 L/kg;
Propofol metabolite = 5.8 L/kg.

Protein bindingBoth fospropofol and its active metabolite propofol are highly protein bound (approximately 98%), primarily to albumin. Fospropofol does not affect the binding of propofol to albumin.
Metabolism

Fospropofol is metabolized into propofol, formaldehyde, and phosphate by endothelial alkaline phosphatase. The metabolite, formaldehyde, is quickly oxidized into formic acid by glutathione dependent and independent dehydrogenases and erythrocytes. Excess formic acid is eliminated via oxidation to carbon dioxide through the tetrahydrofolate pathway. Propofol is further metabolized into propofol glucuronide, quinol-4-sulfate, quinol-1-fluronide, and quinol-4-glucuronide. The cytochrome P450 enzyme system is not involved with the metabolism of fospropofol.

SubstrateEnzymesProduct
Fospropofol
Not Available
Formic acidDetails
Fospropofol
Not Available
FormaldehydeDetails
Fospropofol
Not Available
PhosphateDetails
Fospropofol
Not Available
PropofolDetails
Route of eliminationChiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. There is negligible renal elimination of unchanged fospropofol (<0.02%).
Half lifeWhen given to a patient, the half-lives are as follows: Fospropofol = 0.81 hours; Propofol metabolite = 1.13 hours
Clearance

Total body clearance (CLp), Fospropofol, healthy subject = 0.28 L/h/kg;
CLp, fospropofol, patients = 0.31 L/h/kg;
CLp/F, propofol, healthy subjects or patients = 2.74 L/h/kg.

ToxicityOverdosage may lead to cardiorespiratory depression, formic acid toxicity (methanol toxicity-like effects), and/or phosphate-induced hypocalemia. Most common adverse reactions (> 20%) are paresthesia and pruritus.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.5105
Blood Brain Barrier + 0.8462
Caco-2 permeable - 0.546
P-glycoprotein substrate Non-substrate 0.6735
P-glycoprotein inhibitor I Non-inhibitor 0.8244
P-glycoprotein inhibitor II Non-inhibitor 0.9747
Renal organic cation transporter Non-inhibitor 0.9124
CYP450 2C9 substrate Non-substrate 0.8021
CYP450 2D6 substrate Non-substrate 0.8086
CYP450 3A4 substrate Non-substrate 0.5052
CYP450 1A2 substrate Non-inhibitor 0.7667
CYP450 2C9 substrate Non-inhibitor 0.7807
CYP450 2D6 substrate Non-inhibitor 0.9205
CYP450 2C19 substrate Non-inhibitor 0.7375
CYP450 3A4 substrate Non-inhibitor 0.8538
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8754
Ames test Non AMES toxic 0.7212
Carcinogenicity Non-carcinogens 0.6902
Biodegradation Not ready biodegradable 0.7478
Rat acute toxicity 2.3516 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8892
hERG inhibition (predictor II) Non-inhibitor 0.926
Pharmacoeconomics
Manufacturers
  • Eisai inc
PackagersNot Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous35 mg/mL
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States62042571998-06-072018-06-07
Properties
Statesolid
Experimental Properties
PropertyValueSource
pKa8.2 - 9.0FDA label
Predicted Properties
PropertyValueSource
water solubility3.02e-01 g/lALOGPS
logP2.23ALOGPS
logP3.6ChemAxon
logS-3ALOGPS
pKa (strongest acidic)1.44ChemAxon
pKa (strongest basic)-5ChemAxon
physiological charge-2ChemAxon
hydrogen acceptor count4ChemAxon
hydrogen donor count2ChemAxon
polar surface area75.99ChemAxon
rotatable bond count6ChemAxon
refractivity72.88ChemAxon
polarizability29ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Garnock-Jones KP, Scott LJ: Fospropofol. Drugs. 2010 Mar 5;70(4):469-77. doi: 10.2165/11204450-000000000-00000. Pubmed
  2. Schywalsky M, Ihmsen H, Tzabazis A, Fechner J, Burak E, Vornov J, Schwilden H: Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rats. Eur J Anaesthesiol. 2003 Mar;20(3):182-90. Pubmed
  3. Bengalorkar GM, Bhuvana K, Sarala N, Kumar T: Fospropofol: clinical pharmacology. J Anaesthesiol Clin Pharmacol. 2011 Jan;27(1):79-83. Pubmed
  4. Garnock-Jones KP, Scott LJ: Fospropofol. Drugs. 2010 Mar 5;70(4):469-77. doi: 10.2165/11204450-000000000-00000. Pubmed
  5. Patwardhan A, Edelmayer R, Annabi E, Price T, Malan P, Dussor G: Receptor specificity defines algogenic properties of propofol and fospropofol. Anesth Analg. 2012 Oct;115(4):837-40. Epub 2012 May 14. Pubmed
External Links
ResourceLink
KEGG DrugD04257
PharmGKBPA165958389
RxListhttp://www.rxlist.com/lusedra-drug.htm
Drugs.comhttp://www.drugs.com/ppa/fospropofol.html
WikipediaFospropofol
ATC CodesNot Available
AHFS Codes
  • 28:04.92
PDB EntriesNot Available
FDA labelshow(536 KB)
MSDSshow(479 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Gamma-aminobutyric acid receptor subunit beta-2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit beta-2 P47870 Details

References:

  1. Franks NP: Molecular targets underlying general anaesthesia. Br J Pharmacol. 2006 Jan;147 Suppl 1:S72-81. Pubmed

2. Gamma-aminobutyric acid receptor subunit beta-3

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: potentiator

Components

Name UniProt ID Details
Gamma-aminobutyric acid receptor subunit beta-3 P28472 Details

References:

  1. Franks NP: Molecular targets underlying general anaesthesia. Br J Pharmacol. 2006 Jan;147 Suppl 1:S72-81. Pubmed

Enzymes

1. Alkaline phosphatase, tissue-nonspecific isozyme

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: substrate

Components

Name UniProt ID Details
Alkaline phosphatase, tissue-nonspecific isozyme P05186 Details

References:

  1. Bergese SD, Dalal P, Vandse R, Satlin A, Lin Z, Candiotti K, Cohen L, Gan TJ: A double-blind, randomized, multicenter, dose-ranging study to evaluate the safety and efficacy of fospropofol disodium as an intravenous sedative for colonoscopy in high-risk populations. Am J Ther. 2013 Mar;20(2):163-71. doi: 10.1097/MJT.0b013e318256ecfc. Pubmed

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. FDA label

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Drug created on May 16, 2010 17:53 / Updated on September 16, 2013 18:04