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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
Fospropofol
External Identifiers
  • GPI 15715
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Lusedrainjection35 mg/mLintravenousEisai, Inc2008-12-12Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AquavanNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Fospropofol disodium
258516-87-9
Thumb
  • InChI Key: LWYLQNWMSGFCOZ-UHFFFAOYSA-L
  • Monoisotopic Mass: 332.07654958
  • Average Mass: 332.2403
DBSALT000090
Categories
UNIILZ257RZP7K
CAS number258516-89-1
WeightAverage: 288.2766
Monoisotopic: 288.112660294
Chemical FormulaC13H21O5P
InChI KeyInChIKey=QVNNONOFASOXQV-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as cumenes. These are aromatic compounds containing a prop-2-ylbenzene moiety.
KingdomOrganic compounds
Super ClassBenzenoids
ClassBenzene and substituted derivatives
Sub ClassCumenes
Direct ParentCumenes
Alternative Parents
Substituents
  • Phenylpropane
  • Cumene
  • Phenol ether
  • Monoalkyl phosphate
  • Alkyl phosphate
  • Phosphoric acid ester
  • Organic phosphoric acid derivative
  • Organic phosphate
  • Hydrocarbon derivative
  • Organooxygen compound
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External DescriptorsNot Available
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption-0.5105
Blood Brain Barrier+0.8462
Caco-2 permeable-0.546
P-glycoprotein substrateNon-substrate0.6735
P-glycoprotein inhibitor INon-inhibitor0.8244
P-glycoprotein inhibitor IINon-inhibitor0.9747
Renal organic cation transporterNon-inhibitor0.9124
CYP450 2C9 substrateNon-substrate0.8021
CYP450 2D6 substrateNon-substrate0.8086
CYP450 3A4 substrateNon-substrate0.5052
CYP450 1A2 substrateNon-inhibitor0.7667
CYP450 2C9 inhibitorNon-inhibitor0.7807
CYP450 2D6 inhibitorNon-inhibitor0.9205
CYP450 2C19 inhibitorNon-inhibitor0.7375
CYP450 3A4 inhibitorNon-inhibitor0.8538
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8754
Ames testNon AMES toxic0.7212
CarcinogenicityNon-carcinogens0.6902
BiodegradationNot ready biodegradable0.7478
Rat acute toxicity2.3516 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8892
hERG inhibition (predictor II)Non-inhibitor0.926
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Injectionintravenous35 mg/mL
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6204257 No2002-07-012022-07-01Us
US6872838 No1998-08-072018-08-07Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
pKa8.2 - 9.0FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.302 mg/mLALOGPS
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 Area75.99 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity72.88 m3·mol-1ChemAxon
Polarizability29 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Garnock-Jones KP, Scott LJ: Fospropofol. Drugs. 2010 Mar 5;70(4):469-77. doi: 10.2165/11204450-000000000-00000. [PubMed:20205488 ]
  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:12650488 ]
  3. Bengalorkar GM, Bhuvana K, Sarala N, Kumar T: Fospropofol: clinical pharmacology. J Anaesthesiol Clin Pharmacol. 2011 Jan;27(1):79-83. [PubMed:21804712 ]
  4. 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:22584560 ]
External Links
ATC CodesNot Available
AHFS Codes
  • 28:04.92
PDB EntriesNot Available
FDA labelDownload (536 KB)
MSDSDownload (479 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
potentiator
General Function:
Inhibitory extracellular ligand-gated ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.
Gene Name:
GABRB2
Uniprot ID:
P47870
Molecular Weight:
59149.895 Da
References
  1. Franks NP: Molecular targets underlying general anaesthesia. Br J Pharmacol. 2006 Jan;147 Suppl 1:S72-81. [PubMed:16402123 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
potentiator
General Function:
Gaba-gated chloride ion channel activity
Specific Function:
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.
Gene Name:
GABRB3
Uniprot ID:
P28472
Molecular Weight:
54115.04 Da
References
  1. Franks NP: Molecular targets underlying general anaesthesia. Br J Pharmacol. 2006 Jan;147 Suppl 1:S72-81. [PubMed:16402123 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
substrate
General Function:
Pyrophosphatase activity
Specific Function:
This isozyme may play a role in skeletal mineralization.
Gene Name:
ALPL
Uniprot ID:
P05186
Molecular Weight:
57304.435 Da
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-Apr;20(2):163-71. doi: 10.1097/MJT.0b013e318256ecfc. [PubMed:22820718 ]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Toxic substance binding
Specific Function:
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.
Gene Name:
ALB
Uniprot ID:
P02768
Molecular Weight:
69365.94 Da
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Drug created on May 16, 2010 17:53 / Updated on June 27, 2016 01:53