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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
SynonymsNot 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
CategoriesNot Available
CAS number258516-87-9
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
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
    Formic acidDetails
    Fospropofol
      FormaldehydeDetails
      Fospropofol
        PhosphateDetails
        Fospropofol
          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

          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

          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

          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

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