Identification

Name
Fospropofol
Accession Number
DB06716  (DB05279)
Type
Small Molecule
Groups
Approved, Illicit, Investigational
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 IDs
GPI 15715
Product Ingredients
IngredientUNIICASInChI Key
Fospropofol disodium30868AY0IF258516-87-9LWYLQNWMSGFCOZ-UHFFFAOYSA-L
Active Moieties
NameKindUNIICASInChI Key
PropofolprodrugYI7VU623SF2078-54-8OLBCVFGFOZPWHH-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LusedraInjection35 mg/1mLIntravenousEisai Limited2008-12-122012-07-31Us
International/Other Brands
Aquavan
Categories
UNII
LZ257RZP7K
CAS number
258516-89-1
Weight
Average: 288.2766
Monoisotopic: 288.112660294
Chemical Formula
C13H21O5P
InChI Key
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

Pharmacology

Indication

For monitored anaesthesia care sedation in patients undergoing diagnostic procedures like bronchoscopy and colonscopy or minor surgical procedures like arthroscopy and bunionectomy.

Associated Therapies
Pharmacodynamics

Fospropofol 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 action

After 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.

TargetActionsOrganism
AGamma-aminobutyric acid receptor subunit beta-2
potentiator
Human
AGamma-aminobutyric acid receptor subunit beta-3
potentiator
Human
Absorption

Adequate 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 binding

Both 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.

Route of elimination

Chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney. There is negligible renal elimination of unchanged fospropofol (<0.02%).

Half life

When 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.

Toxicity

Overdosage 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when Fospropofol is combined with 2,5-Dimethoxy-4-ethylthioamphetamine.
3,4-MethylenedioxyamphetamineThe risk or severity of adverse effects can be increased when 3,4-Methylenedioxyamphetamine is combined with Fospropofol.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Fospropofol.
4-MethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Methoxyamphetamine is combined with Fospropofol.
5-methoxy-N,N-dimethyltryptamineThe risk or severity of adverse effects can be increased when Fospropofol is combined with 5-methoxy-N,N-dimethyltryptamine.
7-NitroindazoleThe risk or severity of adverse effects can be increased when 7-Nitroindazole is combined with Fospropofol.
AcepromazineThe risk or severity of adverse effects can be increased when Acepromazine is combined with Fospropofol.
AceprometazineThe risk or severity of adverse effects can be increased when Aceprometazine is combined with Fospropofol.
AcetazolamideThe risk or severity of adverse effects can be increased when Acetazolamide is combined with Fospropofol.
AcetophenazineThe risk or severity of adverse effects can be increased when Acetophenazine is combined with Fospropofol.
Food Interactions
Not Available

References

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
Human Metabolome Database
HMDB0015661
KEGG Drug
D04257
PubChem Compound
3038498
PubChem Substance
99443268
ChemSpider
2302062
ChEBI
135193
ChEMBL
CHEMBL1201766
PharmGKB
PA165958389
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Fospropofol
FDA label
Download (536 KB)
MSDS
Download (479 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentDrug Safety1
1CompletedTreatmentLactating Women1
1CompletedTreatmentMonitored anesthesia care sedation1
2CompletedTreatmentColon Polyps / Colonoscopy1
2CompletedTreatmentCoronary Artery Bypass Graft Surgery Patients / Ischemic Coronary Artery Disease1
2CompletedTreatmentIntubations / Postoperative Sedation / Respiration, Artificial1
2TerminatedTreatmentColon Polyps / Colonoscopy1
2, 3CompletedDiagnosticProcedural Sedation1
2, 3CompletedTreatmentColonoscopy / Colorectal Polyps1
3CompletedTreatmentAnaesthesia therapy / Bronchoscopy1
3CompletedTreatmentAngioplasty / Coronary Catheterization1
3CompletedTreatmentColon Polyps / Colonoscopy1
3CompletedTreatmentSedation, Conscious1
3TerminatedTreatmentArthroscopy / Bunionectomy / Carpal Tunnel / Osteotomy1
3TerminatedTreatmentFlexible Bronchoscopy1
4CompletedTreatmentComplication of Injection / Pain NOS1
4TerminatedTreatmentOrthopedic Procedures / Procedural Sedation / Regional Anesthesia Block1
Not AvailableWithdrawnSupportive CareImpaired Airway Clearance1
Not AvailableWithdrawnTreatmentInterstitial Cystitis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous35 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6204257No2001-03-202022-07-01Us
US6872838No2005-03-292018-08-07Us

Properties

State
Solid
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 RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

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 cumenes. These are aromatic compounds containing a prop-2-ylbenzene moiety.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Cumenes
Direct Parent
Cumenes
Alternative Parents
Phenylpropanes / Phenoxy compounds / Phenol ethers / Monoalkyl phosphates / Organooxygen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Phenylpropane / Cumene / Phenoxy compound / Phenol ether / Monoalkyl phosphate / Alkyl phosphate / Phosphoric acid ester / Organic phosphoric acid derivative / Organic oxygen compound / Organic oxide
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not 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...
Gene Name
GABRB2
Uniprot ID
P47870
Uniprot Name
Gamma-aminobutyric acid receptor subunit beta-2
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...
Gene Name
GABRB3
Uniprot ID
P28472
Uniprot Name
Gamma-aminobutyric acid receptor subunit beta-3
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
Uniprot Name
Alkaline phosphatase, tissue-nonspecific isozyme
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 colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da

Drug created on May 16, 2010 17:53 / Updated on November 02, 2018 08:31