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Identification
NameDifluprednate
Accession NumberDB06781
TypeSmall Molecule
GroupsApproved
Description

Difluprednate is a topical corticosteroid indicated for the treatment of infammation and pain associated with ocular surgery. It is a butyrate ester of 6(α), 9(α)-difluoro prednisolone acetate. Difluprednate is abbreviated DFBA, or difluoroprednisolone butyrate acetate. It is indicated for treatment of endogenous anterior uveiti.

Structure
Thumb
Synonyms
DFBA
Difluoroprednisolone butyrate acetate
Durezol
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Durezolemulsion.5 mg/mLophthalmicAlcon Laboratories, Inc.2011-01-25Not applicableUs
Durezolemulsion0.05 %ophthalmicAlcon Canada Inc2014-02-19Not applicableCanada
Durezolemulsion.5 mg/mLophthalmicPhysicians Total Care, Inc.2011-08-29Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIS8A06QG2QE
CAS number23674-86-4
WeightAverage: 508.5515
Monoisotopic: 508.227259852
Chemical FormulaC27H34F2O7
InChI KeyInChIKey=WYQPLTPSGFELIB-JTQPXKBDSA-N
InChI
InChI=1S/C27H34F2O7/c1-5-6-23(34)36-26(22(33)14-35-15(2)30)10-8-17-18-12-20(28)19-11-16(31)7-9-24(19,3)27(18,29)21(32)13-25(17,26)4/h7,9,11,17-18,20-21,32H,5-6,8,10,12-14H2,1-4H3/t17-,18-,20-,21-,24-,25-,26-,27-/m0/s1
IUPAC Name
(1R,2S,8S,10S,11S,14R,15S,17S)-14-[2-(acetyloxy)acetyl]-1,8-difluoro-17-hydroxy-2,15-dimethyl-5-oxotetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-3,6-dien-14-yl butanoate
SMILES
[H][C@@]12CC[C@](OC(=O)CCC)(C(=O)COC(C)=O)[C@@]1(C)C[[email protected]](O)[C@@]1(F)[C@@]2([H])C[[email protected]](F)C2=CC(=O)C=C[C@]12C
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as gluco/mineralocorticoids, progestogins and derivatives. These are steroids with a structure based on a hydroxylated prostane moiety.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassSteroids and steroid derivatives
Sub ClassPregnane steroids
Direct ParentGluco/mineralocorticoids, progestogins and derivatives
Alternative Parents
Substituents
  • Progestogin-skeleton
  • Steroid ester
  • 20-oxosteroid
  • 11-hydroxysteroid
  • 11-beta-hydroxysteroid
  • Oxosteroid
  • Hydroxysteroid
  • Halo-steroid
  • 6-halo-steroid
  • 9-halo-steroid
  • 3-oxosteroid
  • 3-oxo-delta-1,4-steroid
  • Delta-1,4-steroid
  • Alpha-acyloxy ketone
  • Acetate salt
  • Cyclic alcohol
  • Cyclic ketone
  • Secondary alcohol
  • Ketone
  • Halohydrin
  • Fluorohydrin
  • Carboxylic acid ester
  • Monocarboxylic acid or derivatives
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Alkyl halide
  • Alkyl fluoride
  • Alcohol
  • Aliphatic homopolycyclic compound
Molecular FrameworkAliphatic homopolycyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the treatment of inflammation and pain associated with ocular surgery.
PharmacodynamicsDifluprednate is a corticosteroid used as an anti-inflammatory steroidal drug used primarily in ocular surgery.
Mechanism of actionCorticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins (lipocortins). It is postulated that these proteins control the biosynthesis of potent mediators of infammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2.
Related Articles
AbsorptionDifluprednate penetrates the corneal epithelium rapidly and effectively. Low systemic absorption.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Difluprednate is rapidly deacetylated in the aqueous humor to difluoroprednisolone butyrate (DFB), the drug’s active metabolite. Endogenous tissue esterases then metabolize DFB to the inert metabolite hydroxyfluoroprednisolone butyrate (HFB), which limits systemic exposure to the active compound.

SubstrateEnzymesProduct
Difluprednate
Not Available
difluoroprednisolone butyrateDetails
Difluprednate
Not Available
Hydroxyfluoroprednisolone butyrate (HFB)Details
Route of elimination78.5% of radioactivity was excreted aftert 24 hours, and 99.5% by 7 days after a single dose of labeled difluprednate instilled in the right eyes of pigmented rabbits.
Half lifeNot Available
ClearanceNot Available
ToxicityPreclinical pharmacokinetic and toxicity studies have established that difluprednate ophthalmic emulsion 0.05% given 4 times a day is not toxic to the eye.
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+0.9904
Blood Brain Barrier+0.9908
Caco-2 permeable+0.6127
P-glycoprotein substrateSubstrate0.7679
P-glycoprotein inhibitor IInhibitor0.6413
P-glycoprotein inhibitor IINon-inhibitor0.789
Renal organic cation transporterNon-inhibitor0.8044
CYP450 2C9 substrateNon-substrate0.8882
CYP450 2D6 substrateNon-substrate0.9152
CYP450 3A4 substrateSubstrate0.7641
CYP450 1A2 substrateNon-inhibitor0.9138
CYP450 2C9 inhibitorNon-inhibitor0.911
CYP450 2D6 inhibitorNon-inhibitor0.8162
CYP450 2C19 inhibitorNon-inhibitor0.94
CYP450 3A4 inhibitorNon-inhibitor0.7263
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9014
Ames testNon AMES toxic0.9326
CarcinogenicityNon-carcinogens0.9242
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.1368 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9677
hERG inhibition (predictor II)Non-inhibitor0.5493
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Emulsionophthalmic.5 mg/mL
Emulsionophthalmic0.05 %
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6114319 Yes1999-11-182019-11-18Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point191-194Ercoli, A. and Gardi, R.; U.S. Patent 3,780,177; December 18,1973; assigned to Warner-Lambert Co.
Predicted Properties
PropertyValueSource
Water Solubility0.0097 mg/mLALOGPS
logP3.28ALOGPS
logP3ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)13.55ChemAxon
pKa (Strongest Basic)-3.4ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area106.97 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity125.38 m3·mol-1ChemAxon
Polarizability51.46 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
References
Synthesis Reference

Ercoli, A. and Gardi, R.; U.S. Patent 3,780,177; December 18,1973; assigned to Warner-Lambert Co.

General References
  1. Korenfeld MS, Silverstein SM, Cooke DL, Vogel R, Crockett RS: Difluprednate ophthalmic emulsion 0.05% for postoperative inflammation and pain. J Cataract Refract Surg. 2009 Jan;35(1):26-34. doi: 10.1016/j.jcrs.2008.09.024. [PubMed:19101421 ]
  2. Jamal KN, Callanan DG: The role of difluprednate ophthalmic emulsion in clinical practice. Clin Ophthalmol. 2009;3:381-90. Epub 2009 Jun 29. [PubMed:19668594 ]
  3. Morton KD, Van de Kar LD, Brownfield MS, Bethea CL: Neuronal cell bodies in the hypothalamic paraventricular nucleus mediate stress-induced renin and corticosterone secretion. Neuroendocrinology. 1989 Jul;50(1):73-80. [PubMed:2666872 ]
External Links
ATC CodesD07AC19
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (149 KB)
MSDSDownload (129 KB)
Interactions
Drug Interactions
Drug
AldesleukinDifluprednate may decrease the antineoplastic activities of Aldesleukin.
CeritinibDifluprednate may increase the hyperglycemic activities of Ceritinib.
Corticorelin ovine triflutateThe therapeutic efficacy of Corticorelin can be decreased when used in combination with Difluprednate.
DeferasiroxThe risk or severity of adverse effects can be increased when Difluprednate is combined with Deferasirox.
HyaluronidaseThe therapeutic efficacy of Hyaluronidase can be decreased when used in combination with Difluprednate.
InfliximabThe risk or severity of adverse effects can be increased when Infliximab is combined with Difluprednate.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
agonist
General Function:
Zinc ion binding
Specific Function:
Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon grow...
Gene Name:
NR3C1
Uniprot ID:
P04150
Molecular Weight:
85658.57 Da
References
  1. Jamal KN, Callanan DG: The role of difluprednate ophthalmic emulsion in clinical practice. Clin Ophthalmol. 2009;3:381-90. Epub 2009 Jun 29. [PubMed:19668594 ]
  2. Tajika T, Takahashi H, Sakai Y, Fujii H, Isowaki A, Sakaki H: Metabolic profiles of difluprednate in rabbit ocular tissues after instillation of difluprednate ophthalmic emulsion. Xenobiotica. 2010 Aug;40(8):569-77. doi: 10.3109/00498254.2010.490308. [PubMed:20509750 ]
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Drug created on September 14, 2010 10:21 / Updated on July 23, 2016 03:08