Identification

Name
Difluprednate
Accession Number
DB06781
Type
Small Molecule
Groups
Approved
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
External IDs
W 6309 / W-6309
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
DurezolEmulsion0.5 mg/1mLOphthalmicAlcon, Inc.2011-01-25Not applicableUs
DurezolEmulsion0.05 %OphthalmicNovartis2014-02-19Not applicableCanada
DurezolEmulsion0.5 mg/1mLOphthalmicPhysicians Total Care, Inc.2011-08-29Not applicableUs
DurezolEmulsion0.5 mg/1mLOphthalmicSirion Therapeutics, Inc.2008-09-012010-06-24Us
International/Other Brands
Durezol
Categories
UNII
S8A06QG2QE
CAS number
23674-86-4
Weight
Average: 508.5515
Monoisotopic: 508.227259852
Chemical Formula
C27H34F2O7
InChI Key
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[C@H](O)[C@@]1(F)[C@@]2([H])C[C@H](F)C2=CC(=O)C=C[C@]12C

Pharmacology

Indication

For the treatment of inflammation and pain associated with ocular surgery.

Associated Conditions
Pharmacodynamics

Difluprednate is a corticosteroid used as an anti-inflammatory steroidal drug used primarily in ocular surgery.

Mechanism of action

Corticosteroids 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.

TargetActionsOrganism
AGlucocorticoid receptor
agonist
Human
Absorption

Difluprednate penetrates the corneal epithelium rapidly and effectively. Low systemic absorption.

Volume of distribution
Not Available
Protein binding
Not 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.

Route of elimination

78.5% 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 life
Not Available
Clearance
Not Available
Toxicity

Preclinical 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
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not 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
Human Metabolome Database
HMDB0061149
KEGG Drug
D01266
KEGG Compound
C12695
PubChem Compound
443936
PubChem Substance
99443292
ChemSpider
391990
ChEBI
31485
ChEMBL
CHEMBL1201749
PharmGKB
PA165958405
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Difluprednate
ATC Codes
D07AC19 — Difluprednate
AHFS Codes
  • 52:08.08 — Corticosteroids
FDA label
Download (149 KB)
MSDS
Download (129 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentAnterior Uveitis (AU)1
2CompletedTreatmentDry Eye Syndrome (DES)1
2CompletedTreatmentInflammatory Reaction2
3CompletedNot AvailableUveitis1
3CompletedTreatmentAnterior Uveitis (AU) / Panuveitis1
3CompletedTreatmentCataracts / Inflammatory Reaction1
3CompletedTreatmentEndogenous Anterior Uveitis1
3CompletedTreatmentInflammatory Reaction5
3CompletedTreatmentPanuveitis / Uveitis1
3Not Yet RecruitingTreatmentCataracts1
4CompletedTreatmentCataracts / Corneal Edema / Retinal Structural Change, Deposit and Degeneration / Visual Acuity Reduced Transiently1
4RecruitingTreatmentCystoid Macular Edema / Macular Edema (ME) / Uveitis1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
EmulsionOphthalmic0.05 %
EmulsionOphthalmic0.5 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US6114319Yes2000-09-052019-11-18Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)191-194Ercoli, 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 FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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)

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
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03fs-2791000000-5b24de22e5f9ba4a3025

Taxonomy

Description
This 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.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Pregnane steroids
Direct Parent
Gluco/mineralocorticoids, progestogins and derivatives
Alternative Parents
Steroid esters / 20-oxosteroids / 11-beta-hydroxysteroids / 3-oxo delta-1,4-steroids / Halogenated steroids / Delta-1,4-steroids / Alpha-acyloxy ketones / Dicarboxylic acids and derivatives / Cyclic ketones / Cyclic alcohols and derivatives
show 7 more
Substituents
Progestogin-skeleton / Steroid ester / 20-oxosteroid / 3-oxo-delta-1,4-steroid / 3-oxosteroid / 11-hydroxysteroid / 11-beta-hydroxysteroid / Oxosteroid / 9-halo-steroid / 6-halo-steroid
show 24 more
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
butyrate ester, corticosteroid hormone (CHEBI:31485)

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 modula...
Gene Name
NR3C1
Uniprot ID
P04150
Uniprot Name
Glucocorticoid receptor
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]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Cerny MA: Prevalence of Non-Cytochrome P450-Mediated Metabolism in Food and Drug Administration-Approved Oral and Intravenous Drugs: 2006-2015. Drug Metab Dispos. 2016 Aug;44(8):1246-52. doi: 10.1124/dmd.116.070763. Epub 2016 Apr 15. [PubMed:27084892]

Drug created on September 14, 2010 10:21 / Updated on November 18, 2018 13:32