Identification

Name
Difluocortolone
Accession Number
DB09095
Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Description

Difluocortolone is a potent topical corticosteroid. It is commonly used in dermatology for the reduction of inflammation and itching. It was submited to the FDA in July 1984 by the pharmaceutical company Schering AG.[3]

Structure
Thumb
Synonyms
  • Diflucortolona
  • Diflucortolone
Product Ingredients
IngredientUNIICASInChI Key
Difluocortolone valerate1A63Z067C859198-70-8HHJIUUAMYGBVSD-YTFFSALGSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Nerisone CreamCream0.1 %TopicalGlaxosmithkline Inc1983-12-312016-07-12Canada
Nerisone Oily CreamCream0.1 %TopicalGlaxosmithkline Inc1983-12-312016-09-30Canada
Nerisone OintmentOintment0.1 %TopicalGlaxosmithkline Inc1983-12-312015-11-03Canada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Nerisalic Oily CreamDifluocortolone valerate (0.1 %) + Salicylic acid (3.0 %)CreamTopicalGlaxosmithkline Inc1995-12-312012-02-21Canada
Categories
UNII
K253365DXI
CAS number
2607-06-9
Weight
Average: 394.459
Monoisotopic: 394.195565708
Chemical Formula
C22H28F2O4
InChI Key
OGPWIDANBSLJPC-RFPWEZLHSA-N
InChI
InChI=1S/C22H28F2O4/c1-11-6-13-14-8-16(23)15-7-12(26)4-5-21(15,3)22(14,24)18(28)9-20(13,2)19(11)17(27)10-25/h4-5,7,11,13-14,16,18-19,25,28H,6,8-10H2,1-3H3/t11-,13+,14+,16+,18+,19-,20+,21+,22+/m1/s1
IUPAC Name
(1R,2S,8S,10S,11S,13R,14S,15S,17S)-1,8-difluoro-17-hydroxy-14-(2-hydroxyacetyl)-2,13,15-trimethyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadeca-3,6-dien-5-one
SMILES
[H][C@@]12C[C@@H](C)[C@H](C(=O)CO)[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

Difluocortolone is used as a topical treatment of the symptoms of inflammatory skin disorders like eczema, seborrheic eczema, lichen planus and psoriasis. All these disorders present as a common characteristic the occurrence of symptoms as itching, swelling, redness and scaling.[4]

Pharmacodynamics

Diflucortolone is a steroid with the properties of being an anti-inflammatory, antipruritic and vasoconstrictive.[1] Its activity causes the vasoconstriction of the blood vessels and thus a decrease in the release of inflammatory substances. These actions produce the effect of skin soothed and elimination of the symptoms.[4]

Mechanism of action

Diflucortolone performs its action by the induction of lipocortins which are phospholipase A2 inhibitory proteins and sequentially inhibiting the release of arachidonic acid. The absence of arachidonic acid translates to the inhibition of the formation, release and activity of endogenous chemical inflammatory mediators. Another mechanism of action is the transrepression in which diflucortolone binds to the glucocorticoid receptor which induces its migration to the nucleus where it stimulates the transcription of anti-inflammatory genes like tyrosine aminotransferase, phophoenolpyruvate carboxykinase, IL-10, etc. and suppress the expression of proinflammatory genes like cytokines, growth factors, adhesion molecules, etc.[1]

TargetActionsOrganism
AAnnexin A3
inducer
Human
AGlucocorticoid receptor
binder
Human
Absorption

The absorption of diflucortolone is made mainly percutaneously but it may be absorbed systemically. The absorption and bioavailability of diflucortolone will be related to the type of formulation found in the medication.[1] The percutaneous absorption depends on the vehicle, dose, treatment area, duration of treatment, the condition of treatment, the status of penetration barrier and localization of treated area in the body.[6] Thus, rectal administration of diflucortolone produces a slow and low absorption with an AUC, Cmax and Tmax of 10.8 ng h/ml, 0.75 ng/ml and 4.7 h, respectively.[5]

Volume of distribution

Less of 1% of the administered dose reaches systemic circulation.[7] In order to exert its functions, diflucortolone has to distribute into the living epidermis and upper dermis. Reports have shown that the skin absorption of diflucortolone is rapid where the absorption gets significantly increased in damaged skin. Diflucortolone gets percutaneously absorbed and distributed into organs and tissues where it will be metabolized. When diflucortolone in an ointment form is applied in healthy skin 0.7% of the administered dose is percutaneously absorbed after a 7-hour exposure.[6]

Protein binding

Diflucortolone gets rapidly metabolized and eliminated, thus there is a very limited circulation of the unchanged drug in blood plasma.[6] Actually, the percutaneous absorption is so low that less than 1% of the admministered dose reaches systemyc circulation.[7]

Metabolism

The metabolism of diflucortolone is done in the liver where it is very rapidly degraded. After 5 minutes of administration of diflucortolone in a dose of 1mg, there is a concentration of intact diflucortolone in plasma of 6-8 ng/ml. The analysis of the metabolites showed the presence of 11-keto-diflucortolone as the major metabolite in the plasma.[2]

Route of elimination

The elimination of diflucortolone is rapid and complete. After 24 hours of dose administration 56% of the dose was eliminated by the urine and after 7 days 98% of the administered dose was recovered. The excretion of diflucortolone is subdivided in urine which accounts for 75% of the administered dose and in feces that accounts for the other 25% of the administered dose. From the eliminated dose, 30% was formed by unconjugated steroids, 20% as steroid-glucuronides and 10% as steroid-sulfates.[2]

Half life

The half-life of diflucortolone is approximately in the range of 4 to 5 h while the half-life of 3H-diflucortolone valerate is approximately 9 h.[2]

Clearance

Diflucortolone gets rapidly eliminated and the metabolites produced are the latest in getting eliminated from the body.[6]

Toxicity

Diflucortolone can cause skin irritation, vesicles or red patches on the skin.[4]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Uva L, Miguel D, Pinheiro C, Antunes J, Cruz D, Ferreira J, Filipe P: Mechanisms of action of topical corticosteroids in psoriasis. Int J Endocrinol. 2012;2012:561018. doi: 10.1155/2012/561018. Epub 2012 Nov 5. [PubMed:23213332]
  2. Mutzel VW: [Pharmacokinetics and biotransformation of diflucortolone valerate in man (author's transl)]. Arzneimittelforschung. 1976;26(7b):1487-92. [PubMed:1036944]
  3. FDA Submission [Link]
  4. Dokteronline [Link]
  5. J-stage papers [Link]
  6. Diflucortolone monograph [Link]
  7. Medicine.ie [Link]
External Links
PubChem Compound
11954369
PubChem Substance
310265022
ChemSpider
10128664
ChEBI
135624
ChEMBL
CHEMBL509924
Wikipedia
Diflucortolone
ATC Codes
D07XC04 — DiflucortoloneD07AC06 — DiflucortoloneD07BC04 — Diflucortolone and antiseptics
MSDS
Download (114 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
Not AvailableCompletedNot AvailableAtopic Dermatitis (AD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CreamTopical
CreamTopical0.1 %
OintmentTopical0.1 %
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)220ºC'MSDS'
boiling point (°C)534ºC at 760 mmHg'MSDS'
water solubility2.030 mg/LLamparczyk H. CRC Handbook of Chromatography. (1992)
logP3.86Lamparczyk H. CRC Handbook of Chromatography. (1992)
Predicted Properties
PropertyValueSource
Water Solubility0.0446 mg/mLALOGPS
logP2.22ALOGPS
logP2.01ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)13.39ChemAxon
pKa (Strongest Basic)-3.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area74.6 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity100.99 m3·mol-1ChemAxon
Polarizability40.22 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
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 21-hydroxysteroids. These are steroids carrying a hydroxyl group at the 21-position of the steroid backbone.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Hydroxysteroids
Direct Parent
21-hydroxysteroids
Alternative Parents
Gluco/mineralocorticoids, progestogins and derivatives / 20-oxosteroids / 11-beta-hydroxysteroids / 3-oxo delta-1,4-steroids / Halogenated steroids / Delta-1,4-steroids / Alpha-hydroxy ketones / Secondary alcohols / Cyclic alcohols and derivatives / Cyclic ketones
show 6 more
Substituents
Progestogin-skeleton / 21-hydroxysteroid / Pregnane-skeleton / 20-oxosteroid / 3-oxo-delta-1,4-steroid / 3-oxosteroid / 11-hydroxysteroid / 11-beta-hydroxysteroid / 9-halo-steroid / 6-halo-steroid
show 22 more
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inducer
General Function
Phospholipase a2 inhibitor activity
Specific Function
Inhibitor of phospholipase A2, also possesses anti-coagulant properties. Also cleaves the cyclic bond of inositol 1,2-cyclic phosphate to form inositol 1-phosphate.
Gene Name
ANXA3
Uniprot ID
P12429
Uniprot Name
Annexin A3
Molecular Weight
36374.85 Da
References
  1. Uva L, Miguel D, Pinheiro C, Antunes J, Cruz D, Ferreira J, Filipe P: Mechanisms of action of topical corticosteroids in psoriasis. Int J Endocrinol. 2012;2012:561018. doi: 10.1155/2012/561018. Epub 2012 Nov 5. [PubMed:23213332]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Binder
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. Uva L, Miguel D, Pinheiro C, Antunes J, Cruz D, Ferreira J, Filipe P: Mechanisms of action of topical corticosteroids in psoriasis. Int J Endocrinol. 2012;2012:561018. doi: 10.1155/2012/561018. Epub 2012 Nov 5. [PubMed:23213332]

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. Nerisone monograph [File]

Drug created on September 16, 2015 11:59 / Updated on November 05, 2018 17:49