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Identification
NameEtretinate
Accession NumberDB00926  (APRD00966)
TypeSmall Molecule
GroupsWithdrawn
Description

Etretinate is a medication used to treat severe psoriasis. It is a synthetic aromatic retinoid. The mechanism of action of etretinate is still incompletely understood although, like retinoic acid, it is thought to interfere with the terminal differentiation of keratinocytes. It is thought to bind to the retinoic acid receptors. Etretinate is also believed to enhance the binding of cAMP to the regulatory RI subunit of cAMP dependent protein kinases. It was removed from the United States market in 1998 and the Canadian market in 1996 as a psoriasis medication, due to the high risk of birth defects. Etretinate is now used to treat T-cell lymphomas. It also appears to inhibit NADH oxidase activity.

Structure
Thumb
SynonymsNot Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International Brands
NameCompany
TegisonNot Available
TigasonChugai Pharmaceutical
Brand mixturesNot Available
SaltsNot Available
CategoriesNot Available
CAS number54350-48-0
WeightAverage: 354.4825
Monoisotopic: 354.219494826
Chemical FormulaC23H30O3
InChI KeyHQMNCQVAMBCHCO-DJRRULDNSA-N
InChI
InChI=1S/C23H30O3/c1-8-26-23(24)14-17(3)11-9-10-16(2)12-13-21-18(4)15-22(25-7)20(6)19(21)5/h9-15H,8H2,1-7H3/b11-9+,13-12+,16-10+,17-14+
IUPAC Name
ethyl 9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoate
SMILES
CCOC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)C(C)=C(OC)C=C1C
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as retinoid esters. These are ester derivatives of retinoic acid. These are obtained by formal condensation of the hydroxy group of retinol with the carboxy group of any carboxylic acid.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassPrenol lipids
Sub ClassRetinoids
Direct ParentRetinoid esters
Alternative Parents
Substituents
  • Retinoid ester
  • Cyclofarsesane sesquiterpenoid
  • Sesquiterpenoid
  • Methoxybenzene
  • Styrene
  • Phenol ether
  • Anisole
  • Fatty acid ester
  • Alkyl aryl ether
  • Fatty acyl
  • Benzenoid
  • Monocyclic benzene moiety
  • Alpha,beta-unsaturated carboxylic ester
  • Enoate ester
  • Carboxylic acid ester
  • Monocarboxylic acid or derivatives
  • Ether
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Carbonyl group
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the treatment of severe psoriasis in adults.
PharmacodynamicsThe active metabolite responsible for etretinate's effects, acitretin, is a retinoid. Retinoids have a structure similar to vitamin A and are involved in the normal growth of skin cells. Acitretin works by inhibiting the excessive cell growth and keratinisation (process by which skin cells become thickened due to the deposition of a protein within them) seen in psoriasis. It therefore reduces the thickening of the skin, plaque formation and scaling.
Mechanism of actionThe mechanism of action of the active metabolite, acitretin, is unknown, however it is believed to work by targeting specific receptors (retinoid receptors) in the skin which help normalize the growth cycle of skin cells.
AbsorptionAbsorbed in the small intestine. Studies in normal volunteers indicate that the absorption of etretinate is greater in patients consuming whole milk or a high-fat diet than in patients in a fasting state.
Volume of distributionNot Available
Protein bindingMore than 99% bound to plasma proteins, predominantly lipoproteins, whereas its active metabolite, acetretin (etretin), is predominantly bound to albumin.
Metabolism

Extensively metabolized, with significant first-pass metabolism to the pharmacologically active acid form. Subsequent metabolism results in the inactive 13-cis acid form, chain-shortened breakdown products, and conjugates that are ultimately excreted.

Route of eliminationNot Available
Half lifeIn one study, the apparent terminal half-life of etretinate after 6 months of therapy was approximately 120 days. In another study of 47 patients who had undergone chronic therapy with etretinate, 5 patients had detectable serum drug concentrations (0.5 to 12 ng/mL) 2.1 to 2.9 years after therapy was completed.
ClearanceNot Available
ToxicitySymptoms of overdose include headache and vertigo.
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+1.0
Blood Brain Barrier+0.541
Caco-2 permeable+0.8686
P-glycoprotein substrateNon-substrate0.5795
P-glycoprotein inhibitor IInhibitor0.5432
P-glycoprotein inhibitor IINon-inhibitor0.884
Renal organic cation transporterNon-inhibitor0.8439
CYP450 2C9 substrateNon-substrate0.8474
CYP450 2D6 substrateNon-substrate0.8222
CYP450 3A4 substrateSubstrate0.5411
CYP450 1A2 substrateInhibitor0.824
CYP450 2C9 substrateNon-inhibitor0.7544
CYP450 2D6 substrateNon-inhibitor0.9149
CYP450 2C19 substrateInhibitor0.5241
CYP450 3A4 substrateNon-inhibitor0.8499
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8041
Ames testNon AMES toxic0.6898
CarcinogenicityNon-carcinogens0.7795
BiodegradationReady biodegradable0.8896
Rat acute toxicity1.8763 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9002
hERG inhibition (predictor II)Non-inhibitor0.9289
Pharmacoeconomics
Manufacturers
  • Hoffmann la roche inc
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point104-105Bollag. W., Ruegg, R. and Ryser, G.; U.S.Patent 4,105,681; August 8,1978; assigned to Hoffmann-LaRoche, Inc. Bollag, W., Ruegg, R. and Ryser, G.; U.S. Patent 4,215,215; July 29, 1980; assigned to Hoffmann-La Roche, Inc.
logP6.5Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.000405 mg/mLALOGPS
logP6.32ALOGPS
logP6.32ChemAxon
logS-5.9ALOGPS
pKa (Strongest Basic)-4.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area35.53 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity113.68 m3·mol-1ChemAxon
Polarizability42.98 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

Bollag. W., Ruegg, R. and Ryser, G.; U.S.Patent 4,105,681; August 8,1978; assigned to Hoffmann-LaRoche, Inc.
Bollag, W., Ruegg, R. and Ryser, G.; U.S. Patent 4,215,215; July 29, 1980; assigned to Hoffmann-La Roche, Inc.

General ReferenceNot Available
External Links
ATC CodesNot Available
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSNot Available
Interactions
Drug Interactions
Drug
DemeclocyclineIncreased risk of intracranial hypertension
DoxycyclineIncreased risk of intracranial hypertension
MethacyclineIncreased risk of intracranial hypertension
MethotrexateAcitretin/etretinate increases the effect and toxicity of methotrexate
MinocyclineIncreased risk of intracranial hypertension
OxytetracyclineIncreased risk of intracranial hypertension
RolitetracyclineIncreased risk of intracranial hypertension
TetracyclineIncreased risk of intracranial hypertension
Food Interactions
  • Avoid alcohol completely up to 2 months after discontinuation.
  • Increases absorption, take with food.

Targets

1. Retinoic acid receptor alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Retinoic acid receptor alpha P10276 Details

References:

  1. Harnish DC, Barua AB, Soprano KJ, Soprano DR: Induction of beta-retinoic acid receptor mRNA by teratogenic doses of retinoids in murine fetuses. Differentiation. 1990 Nov;45(2):103-8. Pubmed
  2. Saurat JH: Retinoids and psoriasis: novel issues in retinoid pharmacology and implications for psoriasis treatment. J Am Acad Dermatol. 1999 Sep;41(3 Pt 2):S2-6. Pubmed
  3. Zitnik RJ, Kotloff RM, Latifpour J, Zheng T, Whiting NL, Schwalb J, Elias JA: Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts. J Immunol. 1994 Feb 1;152(3):1419-27. Pubmed
  4. Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC: Current use and future potential role of retinoids in dermatology. Drugs. 1997 Mar;53(3):358-88. Pubmed
  5. Billoni N, Gautier B, Mahe YF, Bernard BA: Expression of retinoid nuclear receptor superfamily members in human hair follicles and its implication in hair growth. Acta Derm Venereol. 1997 Sep;77(5):350-5. Pubmed

2. Retinoic acid receptor RXR-alpha

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Retinoic acid receptor RXR-alpha P19793 Details

References:

  1. Zitnik RJ, Kotloff RM, Latifpour J, Zheng T, Whiting NL, Schwalb J, Elias JA: Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts. J Immunol. 1994 Feb 1;152(3):1419-27. Pubmed
  2. Orfanos CE, Zouboulis CC, Almond-Roesler B, Geilen CC: Current use and future potential role of retinoids in dermatology. Drugs. 1997 Mar;53(3):358-88. Pubmed
  3. Billoni N, Gautier B, Mahe YF, Bernard BA: Expression of retinoid nuclear receptor superfamily members in human hair follicles and its implication in hair growth. Acta Derm Venereol. 1997 Sep;77(5):350-5. Pubmed

3. Retinoic acid receptor beta

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Retinoic acid receptor beta P10826 Details

References:

  1. Zitnik RJ, Kotloff RM, Latifpour J, Zheng T, Whiting NL, Schwalb J, Elias JA: Retinoic acid inhibition of IL-1-induced IL-6 production by human lung fibroblasts. J Immunol. 1994 Feb 1;152(3):1419-27. Pubmed
  2. Billoni N, Gautier B, Mahe YF, Bernard BA: Expression of retinoid nuclear receptor superfamily members in human hair follicles and its implication in hair growth. Acta Derm Venereol. 1997 Sep;77(5):350-5. Pubmed

4. Retinoic acid receptor RXR-gamma

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Retinoic acid receptor RXR-gamma P48443 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Billoni N, Gautier B, Mahe YF, Bernard BA: Expression of retinoid nuclear receptor superfamily members in human hair follicles and its implication in hair growth. Acta Derm Venereol. 1997 Sep;77(5):350-5. Pubmed

5. Retinoic acid receptor RXR-beta

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Retinoic acid receptor RXR-beta P28702 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed

6. Retinoic acid receptor gamma

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Retinoic acid receptor gamma P13631 Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. Pubmed

Enzymes

1. Cytochrome P450 19A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 19A1 P11511 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cytochrome P450 26A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 26A1 O43174 Details

References:

  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

Carriers

1. Cellular retinoic acid-binding protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Cellular retinoic acid-binding protein 1 P29762 Details

References:

  1. Madani K, Bazzano G, Chou A: Evaluation of retinoids as inhibitors of [3H] all-trans retinoic acid binding to cellular retinoic acid-binding protein in rat skin and testes. Arch Dermatol Res. 1986;278(4):302-6. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on April 22, 2014 12:52