DrugBank: Etretinate (DB00926)

targets (6) enzymes (2) carriers (1)

Identification

Name

Etretinate

Accession Number

DB00926 (APRD00966)

Type

small molecule

Groups

withdrawn

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

Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure

Synonyms

Not Available

Salts

Not Available

Brand names

Name	Company
Tegison
Tigason

Brand mixtures

Not Available

Categories

Keratolytic Agents

CAS number

54350-48-0

Weight

Average: 354.4825
Monoisotopic: 354.219494826

Chemical Formula

C₂₃H₃₀O₃

InChI Key

InChIKey=HQMNCQVAMBCHCO-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+

Plain Text

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

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Not Available

Classes

Not Available

Substructures

Not Available

Pharmacology

Indication

For the treatment of severe psoriasis in adults.

Pharmacodynamics

The 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 action

The 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.

Absorption

Absorbed 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 distribution

Not Available

Protein binding

More 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 elimination

Not Available

Half life

In 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.

Clearance

Not Available

Toxicity

Symptoms of overdose include headache and vertigo.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Hoffmann la roche inc

Packagers

Not Available

Dosage forms

Form	Route	Strength
Tablet	Oral

Prices

Not Available

Patents

Not Available

Properties

State

solid

Experimental Properties

Property	Value	Source
logP	6.5	Not Available

Predicted Properties

Property	Value	Source
water solubility	4.05e-04 g/l	ALOGPS
logP	6.32	ALOGPS
logP	6.32	ChemAxon
logS	-5.9	ALOGPS
pKa (strongest basic)	-4.8	ChemAxon
physiological charge	0	ChemAxon
hydrogen acceptor count	2	ChemAxon
hydrogen donor count	0	ChemAxon
polar surface area	35.53	ChemAxon
rotatable bond count	8	ChemAxon
refractivity	113.68	ChemAxon
polarizability	42.98	ChemAxon

References

Synthesis Reference

Not Available

General Reference

Not Available

External Links

Resource	Link
KEGG Drug	D00316
PubChem Compound	5282375
PubChem Substance	46504486
ChemSpider	3196
ChEBI	4913
ChEMBL	4913
PharmGKB	PA449554
Wikipedia	http://en.wikipedia.org/wiki/Etretinate

ATC Codes

D05BB01

AHFS Codes

Not Available

PDB Entries

Not Available

FDA label

Not Available

MSDS

Not Available

Interactions

Drug Interactions

Drug	Interaction
Demeclocycline	Increased risk of intracranial hypertension
Doxycycline	Increased risk of intracranial hypertension
Methacycline	Increased risk of intracranial hypertension
Methotrexate	Acitretin/etretinate increases the effect and toxicity of methotrexate
Minocycline	Increased risk of intracranial hypertension
Oxytetracycline	Increased risk of intracranial hypertension
Rolitetracycline	Increased risk of intracranial hypertension
Tetracycline	Increased 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 Pharmacological action: yes Actions: agonist This is a receptor for retinoic acid. This metabolite has profound effects on vertebrate development. Retinoic acid is a morphogen and is a powerful teratogen. This receptor controls cell function by directly regulating gene expression Organism class: human UniProt ID: P10276 Gene: RARA Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 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 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 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 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 Pharmacological action: yes Actions: agonist Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA). ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer Organism class: human UniProt ID: P19793 Gene: RXRA Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 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 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 Pharmacological action: yes Actions: agonist This is a receptor for retinoic acid. This metabolite has profound effects on vertebrate development. Retinoic acid is a morphogen and is a powerful teratogen. This receptor controls cell function by directly regulating gene expression Organism class: human UniProt ID: P10826 Gene: RARB Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 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 Pharmacological action: yes Actions: agonist Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA) Organism class: human UniProt ID: P48443 Gene: RXRG Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed 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 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 Pharmacological action: yes Actions: agonist Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA) Organism class: human UniProt ID: P28702 Gene: RXRB Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed 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-1 Pharmacological action: yes Actions: agonist This is a receptor for retinoic acid. This metabolite has profound effects on vertebrate development. Retinoic acid is a morphogen and is a powerful teratogen. This receptor controls cell function by directly regulating gene expression Organism class: human UniProt ID: P13631 Gene: RARG Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed 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 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

Targets

1. Retinoic acid receptor alpha

Pharmacological action: yes
Actions: agonist

This is a receptor for retinoic acid. This metabolite has profound effects on vertebrate development. Retinoic acid is a morphogen and is a powerful teratogen. This receptor controls cell function by directly regulating gene expression

Organism class: human
UniProt ID: P10276 Link_out

Gene: RARA Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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
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
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
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
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

Pharmacological action: yes
Actions: agonist

Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA). ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer

Organism class: human
UniProt ID: P19793 Link_out

Gene: RXRA Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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
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
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

Pharmacological action: yes
Actions: agonist

Organism class: human
UniProt ID: P10826 Link_out

Gene: RARB Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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
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

Pharmacological action: yes
Actions: agonist

Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA)

Organism class: human
UniProt ID: P48443 Link_out

Gene: RXRG Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
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
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

Pharmacological action: yes
Actions: agonist

Nuclear hormone receptor. Involved in the retinoic acid response pathway. Binds 9-cis retinoic acid (9C-RA)

Organism class: human
UniProt ID: P28702 Link_out

Gene: RXRB Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
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-1

Pharmacological action: yes
Actions: agonist

Organism class: human
UniProt ID: P13631 Link_out

Gene: RARG Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
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
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 Actions: inhibitor Catalyzes the formation of aromatic C18 estrogens from C19 androgens UniProt ID: P11511 Gene: CYP19A1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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 Actions: substrate Plays a key role in retinoic acid metabolism. Acts on retinoids, including all-trans-retinoic acid (RA) and its stereoisomer 9-cis-RA. Capable of both 4-hydroxylation and 18- hydroxylation. Responsible for generation of several hydroxylated forms of RA, including 4-OH-RA, 4-oxo-RA and 18-OH-RA UniProt ID: O43174 Gene: CYP26A1 Protein Sequence: FASTA SNPs: SNPJam Report References: 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

Enzymes

1. Cytochrome P450 19A1

Actions: inhibitor

Catalyzes the formation of aromatic C18 estrogens from C19 androgens

UniProt ID: P11511 Link_out

Gene: CYP19A1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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

Actions: substrate

Plays a key role in retinoic acid metabolism. Acts on retinoids, including all-trans-retinoic acid (RA) and its stereoisomer 9-cis-RA. Capable of both 4-hydroxylation and 18- hydroxylation. Responsible for generation of several hydroxylated forms of RA, including 4-OH-RA, 4-oxo-RA and 18-OH-RA

UniProt ID: O43174 Link_out

Gene: CYP26A1
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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 Cytosolic CRABPs may regulate the access of retinoic acid to the nuclear retinoic acid receptors UniProt ID: P29762 Gene: CRABP1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: 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

Carriers

1. Cellular retinoic acid-binding protein 1

Cytosolic CRABPs may regulate the access of retinoic acid to the nuclear retinoic acid receptors

UniProt ID: P29762 Link_out

Gene: CRABP1 Link_out

Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:

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

Comments

Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19