DrugBank: Acitretin (DB00459)

targets (7) enzymes (1) carriers (1)

Identification

Name

Acitretin

Accession Number

DB00459 (APRD00778)

Type

small molecule

Groups

approved

Description

An oral retinoid effective in the treatment of psoriasis. It is the major metabolite of etretinate with the advantage of a much shorter half-life when compared with etretinate. [PubChem]

Structure

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

Synonyms

Not Available

Brand names

Acetretin
Soriatane

Brand name mixtures

Not Available

Categories

Keratolytic Agents

CAS number

55079-83-9

Weight

Average: 326.4293
Monoisotopic: 326.188194698

Chemical Formula

C₂₁H₂₆O₃

InChI Key

InChIKey=IHUNBGSDBOWDMA-UGOGCBOOSA-N

InChI

InChI=1S/C21H26O3/c1-14(8-7-9-15(2)12-21(22)23)10-11-19-16(3)13-20(24-6)18(5)17(19)4/h7-13H,1-6H3,(H,22,23)/b9-7+,11-10+,14-8+,15-12-

Plain Text

IUPAC Name

(2Z,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid

SMILES

COC1=C(C)C(C)=C(\C=C\C(C)=C\C=C\C(C)=C/C(O)=O)C(C)=C1

Plain Text

Mass Spec

Not Available

Taxonomy

Kingdom

Not Available

Classes

Retinoids

Substructures

Hydroxy Compounds
Alkanes and Alkenes
Retinoids
Acetates
Phenols and Derivatives
Carboxylic Acids and Derivatives
Phenylpropenes
Ethers
Benzene and Derivatives
Monoterpenes
Isoprenes
Aromatic compounds
Anisoles
Styrene Derivatives
Phenyl Esters

Pharmacology

Indication

For the treatment of severe psoriasis in adults.

Pharmacodynamics

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 acitretin is unknown, however it is believed to work by targeting specific receptors (retinoid receptors such as RXR and RAR) in the skin which help normalize the growth cycle of skin cells.

Absorption

Oral absorption of acitretin is optimal when given with food, and is linear and proportional with increasing doses from 25 to 100 mg. Approximately 72% (range 47% to 109%) of the administered dose was absorbed after a single 50 mg dose of acitretin was given to 12 healthy subjects.

Volume of distribution

Not Available

Protein binding

Over 99.9% bound to plasma proteins, primarily albumin.

Metabolism

Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted.

Route of elimination

Both parent compound and isomer are further metabolized into chain-shortened breakdown products and conjugates, which are excreted. The chain-shortened metabolites and conjugates of acitretin and cis-acitretin are ultimately excreted in the feces (34% to 54%) and urine (16% to 53%).

Half life

49 hours (range 33 to 96 hours)

Clearance

Not Available

Toxicity

Oral, rat: LD₅₀ = >4000 mg/kg. Symptoms of overdose include headache and vertigo.

Affected organisms

Humans and other mammals

Pathways

Not Available

Pharmacoeconomics

Manufacturers

Stiefel laboratories inc

Packagers

Dosage forms

Form	Route	Strength
Capsule	Oral

Prices

Unit description	Cost	Unit
Soriatane 17.5 mg capsule	30.21 USD	capsule
Soriatane 22.5 mg capsule	30.21 USD	capsule
Soriatane 25 mg capsule	21.71 USD	capsule
Soriatane 10 mg capsule	13.25 USD	capsule

Patents

Not Available

Properties

State

solid

Melting point

228-230 oC

Experimental Properties

Property	Value	Source
water solubility	0.0729 mg/L	PhysProp
logP	5.7	PhysProp

Predicted Properties

Property	Value	Source
water solubility	4.78e-04 g/l	ALOGPS
logP	5.20	ALOGPS
logP	5.59	ChemAxon Molconvert
logS	-5.83	ALOGPS
pKa		ChemAxon Molconvert
hydrogen acceptor count	3	ChemAxon Molconvert
hydrogen donor count	1	ChemAxon Molconvert
polar surface area	46.53	ChemAxon Molconvert
rotatable bond count	6	ChemAxon Molconvert
refractivity	104.17	ChemAxon Molconvert
polarizability	38.71	ChemAxon Molconvert

References

Synthesis Reference

Not Available

General Reference

Not Available

External Links

Resource	Link
PubChem Compound	6437841
PubChem Substance	46509178
ChemSpider	4942363
ChEBI	50173
ChEMBL	50173
Therapeutic Targets Database	DAP000743
Drug Product Database	2070847
RxList	http://www.rxlist.com/cgi/generic3/acitretin.htm
Drugs.com	http://www.drugs.com/cdi/acitretin.html
PDRhealth	http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/sor1698.shtml
Wikipedia	http://en.wikipedia.org/wiki/Acitretin

ATC Codes

D05BB02

AHFS Codes

84:92.00

PDB Entries

Not Available

FDA label

show (530.5 KB)

MSDS

Not Available

Interactions

Drug Interactions

Not Available

Food Interactions

Not Available

Targets
1. 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: 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 Tian K, Norris AW, Lin CL, Li E: The isolation and characterization of purified heterocomplexes of recombinant retinoic acid receptor and retinoid X receptor ligand binding domains. Biochemistry. 1997 May 13;36(19):5669-76. Pubmed 2. 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: 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 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 Tian K, Norris AW, Lin CL, Li E: The isolation and characterization of purified heterocomplexes of recombinant retinoic acid receptor and retinoid X receptor ligand binding domains. Biochemistry. 1997 May 13;36(19):5669-76. Pubmed Tippmann F, Hundt J, Schneider A, Endres K, Fahrenholz F: Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 2009 Jun;23(6):1643-54. Epub 2009 Jan 14. 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: Berggren Soderlund M, Johannesson G, Fex G: Expression of human all-trans-retinoic acid receptor beta and its ligand-binding domain in Escherichia coli. Biochem J. 1995 May 15;308 ( Pt 1):353-9. Pubmed Zouboulis CC: Retinoids—which dermatological indications will benefit in the near future? Skin Pharmacol Appl Skin Physiol. 2001 Sep-Oct;14(5):303-15. Pubmed Tippmann F, Hundt J, Schneider A, Endres K, Fahrenholz F: Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 2009 Jun;23(6):1643-54. Epub 2009 Jan 14. Pubmed 4. 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 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 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 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 7. Retinol-binding protein I, cellular Pharmacological action: unknown Actions: agonist Intracellular transport of retinol Organism class: human UniProt ID: P09455 Gene: RBP1 Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Berni R, Clerici M, Malpeli G, Cleris L, Formelli F: Retinoids: in vitro interaction with retinol-binding protein and influence on plasma retinol. FASEB J. 1993 Sep;7(12):1179-84. Pubmed

Targets

1. 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:

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
Tian K, Norris AW, Lin CL, Li E: The isolation and characterization of purified heterocomplexes of recombinant retinoic acid receptor and retinoid X receptor ligand binding domains. Biochemistry. 1997 May 13;36(19):5669-76. Pubmed

2. 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:

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
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
Tian K, Norris AW, Lin CL, Li E: The isolation and characterization of purified heterocomplexes of recombinant retinoic acid receptor and retinoid X receptor ligand binding domains. Biochemistry. 1997 May 13;36(19):5669-76. Pubmed
Tippmann F, Hundt J, Schneider A, Endres K, Fahrenholz F: Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 2009 Jun;23(6):1643-54. Epub 2009 Jan 14. 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:

Berggren Soderlund M, Johannesson G, Fex G: Expression of human all-trans-retinoic acid receptor beta and its ligand-binding domain in Escherichia coli. Biochem J. 1995 May 15;308 ( Pt 1):353-9. Pubmed
Zouboulis CC: Retinoids—which dermatological indications will benefit in the near future? Skin Pharmacol Appl Skin Physiol. 2001 Sep-Oct;14(5):303-15. Pubmed
Tippmann F, Hundt J, Schneider A, Endres K, Fahrenholz F: Up-regulation of the alpha-secretase ADAM10 by retinoic acid receptors and acitretin. FASEB J. 2009 Jun;23(6):1643-54. Epub 2009 Jan 14. Pubmed

4. 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

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 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
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

7. Retinol-binding protein I, cellular

Pharmacological action: unknown
Actions: agonist

Intracellular transport of retinol

Organism class: human
UniProt ID: P09455 Link_out

Gene: RBP1 Link_out

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

References:

Berni R, Clerici M, Malpeli G, Cleris L, Formelli F: Retinoids: in vitro interaction with retinol-binding protein and influence on plasma retinol. FASEB J. 1993 Sep;7(12):1179-84. Pubmed

Enzymes
1. 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 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. Serum albumin Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood UniProt ID: P02768 Gene: ALB Protein Sequence: FASTA Gene Sequence: FASTA SNPs: SNPJam Report References: Urien S, Claudepierre P, Meyer J, Brandt R, Tillement JP: Comparative binding of etretinate and acitretin to plasma proteins and erythrocytes. Biochem Pharmacol. 1992 Nov 3;44(9):1891-3. Pubmed Preiss JC, Zouboulis CC, Zeitz M, Duchmann R: [Severe erythrodermic psoriasis in a patient with 22q11 deletion syndrome] Med Klin (Munich). 2005 May 13;100(5):275-8. Pubmed Carillet V, Morliere P, Maziere JC, Huppe G, Santus R, Dubertret L: In vitro interactions of the aromatic retinoids Ro 10-9359 (etretinate) and Ro 10-1670 (acitretin), its main metabolite, with human serum lipoproteins and albumin. Biochim Biophys Acta. 1990 Nov 12;1055(2):98-101. Pubmed

Carriers

1. Serum albumin

Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood

UniProt ID: P02768 Link_out

Gene: ALB

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

References:

Urien S, Claudepierre P, Meyer J, Brandt R, Tillement JP: Comparative binding of etretinate and acitretin to plasma proteins and erythrocytes. Biochem Pharmacol. 1992 Nov 3;44(9):1891-3. Pubmed
Preiss JC, Zouboulis CC, Zeitz M, Duchmann R: [Severe erythrodermic psoriasis in a patient with 22q11 deletion syndrome] Med Klin (Munich). 2005 May 13;100(5):275-8. Pubmed
Carillet V, Morliere P, Maziere JC, Huppe G, Santus R, Dubertret L: In vitro interactions of the aromatic retinoids Ro 10-9359 (etretinate) and Ro 10-1670 (acitretin), its main metabolite, with human serum lipoproteins and albumin. Biochim Biophys Acta. 1990 Nov 12;1055(2):98-101. Pubmed

Comments

Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:04

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.