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Identification
NameIsotretinoin
Accession NumberDB00982  (APRD00140)
Typesmall molecule
Groupsapproved
Description

Isotretinoin is a medication used for the treatment of severe acne. It is sometimes used in prevention of certain skin cancers. It is a retinoid, meaning it derives from vitamin A and is found in small quantities naturally in the body. Isotretinoin binds to and activates nuclear retinoic acid receptors (RAR), thereby regulating cell proliferation and differentiation. This agent also exhibits immunomodulatory and anti-inflammatory responses and inhibits ornithine decarboxylase, thereby decreasing polyamine synthesis and keratinization.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
AbsoricaNot Available
Accutane RocheNot Available
MyorisanNot Available
ZENATANENot Available
Brand mixturesNot Available
Categories
CAS number4759-48-2
WeightAverage: 300.4351
Monoisotopic: 300.20893014
Chemical FormulaC20H28O2
InChI KeySHGAZHPCJJPHSC-XFYACQKRSA-N
InChI
InChI=1S/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/b9-6+,12-11+,15-8+,16-14-
IUPAC Name
(2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-tetraenoic acid
SMILES
C\C(\C=C\C1=C(C)CCCC1(C)C)=C/C=C/C(/C)=C\C(O)=O
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassPrenol Lipids
SubclassRetinoids
Direct parentRetinoids
Alternative parentsDiterpenes; Carbocyclic Fatty Acids; Branched Fatty Acids; Unsaturated Fatty Acids; Enones; Carboxylic Acids; Polyamines; Enolates
Substituentsenone; enolate; polyamine; carboxylic acid; carboxylic acid derivative
Classification descriptionThis compound belongs to the retinoids. These are compounds that are related to vitamin A, especially retinol.
Pharmacology
IndicationFor the treatment of severe recalcitrant nodular acne
PharmacodynamicsIsotretinoin, a retinoid, is indicated in the treatment of severe recalcitrant nodular acne. Nodules are inflammatory lesions with a diameter of 5 mm or greater. The nodules may become suppurative or hemorrhagic. "Severe," by definition, means "many" as opposed to "few or several" nodules. Clinical improvement in nodular acne patients occurs in association with a reduction in sebum secretion. The decrease in sebum secretion is temporary and is related to the dose and duration of treatment with Accutane, and reflects a reduction in sebaceous gland size and an inhibition of sebaceous gland differentiation.
Mechanism of actionIsotretinoin noticeably reduces the production of sebum and shrinks the sebaceous glands. It stabilises keratinization and prevents comedones from forming. It also reduces inflammation in moderate-severe inflammatory acne. The exact mechanism of action is unknown, however it is known that it alters DNA transcription.
AbsorptionNot Available
Volume of distributionNot Available
Protein binding99.9%
Metabolism
Route of eliminationIsotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. The metabolites of isotretinoin and any conjugates are ultimately excreted in the feces and urine in relatively equal amounts (total of 65% to 83%).
Half life17-50 hours
Clearance
  • 96 +/- 6.27 L/hr [severe recalcitrant nodular acne pediatric Patients, 12 to 15 Years]
ToxicityIsotretinoin is teratogenic. It also causes mucocutaneous side effects suck as cheilitis, dry skin, and dry eyes.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9925
Blood Brain Barrier + 0.9311
Caco-2 permeable + 0.7603
P-glycoprotein substrate Non-substrate 0.6144
P-glycoprotein inhibitor I Non-inhibitor 0.8912
P-glycoprotein inhibitor II Non-inhibitor 0.8088
Renal organic cation transporter Non-inhibitor 0.8639
CYP450 2C9 substrate Non-substrate 0.8221
CYP450 2D6 substrate Non-substrate 0.9115
CYP450 3A4 substrate Substrate 0.6025
CYP450 1A2 substrate Non-inhibitor 0.9046
CYP450 2C9 substrate Non-inhibitor 0.8831
CYP450 2D6 substrate Non-inhibitor 0.9231
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.9301
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9252
Ames test Non AMES toxic 0.8944
Carcinogenicity Non-carcinogens 0.7081
Biodegradation Ready biodegradable 0.5554
Rat acute toxicity 2.1455 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9562
hERG inhibition (predictor II) Non-inhibitor 0.9538
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
CapsuleOral
Prices
Unit descriptionCostUnit
Accutane 20 mg capsule23.77USDcapsule
Amnesteem 40 mg capsule22.6USDcapsule
Claravis 40 mg capsule22.6USDcapsule
Amnesteem 20 mg capsule19.45USDcapsule
Claravis 20 mg capsule18.7USDcapsule
Claravis 30 mg capsule16.45USDcapsule
Amnesteem 10 mg capsule16.4USDcapsule
Claravis 10 mg capsule15.77USDcapsule
Accutane 40 mg capsule14.88USDcapsule
Accutane 10 mg capsule10.55USDcapsule
Sotret 40 mg capsule10.08USDcapsule
Sotret 20 mg capsule8.67USDcapsule
Sotret 30 mg capsule8.44USDcapsule
Sotret 10 mg capsule7.31USDcapsule
Clarus 40 mg Capsule2.14USDcapsule
Clarus 10 mg Capsule1.05USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP4.2Not Available
Predicted Properties
PropertyValueSource
water solubility4.77e-03 g/lALOGPS
logP5.66ALOGPS
logP5.01ChemAxon
logS-4.8ALOGPS
pKa (strongest acidic)5ChemAxon
physiological charge-1ChemAxon
hydrogen acceptor count2ChemAxon
hydrogen donor count1ChemAxon
polar surface area37.3ChemAxon
rotatable bond count5ChemAxon
refractivity97.79ChemAxon
polarizability36.15ChemAxon
number of rings1ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraMS/MS1D NMR2D NMR
References
Synthesis Reference

Ashok Kumar, Dharmendra Singh, Ganesh Devidas Mahale, Ragnesh Kumar Rana, Mahesh Kharade, “PROCESS FOR PREPARATION OF HIGHLY PURE ISOTRETINOIN.” U.S. Patent US20080207946, issued August 28, 2008.

US20080207946
General Reference
  1. Berard A, Azoulay L, Koren G, Blais L, Perreault S, Oraichi D: Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br J Clin Pharmacol. 2007 Feb;63(2):196-205. Pubmed
  2. Holmes SC, Bankowska U, Mackie RM: The prescription of isotretinoin to women: is every precaution taken? Br J Dermatol. 1998 Mar;138(3):450-5. Pubmed
  3. Amichai B, Shemer A, Grunwald MH: Low-dose isotretinoin in the treatment of acne vulgaris. J Am Acad Dermatol. 2006 Apr;54(4):644-6. Pubmed
  4. Seukeran DC, Cunliffe WJ: Acne vulgaris in the elderly: the response to low-dose isotretinoin. Br J Dermatol. 1998 Jul;139(1):99-101. Pubmed
  5. Tirado Sanchez A, Leon Dorantes G: [Erectile dysfunction during isotretinoin therapy] Actas Urol Esp. 2005 Nov-Dec;29(10):974-6. Pubmed
External Links
ResourceLink
KEGG DrugD00348
ChEBI6067
ChEMBLCHEMBL547
Therapeutic Targets DatabaseDAP000009
PharmGKBPA450128
Drug Product Database582344
RxListhttp://www.rxlist.com/cgi/generic/isotret.htm
Drugs.comhttp://www.drugs.com/cdi/isotretinoin.html
WikipediaIsotretinoin
ATC CodesNot Available
AHFS Codes
  • 84:92.00
PDB EntriesNot Available
FDA labelshow(376 KB)
MSDSshow(37.3 KB)
Interactions
Drug Interactions
Drug
CarbamazepineIsotretinoine decreases the effect of carbamazepine
DemeclocyclineIncreased risk of intracranial hypertension
DoxycyclineIncreased risk of intracranial hypertension
MethacyclineIncreased risk of intracranial hypertension
MinocyclineIncreased risk of intracranial hypertension
OxytetracyclineIncreased risk of intracranial hypertension
RolitetracyclineIncreased risk of intracranial hypertension
TetracyclineIncreased risk of intracranial hypertension
Vitamin AIsotretinoin increases the risk of vitamin A toxicity. Avoid vitamin A supplementation while taking isotretinoin.
Food Interactions
  • Avoid alcohol.
  • Take with a full glass of water Do not take supplements containing Vitamin A.
  • Take with high-fat meal to increase absorption.

Targets

1. Retinoic acid receptor alpha

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: other/unknown

Components

Name UniProt ID Details
Retinoic acid receptor alpha P10276 Details

References:

  1. Dahl AR, Grossi IM, Houchens DP, Scovell LJ, Placke ME, Imondi AR, Stoner GD, De Luca LM, Wang D, Mulshine JL: Inhaled isotretinoin (13-cis retinoic acid) is an effective lung cancer chemopreventive agent in A/J mice at low doses: a pilot study. Clin Cancer Res. 2000 Aug;6(8):3015-24. Pubmed
  2. Zouboulis CC: Isotretinoin revisited: pluripotent effects on human sebaceous gland cells. J Invest Dermatol. 2006 Oct;126(10):2154-6. Pubmed
  3. Vu-Dac N, Gervois P, Torra IP, Fruchart JC, Kosykh V, Kooistra T, Princen HM, Dallongeville J, Staels B: Retinoids increase human apo C-III expression at the transcriptional level via the retinoid X receptor. Contribution to the hypertriglyceridemic action of retinoids. J Clin Invest. 1998 Aug 1;102(3):625-32. Pubmed
  4. Taylor LE, Bennett GD, Finnell RH: Altered gene expression in murine branchial arches following in utero exposure to retinoic acid. J Craniofac Genet Dev Biol. 1995 Jan-Mar;15(1):13-25. Pubmed
  5. Shroot B, Michel S: Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997 Jun;36(6 Pt 2):S96-103. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12