Drug/Small Molecule:
tretinoin

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last updated 10/25/2013

FDA Label for tretinoin and PML, RARA

This label is on the FDA Biomarker List
Genetic testing required

Summary

Tretinoin is a derivative of vitamin A (retinol) used for the treatment of skin conditions and acute promyelocytic leukemia (APL). APL is characterized by the translocation t(15;17) and PML/RAR alpha (RARA) fusion protein.

Annotation

Excerpt from the tretinoin (Vesanoid) label:

Confirmation of the diagnosis of APL should be sought by detection of the t(15;17) genetic marker by cytogenetic studies. If these are negative, PML/RAR alpha fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to VESANOID has not been demonstrated; therefore, patients who lack the genetic marker should be considered for alternative treatment.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the tretinoin (Vesanoid) drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Genes and/or phenotypes found in this label

  • Leukemia, Promyelocytic, Acute
    • Warnings section
    • source: PHONT
  • PML
    • Indications & usage section, Warnings section, Clinical studies section, efficacy
    • source: FDA Label
  • RARA
    • Indications & usage section, Warnings section, Clinical studies section, efficacy
    • source: FDA Label

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • ATRA
  • All Trans Retinoic Acid
  • All Trans-Retinoic Acid
  • Retionic Acid
  • beta-Retinoic Acid
  • tretinoin
Trade Names
  • Aberel
  • Accutane
  • Airol
  • Aknefug
  • Aknoten
  • Amnesteem
  • Atra-IV
  • Claravis
  • Dermairol
  • Eudyna
  • Lsotretinoin
  • Retisol-A
  • Solage
  • Sotret
  • Stieva-A
  • Stieva-a Forte
  • Tri-Luma
  • Vesanoid
  • Vitinoin
Brand Mixture Names

PharmGKB Accession Id:
PA451746

Description

Tretinoin, also known as all-trans-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A (retinol). Retinoids such as tretinoin are important regulators of cell reproduction, proliferation, and differentiation and are used to treat acne and photodamaged skin and to manage keratinization disorders such as ichthyosis and keratosis follicularis. Tretinoin also represents the class of anticancer drugs called differentiating agents and is used in the treatment of acute promyelocytic leukemia (APL).

Source: Drug Bank

Indication

For the the induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant); For the topical treatment of acne vulgaris, flat warts and other skin conditions (psoriasis, ichthyosis congenita, icthyosis vulgaris, lamellar icthyosis, keratosis palmaris et plantaris, epidermolytic hyperkeratosis, senile comedones, senile keratosis, keratosis follicularis (Darier's disease), and basal cell carcinomas.); For palliative therapy to improve fine wrinkling, mottled hyperpigmentation, roughness associated with photodamage.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Tretinoin binds to alpha, beta, and gamma retinoic acid receptors (RARs). RAR-alpha and RAR-beta have been associated with the development of acute promyelocytic leukemia and squamous cell cancers, respectively. RAR-gamma is associated with retinoid effects on mucocutaneous tissues and bone. Although the exact mechanism of action of tretinoin is unknown, current evidence suggests that the effectiveness of tretinoin in acne is due primarily to its ability to modify abnormal follicular keratinization. Comedones form in follicles with an excess of keratinized epithelial cells. Tretinoin promotes detachment of cornified cells and the enhanced shedding of corneocytes from the follicle. By increasing the mitotic activity of follicular epithelia, tretinoin also increases the turnover rate of thin, loosely-adherent corneocytes. Through these actions, the comedo contents are extruded and the formation of the microcomedo, the precursor lesion of acne vulgaris, is reduced. Tretinoin is not a cytolytic agent but instead induces cytodifferentiation and decreased proliferation of APL cells in culture and in vivo. When Tretinoin is given systemically to APL patients, tretinoin treatment produces an initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission (CR). The exact mechanism of action of tretinoin in APL is unknown.

Source: Drug Bank

Pharmacology

Tretinoin, also known as all-_trans_-retinoic acid (ATRA), is a naturally occurring derivative of vitamin A (retinol). Retinoids such as tretinoin are important regulators of cell reproduction, proliferation, and differentiation and are used to treat acne and photodamaged skin and to manage keratinization disorders such as ichthyosis and keratosis follicularis. Tretinoin also represents the class of anticancer drugs called differentiating agents and is used in the treatment of acute promyelocytic leukemia (APL).

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic

Source: Drug Bank

Protein Binding

> 95%

Source: Drug Bank

Absorption

1-31% (topical)

Source: Drug Bank

Half-Life

0.5-2 hours

Source: Drug Bank

Chemical Properties

Chemical Formula

C20H28O2

Source: Drug Bank

Isomeric SMILES

CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C

Source: Drug Bank

CC(C=CC1=C(C)CCCC1(C)C)=CC=CC(C)=CC(O)=O

Source: Drug Bank

Canonical SMILES

CC1=C(C(CCC1)(C)C)/C=C/C(=C/C=C/C(=C/C(=O)O)/C)/C

Source: PharmGKB

Average Molecular Weight

300.4351

Source: Drug Bank

Monoisotopic Molecular Weight

300.20893014

Source: Drug Bank

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

PharmGKB contains no curated pathways for this drug. If you would like to volunteer to work on a pathway, please let us know.

External Pathways

Links to non-PharmGKB pathways.

  1. RXR and RAR heterodimerization with other nuclear receptor - (Pathway Interaction Database NCI-Nature Curated)

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

EvidenceGene
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
PML
No Dosing Guideline available DL No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
RARA

Drug Targets

Gene Description
ALDH1A1 (source: Drug Bank)
ALDH1A2 (source: Drug Bank)
GPRC5A (source: Drug Bank)
NR0B1 (source: Drug Bank)
RARG (source: Drug Bank)
RARRES1 (source: Drug Bank)
RXRB (source: Drug Bank)
RXRG (source: Drug Bank)

Drug Interactions

Drug Description
tretinoin Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events. (source: Drug Bank)
atazanavir The strong CYP2C8 inhibitor, Atazanavir, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Atazanavir is initiated, discontinued to dose changed. (source: Drug Bank)
carbamazepine The strong CYP2C8 inducer, Carbamazepine, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Carbamazepine is initiated, discontinued or dose changed. (source: Drug Bank)
celecoxib The moderate CYP2C8 inhibitor, Celecoxib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Celecoxib is initiated, discontinued to dose changed. (source: Drug Bank)
demeclocycline Demeclocycline may increase the adverse effects of oral Tretinoin. Increased risk of pseudotumour cerebri. Concurrent therapy should be avoided. (source: Drug Bank)
desogestrel Oral Tretinoin may decrease the effect of oral contraceptive, Desogestrel. An alternate form of contraception should be used during concomitant therapy. (source: Drug Bank)
doxycycline Doxycycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided. (source: Drug Bank)
drospirenone Oral Tretinoin may decrease the effect of oral contraceptive, Drospirenone. An alternate form of contraception should be used during concomitant therapy. (source: Drug Bank)
ethynodiol diacetate Oral Tretinoin may decrease the effect of oral contraceptive, Ethynodiol Diacetate. An alternate form of contraception should be used during concomitant therapy. (source: Drug Bank)
etonogestrel Oral Tretinoin may decrease the effect of oral contraceptive, Etonogestrel. An alternate form of contraception should be used during concomitant therapy. (source: Drug Bank)
felodipine The moderate CYP2C8 inhibitor, Felopidine, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Felopidine is initiated, discontinued to dose changed. (source: Drug Bank)
fosphenytoin The strong CYP2C8 inducer, Fosphenytoin, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Fosphenytoin is initiated, discontinued or dose changed. (source: Drug Bank)
gemfibrozil The strong CYP2C8 inhibitor, Gemfibrozil, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Gemfibrozil is initiated, discontinued to dose changed. (source: Drug Bank)
irbesartan The moderate CYP2C8 inhibitor, Irbesartan, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Irbesartan is initiated, discontinued to dose changed. (source: Drug Bank)
lapatinib The moderate CYP2C8 inhibitor, Lapatinib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Lapatinib is initiated, discontinued to dose changed. (source: Drug Bank)
levonorgestrel Oral Tretinoin may decrease the effect of oral contraceptive, Levonorgestrel. An alternate form of contraception should be used during concomitant therapy. (source: Drug Bank)
losartan The moderate CYP2C8 inhibitor, Losartan, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Losartan is initiated, discontinued to dose changed. (source: Drug Bank)
mestranol Oral Tretinoin may decrease the effect of oral contraceptive, Mestranol. An alternate form of contraception should be used during concomitant therapy. (source: Drug Bank)
minocycline Minocycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided. (source: Drug Bank)
natalizumab Oral tretinoin may increase the adverse/toxic effects of Natalizumab. Concurrent therapy should be avoided. (source: Drug Bank)
nilotinib The moderate CYP2C8 inhibitor, Nilotinib, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Nilotinib is initiated, discontinued to dose changed. (source: Drug Bank)
norethindrone Oral Tretinoin may decrease the effect of oral contraceptive, Norethindrone. An alternate form of contraception should be used during concomitant therapy. (source: Drug Bank)
norgestimate Oral Tretinoin may decrease the effect of oral contraceptive, Norgestimate. An alternate form of contraception should be used during concomitant therapy. (source: Drug Bank)
norgestrel Oral Tretinoin may decrease the effect of oral contraceptive, Norgestrel. An alternate form of contraception should be used during concomitant therapy. (source: Drug Bank)
oxytetracycline Oxytetracycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided. (source: Drug Bank)
phenobarbital The strong CYP2C8 inducer, Phenobarbital, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Phenobarbital is initiated, discontinued or dose changed. (source: Drug Bank)
phenytoin The strong CYP2C8 inducer, Phenytoin, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Phenytoin is initiated, discontinued or dose changed. (source: Drug Bank)
pioglitazone The moderate CYP2C8 inhibitor, Pioglitazone, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Pioglitazone is initiated, discontinued to dose changed. (source: Drug Bank)
primidone The strong CYP2C8 inducer, Primidone, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Primidone is initiated, discontinued or dose changed. (source: Drug Bank)
quinine The moderate CYP2C8 inhibitor, Quinine, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Quinine is initiated, discontinued to dose changed. (source: Drug Bank)
rabeprazole The moderate CYP2C8 inhibitor, Rabaprazole, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Rabaprazole is initiated, discontinued to dose changed. (source: Drug Bank)
rifampin The strong CYP2C8 inducer, Rifampin, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Rifampin is initiated, discontinued or dose changed. (source: Drug Bank)
rifapentine The strong CYP2C8 inducer, Rifapentine, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Rifapentine is initiated, discontinued or dose changed. (source: Drug Bank)
ritonavir The strong CYP2C8 inhibitor, Ritonavir, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Ritonavir is initiated, discontinued to dose changed. (source: Drug Bank)
rosiglitazone The moderate CYP2C8 inhibitor, Rosiglitazone, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Rosiglitazone is initiated, discontinued to dose changed. (source: Drug Bank)
secobarbital The strong CYP2C8 inducer, Secobarbital, may increase the metabolism and clearance of oral Tretinoin. Consider alternate therapy to avoid failure of Tretinoin therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Secobarbital is initiated, discontinued or dose changed. (source: Drug Bank)
sorafenib The strong CYP2C8 inhibitor, Sorafenib, may decrease the metabolism and clearance of oral Tretinoin. Consider alternate therapy or monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Sorafenib is initiated, discontinued to dose changed. (source: Drug Bank)
tamoxifen The moderate CYP2C8 inhibitor, Tamoxifen, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Tamoxifen is initiated, discontinued to dose changed. (source: Drug Bank)
tetracycline Demeclocycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided. (source: Drug Bank)
tigecycline Demeclocycline may increase the adverse effects of oral Tretinoin. Increase risk of pseudotumour cerebri. Concurrent therapy should be avoided. (source: Drug Bank)
trastuzumab Increased risk of leukopenia and anemia due to synergistic effects. Monitor for signs and symptoms of adverse events during concomitant therapy. (source: Drug Bank)
trimethoprim The moderate CYP2C8 inhibitor, Trimethoprim, may decrease the metabolism and clearance of oral Tretinoin. Monitor for changes in Tretinoin effectiveness and adverse/toxic effects if Trimethoprim is initiated, discontinued to dose changed. (source: Drug Bank)
tretinoin Tretinoin increases the risk of vitamin A toxicity. Avoid vitamin A supplementation while taking systemic tretinoin. (source: Drug Bank)

Curated Information ?

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to tretinoin: 8

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Challenges in pharmacogenetics. European journal of clinical pharmacology. 2013. Cascorbi Ingolf, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Systematic review of pharmacoeconomic studies of pharmacogenomic tests. Pharmacogenomics. 2010. Beaulieu Mathieu, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
RARalpha2 expression is associated with disease progression and plays a crucial role in efficacy of ATRA treatment in myeloma. Blood. 2009. Wang Siqing, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Regulation of leukemic cell differentiation and retinoid-induced gene expression by statins. Molecular cancer therapeutics. 2009. Sassano Antonella, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Analytical and bioanalytical chemistry. 2008. Zanger Ulrich M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Comparison of anthracycline-based combination chemotherapy with or without all-trans retinoic acid in acute promyelocytic leukemia. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP. 2008. Raza Shahid, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica; the fate of foreign compounds in biological systems. 2008. Zhou S-F. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Mutations in the E-domain of RAR portion of the PML/RAR chimeric gene may confer clinical resistance to all-trans retinoic acid in acute promyelocytic leukemia. Blood. 1998. Imaizumi M, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0062-0187-02
DrugBank:
DB00755
ChEBI:
15367
KEGG Compound:
C00777
KEGG Drug:
D00094
PubChem Compound:
444795
5538
PubChem Substance:
46504843
7847162
Drugs Product Database (DPD):
2243914
ChemSpider:
5337
Therapeutic Targets Database:
DNC000117
FDA Drug Label at DailyMed:
e334034e-36d5-4e2d-b2ec-d1410b3374c3

Clinical Trials

These are trials that mention tretinoin and are related to either pharmacogenetics or pharmacogenomics.

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.