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Identification
NameTrametinib
Accession NumberDB08911
Typesmall molecule
Groupsapproved
Description

Trametinib dimethyl sulfoxide is a kinase inhibitor. Each 1-mg tablet contains 1.127 mg trametinib dimethyl sulfoxide equivalent to 1 mg of trametinib non-solvated parent. FDA approved on May 29, 2013.

Structure
Thumb
Synonyms
SynonymLanguageCode
Trametinib Dimethyl Sulfoxide Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
MekinistGlaxoSmithKline LLC
Brand mixturesNot Available
CategoriesNot Available
CAS number871700-17-3
WeightAverage: 615.3948
Monoisotopic: 615.077875874
Chemical FormulaC26H23FIN5O4
InChI KeyInChIKey=LIRYPHYGHXZJBZ-UHFFFAOYSA-N
InChI
InChI=1S/C26H23FIN5O4/c1-13-22-21(23(31(3)24(13)35)30-20-10-7-15(28)11-19(20)27)25(36)33(17-8-9-17)26(37)32(22)18-6-4-5-16(12-18)29-14(2)34/h4-7,10-12,17,30H,8-9H2,1-3H3,(H,29,34)
IUPAC Name
N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-1H,2H,3H,4H,6H,7H-pyrido[4,3-d]pyrimidin-1-yl}phenyl)acetamide
SMILES
CN1C(=O)C(C)=C2N(C(=O)N(C3CC3)C(=O)C2=C1NC1=CC=C(I)C=C1F)C1=CC(NC(C)=O)=CC=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassPyridopyrimidines
SubclassNot Available
Direct parentPyridopyrimidines
Alternative parentsAnilides; Pyrimidones; Aminopyridines and Derivatives; Pyridinones; Fluorobenzenes; Iodobenzenes; Aryl Iodides; Aryl Fluorides; Secondary Carboxylic Acid Amides; Carboxylic Acids; Enolates; Polyamines; Secondary Amines; Organoiodides; Organofluorides
Substituentsaminopyridine; fluorobenzene; pyridinone; pyrimidone; iodobenzene; pyrimidine; benzene; aryl iodide; aryl fluoride; aryl halide; pyridine; carboxamide group; secondary carboxylic acid amide; polyamine; carboxylic acid derivative; enolate; secondary amine; carboxylic acid; organohalogen; amine; organofluoride; organoiodide; organonitrogen compound
Classification descriptionThis compound belongs to the pyridopyrimidines. These are compounds containing a pyridopyrimidine, which consists of a pyridine fused to a pyrimidine.
Pharmacology
IndicationTrametinib is indicated for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test.
PharmacodynamicsWhen 1 mg and 2 mg trametinib is given to patients with BRAF V600 mutation-positive melanoma, an inhibition of phosphorylated ERK and Ki67, and an increase in p27 was observed. These changes indicate that trametinib caused a decrease in cell proliferation and an increase in apoptosis, respectively.
Mechanism of actionTrametinib is a reversible, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. Trametinib helps with melanoma with the BRAF V600E or V600K as the mutation results in the constitutive activation of the BRAF pathway which includes MEK1 and MEK2.
AbsorptionTrametinib is rapidly absorbed. When an oral administration of trametinib was given to patients with BRAF V600 mutation-positive melanoma, peak plasma concentration occurred 1.5 hours post-dose (Tmax). A single 2 mg oral dose has a bioavailability of 72%. When a dose of 2mg/day is given, the peak plasma concentration (Cmax) is 22.2 ng/mL.
Volume of distribution

Apparent volume of distribution (Vd/F) = 214 L

Protein binding97.4% bound to human plasma proteins.
Metabolism

Trametinib is metabolized predominantly via deacetylation alone or with mono-oxygenation or in combination with glucuronidation biotransformation pathways in vitro. Deacetylation is likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. The cytochrome P450 enzyme system is not involved with the metabolism of trametinib. The predominant circulating component in the plasma is the parent compound.

Route of elimination80% of the dose is excreted in the feces. <20% of the dose is excreted in the urine with <0.1% of the excreted dose in the form of the parent compound.
Half lifeElimination half-life = 3.9-4.8 days.
Clearance

Apparent clearance = 4.9 L/h.

ToxicityMost common adverse reactions (≥20%) for trametinib include rash, diarrhea, and lymphedema.
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 + 0.9733
Blood Brain Barrier + 0.8217
Caco-2 permeable - 0.5193
P-glycoprotein substrate Non-substrate 0.5945
P-glycoprotein inhibitor I Non-inhibitor 0.6449
P-glycoprotein inhibitor II Non-inhibitor 0.8622
Renal organic cation transporter Non-inhibitor 0.899
CYP450 2C9 substrate Non-substrate 0.7215
CYP450 2D6 substrate Non-substrate 0.8232
CYP450 3A4 substrate Substrate 0.5735
CYP450 1A2 substrate Non-inhibitor 0.8599
CYP450 2C9 substrate Non-inhibitor 0.5775
CYP450 2D6 substrate Non-inhibitor 0.9521
CYP450 2C19 substrate Non-inhibitor 0.8769
CYP450 3A4 substrate Non-inhibitor 0.836
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9337
Ames test AMES toxic 0.5498
Carcinogenicity Non-carcinogens 0.8078
Biodegradation Not ready biodegradable 1.0
Rat acute toxicity 2.3412 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9539
hERG inhibition (predictor II) Non-inhibitor 0.6602
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral0.5 mg, 1 mg, 2 mg
PricesNot Available
Patents
CountryPatent NumberApprovedExpires (estimated)
United States73784232013-05-292025-09-13
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
water solubility3.07e-02 g/lALOGPS
logP3.45ALOGPS
logP3.18ChemAxon
logS-4.3ALOGPS
pKa (strongest acidic)12.6ChemAxon
pKa (strongest basic)-3.7ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count5ChemAxon
hydrogen donor count2ChemAxon
polar surface area102.06ChemAxon
rotatable bond count5ChemAxon
refractivity156.38ChemAxon
polarizability55.43ChemAxon
number of rings5ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis ReferenceNot Available
General Reference
  1. Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23. Pubmed
External Links
ResourceLink
KEGG DrugD10175
RxListhttp://www.rxlist.com/mekinist-drug.htm
Drugs.comhttp://www.drugs.com/mekinist.html
WikipediaTrametinib
ATC CodesNot Available
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelshow(517 KB)
MSDSNot Available
Interactions
Drug InteractionsSearched, but no interactions found.
Food InteractionsNot Available

1. Dual specificity mitogen-activated protein kinase kinase 1

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Dual specificity mitogen-activated protein kinase kinase 1 Q02750 Details

References:

  1. FDA label
  2. Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23. Pubmed

2. Dual specificity mitogen-activated protein kinase kinase 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Dual specificity mitogen-activated protein kinase kinase 2 P36507 Details

References:

  1. FDA label
  2. Salama AK, Kim KB: Trametinib (GSK1120212) in the treatment of melanoma. Expert Opin Pharmacother. 2013 Apr;14(5):619-27. doi: 10.1517/14656566.2013.770475. Epub 2013 Feb 23. Pubmed

1. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. FDA label

2. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inducer

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. FDA label

Comments
Drug created on June 24, 2013 15:36 / Updated on September 16, 2013 18:11