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Identification
NameTrametinib
Accession NumberDB08911
TypeSmall Molecule
GroupsApproved
DescriptionTrametinib 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
GSK 1120212
JTP 74057
Trametinib Dimethyl Sulfoxide
Trametinibum
External Identifiers
  • GSK1120212
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Mekinisttablet1 mgoralNovartis Pharmaceuticals Canada IncNot applicableNot applicableCanada
Mekinisttablet, film coated2 mg/1oralGlaxo Smith Kline Llc2013-06-17Not applicableUs
MekinistFilm-coated tablet2 mgOral useNovartis Europharm Limited2014-06-30Not applicableEu
Mekinisttablet, film coated2 mg/1oralNovartis Pharmaceuticals Corporation2016-03-17Not applicableUs
MekinistFilm-coated tablet0.5 mgOral useNovartis Europharm Limited2014-06-30Not applicableEu
Mekinisttablet, film coated.5 mg/1oralGlaxo Smith Kline Llc2013-06-17Not applicableUs
Mekinisttablet0.5 mgoralNovartis Pharmaceuticals Canada Inc2013-08-28Not applicableCanada
MekinistFilm-coated tablet0.5 mgOral useNovartis Europharm Limited2014-06-30Not applicableEu
Mekinisttablet, film coated1 mg/1oralGlaxo Smith Kline Llc2013-06-172015-12-29Us
Mekinisttablet2 mgoralNovartis Pharmaceuticals Canada Inc2013-08-28Not applicableCanada
MekinistFilm-coated tablet2 mgOral useNovartis Europharm Limited2014-06-30Not applicableEu
Mekinisttablet, film coated.5 mg/1oralNovartis Pharmaceuticals Corporation2016-03-17Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII33E86K87QN
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as pyridopyrimidines. These are compounds containing a pyridopyrimidine, which consists of a pyridine fused to a pyrimidine. Pyridine is 6-membered ring consisting of five carbon atoms and a nitrogen atom. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPyridopyrimidines
Sub ClassNot Available
Direct ParentPyridopyrimidines
Alternative Parents
Substituents
  • N-arylamide
  • Pyridopyrimidine
  • Acetanilide
  • Methylpyridine
  • Pyrimidone
  • Pyridinone
  • Iodobenzene
  • Halobenzene
  • Fluorobenzene
  • Aminopyridine
  • Benzenoid
  • Pyrimidine
  • Pyridine
  • Monocyclic benzene moiety
  • Aryl iodide
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Acetamide
  • Vinylogous amide
  • Urea
  • Secondary carboxylic acid amide
  • Lactam
  • Carboxamide group
  • Azacycle
  • Secondary amine
  • Carboxylic acid derivative
  • Carboxylic acid amide
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organoiodide
  • Organofluoride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption+0.9733
Blood Brain Barrier+0.8217
Caco-2 permeable-0.5193
P-glycoprotein substrateNon-substrate0.5945
P-glycoprotein inhibitor INon-inhibitor0.6449
P-glycoprotein inhibitor IINon-inhibitor0.8622
Renal organic cation transporterNon-inhibitor0.899
CYP450 2C9 substrateNon-substrate0.7215
CYP450 2D6 substrateNon-substrate0.8232
CYP450 3A4 substrateSubstrate0.5735
CYP450 1A2 substrateNon-inhibitor0.8599
CYP450 2C9 inhibitorNon-inhibitor0.5775
CYP450 2D6 inhibitorNon-inhibitor0.9521
CYP450 2C19 inhibitorNon-inhibitor0.8769
CYP450 3A4 inhibitorNon-inhibitor0.836
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9337
Ames testAMES toxic0.5498
CarcinogenicityNon-carcinogens0.8078
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.3412 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9539
hERG inhibition (predictor II)Non-inhibitor0.6602
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Film-coated tabletOral use0.5 mg
Film-coated tabletOral use2 mg
Tabletoral0.5 mg
Tabletoral1 mg
Tabletoral2 mg
Tablet, film coatedoral.5 mg/1
Tablet, film coatedoral1 mg/1
Tablet, film coatedoral2 mg/1
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7378423 No2005-09-132025-09-13Us
US8580304 No2012-01-282032-01-28Us
US8703781 No2010-10-152030-10-15Us
US8835443 No2005-09-132025-09-13Us
US9155706 No2012-01-282032-01-28Us
US9271941 No2012-01-282032-01-28Us
Properties
StateSolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.0307 mg/mLALOGPS
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 Area102.06 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity156.38 m3·mol-1ChemAxon
Polarizability55.43 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  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:23432625 ]
External Links
ATC CodesL01XE25
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (517 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Trametinib.
AmodiaquineThe serum concentration of Amodiaquine can be increased when it is combined with Trametinib.
AripiprazoleThe serum concentration of Aripiprazole can be decreased when it is combined with Trametinib.
BevacizumabBevacizumab may increase the cardiotoxic activities of Trametinib.
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Trametinib.
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Trametinib.
DabrafenibThe risk or severity of adverse effects can be increased when Trametinib is combined with Dabrafenib.
DeslanosideDeslanoside may decrease the cardiotoxic activities of Trametinib.
DigitoxinDigitoxin may decrease the cardiotoxic activities of Trametinib.
DigoxinDigoxin may decrease the cardiotoxic activities of Trametinib.
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Trametinib.
HydrocodoneThe serum concentration of Hydrocodone can be decreased when it is combined with Trametinib.
NimodipineThe serum concentration of Nimodipine can be decreased when it is combined with Trametinib.
NintedanibThe serum concentration of Nintedanib can be decreased when it is combined with Trametinib.
OuabainOuabain may decrease the cardiotoxic activities of Trametinib.
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Trametinib.
SaxagliptinThe serum concentration of Saxagliptin can be decreased when it is combined with Trametinib.
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Trametinib.
Food Interactions
  • When taken with a high-fat, high-calorie meal, AUC and Cmax decreased. Tmax was also prolonged compared to fasted conditions.

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Receptor signaling protein tyrosine phosphatase activity
Specific Function:
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Binding of extracellular ligands such as growth factors, cytokines and hormones to their cell-surface receptors activates RAS and this initiates RAF1 activation. RAF1 then further activates the dual-specificity protein kinases MAP2K1/MEK1 and MAP2K2/MEK2. Both MAP2K1/MEK1 and MAP2...
Gene Name:
MAP2K1
Uniprot ID:
Q02750
Molecular Weight:
43438.65 Da
References
  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:23432625 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Scaffold protein binding
Specific Function:
Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in a Thr-Glu-Tyr sequence located in MAP kinases. Activates the ERK1 and ERK2 MAP kinases (By similarity).
Gene Name:
MAP2K2
Uniprot ID:
P36507
Molecular Weight:
44423.735 Da
References
  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:23432625 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. In the epoxidation of arachidonic acid it generates only 14,15- and 11,12-cis-epoxyeicosatrienoic acids. It is the principal enzyme...
Gene Name:
CYP2C8
Uniprot ID:
P10632
Molecular Weight:
55824.275 Da
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
Comments
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Drug created on June 24, 2013 15:36 / Updated on September 26, 2016 02:49