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IdentificationPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomyIdentification
- Name
- Enzalutamide
- Accession Number
- DB08899 (DB05094)
- Type
- Small Molecule
- Groups
- Approved
- Description
Enzalutamide is an androgen receptor inhibitor for the treatment of castration-resistant prostate cancer. FDA approved on August 31, 2012.
- Structure
Structure for Enzalutamide (DB08899)
- Synonyms
- Enzalutamida
- Enzalutamide
- External IDs
- MDV 3100 / MDV-3100 / MDV3100
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Xtandi Capsule 40 mg Oral Astellas Pharma Inc 2013-06-07 Not applicable Canada 
Xtandi Capsule 40 mg/1 Oral Astellas Pharma US, Inc. 2012-08-31 Not applicable US 
Xtandi Capsule 40 mg Oral Astellas Pharma Europe Bv 2013-06-21 Not applicable EU 
- Categories
- Androgen Receptor Antagonists
- Androgen Receptor Inhibitor
- Antiandrogens
- Antiandrogens, non-steroidal
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP2B6 Inhibitors
- Cytochrome P-450 CYP2C19 Inducers
- Cytochrome P-450 CYP2C19 Inducers (moderate)
- Cytochrome P-450 CYP2C8 Inhibitors
- Cytochrome P-450 CYP2C8 Inhibitors (moderate)
- Cytochrome P-450 CYP2C8 Substrates
- Cytochrome P-450 CYP2C9 Inducers
- Cytochrome P-450 CYP2C9 Inducers (moderate)
- Cytochrome P-450 CYP2C9 Substrates
- Cytochrome P-450 CYP2D6 Inducers
- Cytochrome P-450 CYP2D6 Inducers (moderate)
- Cytochrome P-450 CYP2D6 Inducers (weak)
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inducers (strong)
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strong)
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P-450 Enzyme Inhibitors
- Cytochrome P450 2C19 Inducers
- Cytochrome P450 2C9 Inducers
- Cytochrome P450 3A4 Inducers
- Endocrine Therapy
- Hormone Antagonists and Related Agents
- Hydantoins
- Imidazoles
- Imidazolidines
- P-glycoprotein/ABCB1 Inhibitors
- UNII
- 93T0T9GKNU
- CAS number
- 915087-33-1
- Weight
- Average: 464.436
Monoisotopic: 464.093009286 - Chemical Formula
- C21H16F4N4O2S
- InChI Key
- WXCXUHSOUPDCQV-UHFFFAOYSA-N
- InChI
- InChI=1S/C21H16F4N4O2S/c1-20(2)18(31)28(12-5-4-11(10-26)15(8-12)21(23,24)25)19(32)29(20)13-6-7-14(16(22)9-13)17(30)27-3/h4-9H,1-3H3,(H,27,30)
- IUPAC Name
- 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide
- SMILES
- CNC(=O)C1=C(F)C=C(C=C1)N1C(=S)N(C(=O)C1(C)C)C1=CC=C(C#N)C(=C1)C(F)(F)F
Pharmacology
- Indication
Enzalutamide is indicated for the treatment of patients with metastatic castration-resistant prostate cancer who have previously received docetaxel.
- Associated Conditions
- Pharmacodynamics
Resitance to enzalutamide therapy has been observed. This may occurred due to an upregulation of NF-κB2/p52.
- Mechanism of action
Enzalutamide is a competitive androgen receptor inhibitor that effects multiple stages of the signalling pathway. It is able to inhibit androgen binding to its receptor, androgen receptor nuclear translocation, and subsequent interaction with DNA. As a result, proliferation of prostate cancer cells decreases which ultimately leads to apoptosis and decreased tumour volume.
Target Actions Organism AAndrogen receptor inhibitorHumans - Absorption
The pharmacokinetic profile of enzalutamide and N-desmethyl enzalutamide (its major active metabolite) is described by a linear two-compartment model with first-order absorption. Enzalutamide also accumulates. Food does not affect its absorption. Tmax, prostate cancer patients = 1 hour (range of 0.5-3 hours); Cmax, steady state, enzalutamide = 16.6 μg/mL; Cmax, steady state, N-desmethyl enzalutamide = 12.7 μg/mL; Time to steady state, daily dosing = 28 days;
- Volume of distribution
Apparent volume of distribution (Vd/F), single oral dose = 110 L
- Protein binding
Enzalutamide is 97% to 98% bound to plasma proteins, primarily albumin. N-desmethyl enzalutamide is 95% bound to plasma proteins.
- Metabolism
Enzalutamide is hepatically metabolized, primarily by CYP2C8 and CYP3A4. The enzyme that converts enzalutamide to its active metabolite, N-desmethyl enzalutamide, is CYP2C8. The activity of N-desmethyl-enzalutamide is similar to that of the parent compound.
- Route of elimination
Enzalutamide is primarily eliminated by hepatic metabolism. 71% of the dose is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).
- Half life
The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days). Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8 to 8.6 days.
- Clearance
Apparent clearance (CL/F), single oral dose = 0.56 L/h (range of 0.33 - 1.02 L/h)
- Toxicity
The most common adverse reactions (≥ 5%) are asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.
- Affected organisms
- Humans and other mammals
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
Drug Interaction (R)-warfarin The metabolism of (R)-warfarin can be increased when combined with Enzalutamide. (S)-Warfarin The metabolism of (S)-Warfarin can be increased when combined with Enzalutamide. 3,5-diiodothyropropionic acid The metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Enzalutamide. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be increased when combined with Enzalutamide. 4-Methoxyamphetamine The metabolism of 4-Methoxyamphetamine can be increased when combined with Enzalutamide. 5-androstenedione The metabolism of 5-androstenedione can be increased when combined with Enzalutamide. 6-Deoxyerythronolide B The metabolism of Enzalutamide can be decreased when combined with 6-Deoxyerythronolide B. 6-O-benzylguanine The metabolism of 6-O-benzylguanine can be increased when combined with Enzalutamide. 7-ethyl-10-hydroxycamptothecin The metabolism of 7-ethyl-10-hydroxycamptothecin can be increased when combined with Enzalutamide. 9-aminocamptothecin The metabolism of 9-aminocamptothecin can be increased when combined with Enzalutamide. - Food Interactions
- Not Available
References
- General References
- Nadiminty N, Tummala R, Liu C, Yang J, Lou W, Evans CP, Gao AC: NF-kappaB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants. Mol Cancer Ther. 2013 Aug;12(8):1629-37. doi: 10.1158/1535-7163.MCT-13-0027. Epub 2013 May 22. [PubMed:23699654]
- External Links
- KEGG Drug
- D10218
- PubChem Compound
- 15951529
- PubChem Substance
- 175427141
- ChemSpider
- 13093347
- BindingDB
- 50425732
- ChEBI
- 68534
- ChEMBL
- CHEMBL1082407
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Enzalutamide
- ATC Codes
- L02BB04 — Enzalutamide
- AHFS Codes
- 10:00.00 — Antineoplastic Agents
- FDA label
- Download (393 KB)
- MSDS
- Download (89.7 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Capsule Oral 40 mg Capsule Oral 40 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) US8183274 No 2012-05-22 2026-05-15 US US9126941 No 2015-09-08 2026-05-15 US US7709517 No 2010-05-04 2027-08-13 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source water solubility Insoluble FDA label - Predicted Properties
Property Value Source Water Solubility 0.00136 mg/mL ALOGPS logP 3.75 ALOGPS logP 4.16 ChemAxon logS -5.5 ALOGPS pKa (Strongest Acidic) 13.05 ChemAxon pKa (Strongest Basic) -1.7 ChemAxon Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 3 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 76.44 Å2 ChemAxon Rotatable Bond Count 4 ChemAxon Refractivity 113.48 m3·mol-1 ChemAxon Polarizability 42.71 Å3 ChemAxon Number of Rings 3 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter Yes ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 0.9356 Blood Brain Barrier + 0.8514 Caco-2 permeable + 0.5219 P-glycoprotein substrate Non-substrate 0.7609 P-glycoprotein inhibitor I Inhibitor 0.6464 P-glycoprotein inhibitor II Inhibitor 0.5693 Renal organic cation transporter Non-inhibitor 0.899 CYP450 2C9 substrate Non-substrate 0.7447 CYP450 2D6 substrate Non-substrate 0.8061 CYP450 3A4 substrate Substrate 0.5589 CYP450 1A2 substrate Non-inhibitor 0.5613 CYP450 2C9 inhibitor Inhibitor 0.7126 CYP450 2D6 inhibitor Non-inhibitor 0.9148 CYP450 2C19 inhibitor Inhibitor 0.6882 CYP450 3A4 inhibitor Inhibitor 0.6184 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.6711 Ames test Non AMES toxic 0.683 Carcinogenicity Non-carcinogens 0.7232 Biodegradation Not ready biodegradable 1.0 Rat acute toxicity 2.4319 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9911 hERG inhibition (predictor II) Inhibitor 0.7079
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available MS/MS Spectrum - , positive LC-MS/MS splash10-014i-0321900000-b1c610c4a717fdea030e
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as phenylimidazolidines. These are polycyclic compounds containing an imidazoline substituted by a phenyl group.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Azolidines
- Sub Class
- Imidazolidines
- Direct Parent
- Phenylimidazolidines
- Alternative Parents
- Trifluoromethylbenzenes / 2-halobenzoic acids and derivatives / Alpha amino acids and derivatives / N-phenylthioureas / Benzamides / Benzoyl derivatives / Benzonitriles / Fluorobenzenes / Aryl fluorides / Imidazolidinones show 11 more
- Substituents
- Phenylimidazolidine / Alpha-amino acid or derivatives / Trifluoromethylbenzene / N-phenylthiourea / 2-halobenzoic acid or derivatives / Halobenzoic acid or derivatives / Benzamide / Benzoic acid or derivatives / Benzonitrile / Benzoyl show 29 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- benzamides, nitrile, imidazolidinone, monofluorobenzenes, (trifluoromethyl)benzenes, thiocarbonyl compound (CHEBI:68534)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Zinc ion binding
- Specific Function
- Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription ...
- Gene Name
- AR
- Uniprot ID
- P10275
- Uniprot Name
- Androgen receptor
- Molecular Weight
- 98987.9 Da
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInhibitor
- 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 un...
- Gene Name
- CYP2C8
- Uniprot ID
- P10632
- Uniprot Name
- Cytochrome P450 2C8
- Molecular Weight
- 55824.275 Da
References
- Backman JT, Filppula AM, Niemi M, Neuvonen PJ: Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacol Rev. 2016 Jan;68(1):168-241. doi: 10.1124/pr.115.011411. [PubMed:26721703]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInducer
- 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 react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, Mol R, Mordenti J, Ouatas T: Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet. 2015 Oct;54(10):1057-69. doi: 10.1007/s40262-015-0283-1. [PubMed:25929560]
- Enzalutamide FDA label [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- SubstrateInducer
- 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 un...
- Gene Name
- CYP2C9
- Uniprot ID
- P11712
- Uniprot Name
- Cytochrome P450 2C9
- Molecular Weight
- 55627.365 Da
References
- Golshayan AR, Antonarakis ES: Enzalutamide: an evidence-based review of its use in the treatment of prostate cancer. Core Evid. 2013;8:27-35. doi: 10.2147/CE.S34747. Epub 2013 Apr 4. [PubMed:23589709]
- Enzalutamide FDA label [File]
- Xtandi Monograph [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
- Gene Name
- CYP2C19
- Uniprot ID
- P33261
- Uniprot Name
- Cytochrome P450 2C19
- Molecular Weight
- 55930.545 Da
References
- Gibbons JA, de Vries M, Krauwinkel W, Ohtsu Y, Noukens J, van der Walt JS, Mol R, Mordenti J, Ouatas T: Pharmacokinetic Drug Interaction Studies with Enzalutamide. Clin Pharmacokinet. 2015 Oct;54(10):1057-69. doi: 10.1007/s40262-015-0283-1. [PubMed:25929560]
- Ezalutamide FDA label [File]
- Kind
- Protein
- Organism
- Humans
- 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 un...
- Gene Name
- CYP2B6
- Uniprot ID
- P20813
- Uniprot Name
- Cytochrome P450 2B6
- Molecular Weight
- 56277.81 Da
References
- Enzalutamide FDA Review [File]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inducer
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- Benoist GE, Hendriks RJ, Mulders PF, Gerritsen WR, Somford DM, Schalken JA, van Oort IM, Burger DM, van Erp NP: Pharmacokinetic Aspects of the Two Novel Oral Drugs Used for Metastatic Castration-Resistant Prostate Cancer: Abiraterone Acetate and Enzalutamide. Clin Pharmacokinet. 2016 Nov;55(11):1369-1380. doi: 10.1007/s40262-016-0403-6. [PubMed:27106175]
- Xtandi [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Oxygen binding
- 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 un...
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Xtandi monograph [File]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Toxic substance binding
- Specific Function
- 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 colloid...
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Serum albumin
- Molecular Weight
- 69365.94 Da
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
Drug created on June 04, 2013 23:12 / Updated on February 16, 2019 05:56