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IdentificationPharmacologyInteractionsReferencesTrialsEconomicsPropertiesSpectraTaxonomyIdentification
- Name
- Mitotane
- Accession Number
- DB00648 (APRD00494)
- Type
- Small Molecule
- Groups
- Approved
- Description
A derivative of the insecticide dichlorodiphenyldichloroethane that specifically inhibits cells of the adrenal cortex and their production of hormones. It is used to treat adrenocortical tumors and causes CNS damage, but no bone marrow depression. [PubChem]
- Structure
Structure for Mitotane (DB00648)
- Synonyms
- Mitotan
- Mitotane
- Mitotano
- Mitotanum
- Piprine-DDD, O-
- External IDs
- CB 313 / NSC 38721
- Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Lysodren Tablet 500 mg/1 Oral Laboratoire HRA Pharma 2009-01-06 Not applicable US 
Lysodren Tablet 500 mg Oral Bristol Myers Squibb 1979-12-31 Not applicable Canada 
Lysodren Tablet 500 mg/1 Oral E.R. Squibb & Sons, L.L.C. 2009-06-01 2021-03-31 US Lysodren Tablet 500 mg Oral Laboratoire HRA Pharma 2004-04-28 Not applicable EU 
- International/Other Brands
- Lisodren (Bristol-Myers Squibb) / Lysodren / Opeprim (Yakult Honsha)
- Categories
- Antineoplastic Agents
- Antineoplastic Agents, Hormonal
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP3A Inducers
- Cytochrome P-450 CYP3A Inducers (strong)
- Cytochrome P-450 CYP3A4 Inducers
- Cytochrome P-450 CYP3A4 Inducers (strong)
- Cytochrome P-450 Enzyme Inducers
- Cytochrome P450 3A4 Inducers
- Hydrocarbons, Chlorinated
- Hydrocarbons, Halogenated
- P-glycoprotein/ABCB1 Inhibitors
- UNII
- 78E4J5IB5J
- CAS number
- 53-19-0
- Weight
- Average: 320.041
Monoisotopic: 317.953661148 - Chemical Formula
- C14H10Cl4
- InChI Key
- JWBOIMRXGHLCPP-UHFFFAOYSA-N
- InChI
- InChI=1S/C14H10Cl4/c15-10-7-5-9(6-8-10)13(14(17)18)11-3-1-2-4-12(11)16/h1-8,13-14H
- IUPAC Name
- 1-chloro-4-[2,2-dichloro-1-(2-chlorophenyl)ethyl]benzene
- SMILES
- ClC(Cl)C(C1=CC=C(Cl)C=C1)C1=CC=CC=C1Cl
Pharmacology
- Indication
For treatment of inoperable adrenocortical tumours; Cushing's syndrome
- Associated Conditions
- Pharmacodynamics
Mitotane is an oral chemotherapeutic agent indicated in the treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional types. Mitotane can best be described as an adrenal cytotoxic agent, although it can cause adrenal inhibition, apparently without cellular destruction. The administration of Mitotane alters the extra-adrenal metabolism of cortisol in man; leading to a reduction in measurable 17-hydroxy corticosteroids, even though plasma levels of corticosteroids do not fall. The drug apparently causes increased formation of 6-B-hydroxyl cortisol.
- Mechanism of action
Its biochemical mechanism of action is unknown, although data are available to suggest that the drug modifies the peripheral metabolism of steroids as well as directly suppressing the adrenal cortex.
Target Actions Organism ACytochrome P450 11B1, mitochondrial inducerHuman UAdrenodoxin, mitochondrial unknownHuman UEstrogen receptor alpha Not Available Human UProgesterone receptor Not Available Human UAndrogen receptor antagonistHuman - Absorption
About 40% oral Lysodren is absorbed
- Volume of distribution
- Not Available
- Protein binding
6%
- Metabolism
Hepatic and renal
- Route of elimination
A variable amount of metabolite (1%-17%) is excreted in the bile and the balance is apparently stored in the tissues.
- Half life
18-159 days
- Clearance
- Not Available
- Toxicity
- Not Available
- 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 Mitotane. (S)-Warfarin The metabolism of (S)-Warfarin can be increased when combined with Mitotane. 3,5-diiodothyropropionic acid The metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Mitotane. 4-hydroxycoumarin The metabolism of 4-hydroxycoumarin can be increased when combined with Mitotane. 5-androstenedione The metabolism of 5-androstenedione can be increased when combined with Mitotane. 6-O-benzylguanine The metabolism of 6-O-benzylguanine can be increased when combined with Mitotane. Abemaciclib The metabolism of Abemaciclib can be increased when combined with Mitotane. Abiraterone The metabolism of Abiraterone can be increased when combined with Mitotane. Acebutolol The serum concentration of Acebutolol can be increased when it is combined with Mitotane. Acenocoumarol The metabolism of Acenocoumarol can be increased when combined with Mitotane. - Food Interactions
- Take without regard to meals.
References
- General References
- Not Available
- External Links
- Human Metabolome Database
- HMDB0014786
- KEGG Drug
- D00420
- PubChem Compound
- 4211
- PubChem Substance
- 46508319
- ChemSpider
- 4066
- ChEBI
- 6954
- ChEMBL
- CHEMBL1670
- Therapeutic Targets Database
- DAP000033
- PharmGKB
- PA164746157
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Mitotane
- ATC Codes
- L01XX23 — Mitotane
- AHFS Codes
- 10:00.00 — Antineoplastic Agents
- MSDS
- Download (57 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 1 Completed Treatment Prostate Cancer 1 2 Terminated Treatment Recurrent Adrenocortical Carcinoma / Stage III Adrenocortical Carcinoma / Stage IV Adrenocortical Carcinoma 1 3 Active Not Recruiting Treatment Stage I Adrenocortical Carcinoma / Stage II Adrenocortical Carcinoma / Stage III Adrenocortical Carcinoma / Stage IV Adrenocortical Carcinoma 1 3 Completed Treatment Carcinoma, Adrenal Cortical 1 3 Recruiting Treatment ENSAT Stage I Adrenal Cortex Carcinoma / ENSAT Stage II Adrenal Cortex Carcinoma / ENSAT Stage III Adrenal Cortex Carcinoma 1 3 Unknown Status Treatment Adrenocortical Carcinoma 1
Pharmacoeconomics
- Manufacturers
- Bristol myers squibb
- Packagers
- B&B Pharmaceuticals
- Bristol-Myers Squibb Co.
- Mead Johnson and Co.
- Dosage forms
Form Route Strength Tablet Oral 500 mg Tablet Oral 500 mg/1 - Prices
Unit description Cost Unit Mitotane powder 7.75USD g Lysodren 500 mg tablet 5.13USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 77 °C PhysProp water solubility 0.1 mg/L (at 25 °C) BIGGAR,JW & RIGGS,RI (1974) logP 6 Not Available logS -6.51 ADME Research, USCD - Predicted Properties
Property Value Source Water Solubility 9.42e-06 mg/mL ALOGPS logP 6.08 ALOGPS logP 6.11 ChemAxon logS -7.5 ALOGPS Physiological Charge 0 ChemAxon Hydrogen Acceptor Count 0 ChemAxon Hydrogen Donor Count 0 ChemAxon Polar Surface Area 0 Å2 ChemAxon Rotatable Bond Count 3 ChemAxon Refractivity 79.97 m3·mol-1 ChemAxon Polarizability 29.93 Å3 ChemAxon Number of Rings 2 ChemAxon Bioavailability 1 ChemAxon Rule of Five No ChemAxon Ghose Filter No ChemAxon Veber's Rule Yes ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
Property Value Probability Human Intestinal Absorption + 0.9942 Blood Brain Barrier + 0.9905 Caco-2 permeable + 0.8815 P-glycoprotein substrate Non-substrate 0.8053 P-glycoprotein inhibitor I Non-inhibitor 0.9004 P-glycoprotein inhibitor II Non-inhibitor 0.988 Renal organic cation transporter Non-inhibitor 0.7959 CYP450 2C9 substrate Non-substrate 0.7899 CYP450 2D6 substrate Non-substrate 0.818 CYP450 3A4 substrate Non-substrate 0.7045 CYP450 1A2 substrate Inhibitor 0.9542 CYP450 2C9 inhibitor Inhibitor 0.7241 CYP450 2D6 inhibitor Non-inhibitor 0.9349 CYP450 2C19 inhibitor Inhibitor 0.8993 CYP450 3A4 inhibitor Non-inhibitor 0.8629 CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.8 Ames test Non AMES toxic 0.9751 Carcinogenicity Non-carcinogens 0.575 Biodegradation Not ready biodegradable 0.9596 Rat acute toxicity 2.1911 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9221 hERG inhibition (predictor II) Non-inhibitor 0.875
Spectra
- Mass Spec (NIST)
- Download (8.84 KB)
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available GC-MS Spectrum - GC-EI-Q GC-MS splash10-000i-2590000000-2d3f8090ffa4733bf9ee Mass Spectrum (Electron Ionization) MS splash10-000i-2690000000-770065ddc57899130a31 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 1H NMR Spectrum 1D NMR Not Applicable 13C NMR Spectrum 1D NMR Not Applicable
Taxonomy
- Description
- This compound belongs to the class of organic compounds known as diphenylmethanes. These are compounds containing a diphenylmethane moiety, which consists of a methane wherein two hydrogen atoms are replaced by two phenyl groups.
- Kingdom
- Organic compounds
- Super Class
- Benzenoids
- Class
- Benzene and substituted derivatives
- Sub Class
- Diphenylmethanes
- Direct Parent
- Diphenylmethanes
- Alternative Parents
- Chlorobenzenes / Aryl chlorides / Organochlorides / Hydrocarbon derivatives / Alkyl chlorides
- Substituents
- Diphenylmethane / Halobenzene / Chlorobenzene / Aryl halide / Aryl chloride / Hydrocarbon derivative / Organochloride / Organohalogen compound / Alkyl halide / Alkyl chloride
- Molecular Framework
- Aromatic homomonocyclic compounds
- External Descriptors
- Not Available
Targets
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Yes
- Actions
- Inducer
- General Function
- Steroid 11-beta-monooxygenase activity
- Specific Function
- Has steroid 11-beta-hydroxylase activity. In addition to this activity, the 18 or 19-hydroxylation of steroids and the aromatization of androstendione to estrone have also been ascribed to cytochro...
- Gene Name
- CYP11B1
- Uniprot ID
- P15538
- Uniprot Name
- Cytochrome P450 11B1, mitochondrial
- Molecular Weight
- 57572.44 Da
References
- Lindhe O, Skogseid B, Brandt I: Cytochrome P450-catalyzed binding of 3-methylsulfonyl-DDE and o,p'-DDD in human adrenal zona fasciculata/reticularis. J Clin Endocrinol Metab. 2002 Mar;87(3):1319-26. [PubMed:11889204]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Unknown
- General Function
- Iron ion binding
- Specific Function
- Participates in the synthesis of thyroid hormones. Essential for the synthesis of various steroid hormones, participates in the reduction of mitochondrial cytochrome P450 for steroidogenesis. Trans...
- Gene Name
- FDX1
- Uniprot ID
- P10109
- Uniprot Name
- Adrenodoxin, mitochondrial
- Molecular Weight
- 19392.475 Da
References
- Kandul SV, Iatsyk MI, Kononenko VIa: [Comparative study of the effect of chloditan on the concentration of cytochrome P-450 and adrenodoxin in various organs of the dog and rat]. Fiziol Zh. 1986 Sep-Oct;32(5):579-84. [PubMed:3770229]
- Cabrini DA, Campos MM, Tratsk KS, Merino VF, Silva JA Jr, Souza GE, Avellar MC, Pesquero JB, Calixto JB: Molecular and pharmacological evidence for modulation of kinin B(1) receptor expression by endogenous glucocorticoids hormones in rats. Br J Pharmacol. 2001 Jan;132(2):567-77. [PubMed:11159707]
- Cai W, Counsell RE, Schteingart DE, Sinsheimer JE, Vaz AD, Wotring LL: Adrenal proteins bound by a reactive intermediate of mitotane. Cancer Chemother Pharmacol. 1997;39(6):537-40. [PubMed:9118466]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- General Function
- Zinc ion binding
- Specific Function
- Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissu...
- Gene Name
- ESR1
- Uniprot ID
- P03372
- Uniprot Name
- Estrogen receptor
- Molecular Weight
- 66215.45 Da
References
- Scippo ML, Argiris C, Van De Weerdt C, Muller M, Willemsen P, Martial J, Maghuin-Rogister G: Recombinant human estrogen, androgen and progesterone receptors for detection of potential endocrine disruptors. Anal Bioanal Chem. 2004 Feb;378(3):664-9. Epub 2003 Oct 25. [PubMed:14579009]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- General Function
- Zinc ion binding
- Specific Function
- The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor ...
- Gene Name
- PGR
- Uniprot ID
- P06401
- Uniprot Name
- Progesterone receptor
- Molecular Weight
- 98979.96 Da
References
- Scippo ML, Argiris C, Van De Weerdt C, Muller M, Willemsen P, Martial J, Maghuin-Rogister G: Recombinant human estrogen, androgen and progesterone receptors for detection of potential endocrine disruptors. Anal Bioanal Chem. 2004 Feb;378(3):664-9. Epub 2003 Oct 25. [PubMed:14579009]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- Actions
- Antagonist
- 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
References
- Maness SC, McDonnell DP, Gaido KW: Inhibition of androgen receptor-dependent transcriptional activity by DDT isomers and methoxychlor in HepG2 human hepatoma cells. Toxicol Appl Pharmacol. 1998 Jul;151(1):135-42. [PubMed:9705896]
Enzymes
- 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 react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
Carriers
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- General Function
- Androgen binding
- Specific Function
- Functions as an androgen transport protein, but may also be involved in receptor mediated processes. Each dimer binds one molecule of steroid. Specific for 5-alpha-dihydrotestosterone, testosterone...
- Gene Name
- SHBG
- Uniprot ID
- P04278
- Uniprot Name
- Sex hormone-binding globulin
- Molecular Weight
- 43778.755 Da
References
- Nader N, Raverot G, Emptoz-Bonneton A, Dechaud H, Bonnay M, Baudin E, Pugeat M: Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J Clin Endocrinol Metab. 2006 Jun;91(6):2165-70. Epub 2006 Mar 21. [PubMed:16551731]
- van Seters AP, Moolenaar AJ: Mitotane increases the blood levels of hormone-binding proteins. Acta Endocrinol (Copenh). 1991 May;124(5):526-33. [PubMed:1903011]
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- Unknown
- General Function
- Steroid binding
- Specific Function
- Major transport protein for glucocorticoids and progestins in the blood of almost all vertebrate species.
- Gene Name
- SERPINA6
- Uniprot ID
- P08185
- Uniprot Name
- Corticosteroid-binding globulin
- Molecular Weight
- 45140.49 Da
References
- Nader N, Raverot G, Emptoz-Bonneton A, Dechaud H, Bonnay M, Baudin E, Pugeat M: Mitotane has an estrogenic effect on sex hormone-binding globulin and corticosteroid-binding globulin in humans. J Clin Endocrinol Metab. 2006 Jun;91(6):2165-70. Epub 2006 Mar 21. [PubMed:16551731]
- Tron'ko MD: [Effect of chlodithane (o,p'-DDD) on transcortin binding ability in Itsenko-Cushing's disease]. Fiziol Zh. 1970 Nov-Dec;16(6):844-5. [PubMed:5520073]
Drug created on June 13, 2005 07:24 / Updated on October 23, 2018 21:48