Mitotane

Identification

Summary

Mitotane is an adrenal cortex inhibitor used to treat adrenocortical tumors and Cushing's syndrome.

Brand Names
Lysodren
Generic Name
Mitotane
DrugBank Accession Number
DB00648
Background

Mitotane is an adrenolytic isomer of the insecticide dichlorodiphenyldichloroethane (DDD) - itself a metabolite of dichlorodiphenyltrichloroethane (DDT) - that inhibits cells of the adrenal cortex and their production of hormones. It has been in use since 1959 for the treatment of inoperable adrenocortical carcinoma1 and is used off-label for the management of Cushing's syndrome.2

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 320.041
Monoisotopic: 317.953661148
Chemical Formula
C14H10Cl4
Synonyms
  • 1-chloro-2-[2,2-dichloro-1-(4-chlorophenyl)ethyl]-benzene
  • Mitotan
  • Mitotane
  • Mitotano
  • Mitotanum
  • o,p'-DDD
External IDs
  • CB 313
  • CB-313
  • NSC 38721

Pharmacology

Indication

Mitotane is indicated for the treatment of inoperable, functional or nonfunctional, adrenocortical carcinoma.4

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofCushing's syndrome••• •••••
Treatment ofInoperable adrenocortical carcinoma••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

The administration of mitotane alters the peripheral metabolism of steroids, leading to a reduction in plasma 17-hydroxycorticosteroids and an increase in 6-β-hydroxycortisol in addition to normal corticosteroid levels.4

Mechanism of action

The mechanism of action of mitotane 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.4 The specificity of mitotane towards the adrenal cortex may derive from the metabolic transformation to its active form via an enzyme system unique to the adrenal cortex tissue.1

TargetActionsOrganism
ACytochrome P450 11B1, mitochondrial
inducer
Humans
UEstrogen receptor alphaNot AvailableHumans
UProgesterone receptorNot AvailableHumans
UAndrogen receptor
antagonist
Humans
UAdrenodoxin, mitochondrial
unknown
Humans
Absorption

The bioavailability of mitotane following oral administration is 40%.4

Volume of distribution

Mitotane is extensively distributed and found in most tissues in the body.4 Fat is the primary site of distribution.4

Protein binding

6%

Metabolism

Mitotane undergoes extensive metabolism - both hepatic and extrahepatic - and no unchanged parent drug is excreted in the bile or urine.4 The major circulating metabolite of mitotane is 1,1-(o,p'-dichlorodiphenyl) acetic acid (o,p’-DDA).4

Hover over products below to view reaction partners

Route of elimination

Approximately 10% of an administered dose is recovered in the urine as water-soluble metabolites, with a varying amount of metabolite (1%-17%) excreted in the bile.4

Half-life

The plasma terminal half-life of mitotane ranges from 18 to 159 days, with a median of 53 days.4

Clearance

Not Available

Adverse Effects
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Toxicity

Overdosage with mitotane can occur when plasma levels are above 20 mg/L.4 Symptoms can include central nervous system toxicity, including sedation, lethargy, and vertigo, as well as muscular weakness and gait disturbance.4 Mitotane is lipophilic and may therefore take weeks to adequately clear from a patient. It is unlikely to be dialyzable. In the event of a suspected overdose, consider increasing the frequency of mitotane plasma level monitoring. Withhold mitotane as clinically indicated for signs or symptoms of toxicity.4

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe metabolism of 1,2-Benzodiazepine can be increased when combined with Mitotane.
AbemaciclibThe metabolism of Abemaciclib can be increased when combined with Mitotane.
AbirateroneThe metabolism of Abiraterone can be increased when combined with Mitotane.
AcalabrutinibThe metabolism of Acalabrutinib can be increased when combined with Mitotane.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Mitotane.
Food Interactions
  • Take with food. The timing of mitotane administration relative to food intake should remain consistent. Co-administration with high-fat food enhances absorption.

Products

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International/Other Brands
Lisodren (Bristol-Myers Squibb) / Opeprim (Yakult Honsha)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LysodrenTablet500 mg/1OralE.R. Squibb & Sons, L.L.C.2009-06-012021-03-31US flag
LysodrenTablet500 mgOralHRA Pharma Rare Diseases2016-09-08Not applicableEU flag
LysodrenTablet500 mgOralHRA Pharma Rare Diseases1979-12-31Not applicableCanada flag
LysodrenTablet500 mg/1OralHRA Pharma Rare Diseases1978-10-15Not applicableUS flag

Categories

ATC Codes
L01XX23 — Mitotane
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
Alkyl chloride / Alkyl halide / Aromatic homomonocyclic compound / Aryl chloride / Aryl halide / Chlorobenzene / Diphenylmethane / Halobenzene / Hydrocarbon derivative / Organochloride
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans

Chemical Identifiers

UNII
78E4J5IB5J
CAS number
53-19-0
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

References

General References
  1. Waszut U, Szyszka P, Dworakowska D: Understanding mitotane mode of action. J Physiol Pharmacol. 2017 Feb;68(1):13-26. [Article]
  2. Broersen LHA, Jha M, Biermasz NR, Pereira AM, Dekkers OM: Effectiveness of medical treatment for Cushing's syndrome: a systematic review and meta-analysis. Pituitary. 2018 Dec;21(6):631-641. doi: 10.1007/s11102-018-0897-z. [Article]
  3. FDA Approved Drug Products: LYSODREN (mitotane) tablets [Link]
  4. FDA Approved Drug Products: Lysodren (mitotane) tablets for oral use (January 2024) [Link]
  5. Cayman Chemical: Mitotane MSDS [Link]
Human Metabolome Database
HMDB0014786
KEGG Drug
D00420
PubChem Compound
4211
PubChem Substance
46508319
ChemSpider
4066
BindingDB
50239991
RxNav
7004
ChEBI
6954
ChEMBL
CHEMBL1670
Therapeutic Targets Database
DAP000033
PharmGKB
PA164746157
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Mitotane
MSDS
Download (57 KB)

Clinical Trials

Clinical Trials

Pharmacoeconomics

Manufacturers
  • Bristol myers squibb
Packagers
  • B&B Pharmaceuticals
  • Bristol-Myers Squibb Co.
  • Mead Johnson and Co.
Dosage Forms
FormRouteStrength
TabletOral500 mg
TabletOral500 mg/1
Prices
Unit descriptionCostUnit
Mitotane powder7.75USD g
Lysodren 500 mg tablet5.13USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)77 °CPhysProp
water solubility0.1 mg/L (at 25 °C)BIGGAR,JW & RIGGS,RI (1974)
logP6Not Available
logS-6.51ADME Research, USCD
Predicted Properties
PropertyValueSource
Water Solubility9.42e-06 mg/mLALOGPS
logP6.08ALOGPS
logP6.11Chemaxon
logS-7.5ALOGPS
Physiological Charge0Chemaxon
Hydrogen Acceptor Count0Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area0 Å2Chemaxon
Rotatable Bond Count3Chemaxon
Refractivity79.97 m3·mol-1Chemaxon
Polarizability29.93 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterNoChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9942
Blood Brain Barrier+0.9905
Caco-2 permeable+0.8815
P-glycoprotein substrateNon-substrate0.8053
P-glycoprotein inhibitor INon-inhibitor0.9004
P-glycoprotein inhibitor IINon-inhibitor0.988
Renal organic cation transporterNon-inhibitor0.7959
CYP450 2C9 substrateNon-substrate0.7899
CYP450 2D6 substrateNon-substrate0.818
CYP450 3A4 substrateNon-substrate0.7045
CYP450 1A2 substrateInhibitor0.9542
CYP450 2C9 inhibitorInhibitor0.7241
CYP450 2D6 inhibitorNon-inhibitor0.9349
CYP450 2C19 inhibitorInhibitor0.8993
CYP450 3A4 inhibitorNon-inhibitor0.8629
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8
Ames testNon AMES toxic0.9751
CarcinogenicityNon-carcinogens0.575
BiodegradationNot ready biodegradable0.9596
Rat acute toxicity2.1911 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9221
hERG inhibition (predictor II)Non-inhibitor0.875
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Download (8.84 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0019-3190000000-3e8980db36b0ac7be7c9
GC-MS Spectrum - GC-EI-QGC-MSsplash10-000i-2590000000-2d3f8090ffa4733bf9ee
Mass Spectrum (Electron Ionization)MSsplash10-000i-2690000000-770065ddc57899130a31
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-014i-0039000000-3c403b01150c1ceb1813
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-00lr-0094000000-b713f6e04e24f00d8ab5
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0159-0059000000-61b46f0f6d9ad83ae2fe
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0fsi-9067000000-e67c2578372634c1b1d7
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0079-0590000000-1e2bb7506c8412039460
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9000000000-a7d4833fca6712e5a794
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-152.3858332
predicted
DarkChem Lite v0.1.0
[M-H]-157.19704
predicted
DeepCCS 1.0 (2019)
[M+H]+159.55504
predicted
DeepCCS 1.0 (2019)
[M+Na]+165.64818
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
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
  1. 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. [Article]
Kind
Protein
Organism
Humans
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
  1. 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. [Article]
Kind
Protein
Organism
Humans
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
  1. 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. [Article]
Kind
Protein
Organism
Humans
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
  1. 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. [Article]
Kind
Protein
Organism
Humans
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
  1. 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. [Article]
  2. 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. [Article]
  3. 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. [Article]

Enzymes

Kind
Protein
Organism
Humans
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
References
  1. FDA Approved Drug Products: Lysodren (mitotane) tablets for oral use (January 2024) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
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
  1. FDA Approved Drug Products: Lysodren (mitotane) tablets for oral use (January 2024) [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
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
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. FDA Approved Drug Products: Lysodren (mitotane) tablets for oral use (January 2024) [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Upregulator
General Function
Serine-type endopeptidase inhibitor activity
Specific Function
Major thyroid hormone transport protein in serum.
Gene Name
SERPINA7
Uniprot ID
P05543
Uniprot Name
Thyroxine-binding globulin
Molecular Weight
46324.12 Da
References
  1. FDA Approved Drug Products: Cytomel (liothyronine sodium) oral tablets [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Upregulator
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
  1. 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. [Article]
  2. van Seters AP, Moolenaar AJ: Mitotane increases the blood levels of hormone-binding proteins. Acta Endocrinol (Copenh). 1991 May;124(5):526-33. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Upregulator
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
  1. 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. [Article]
  2. 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. [Article]

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
References
  1. Gagliano T, Gentilin E, Benfini K, Di Pasquale C, Tassinari M, Falletta S, Feo C, Tagliati F, Uberti ED, Zatelli MC: Mitotane enhances doxorubicin cytotoxic activity by inhibiting P-gp in human adrenocortical carcinoma cells. Endocrine. 2014 Dec;47(3):943-51. doi: 10.1007/s12020-014-0374-z. Epub 2014 Aug 6. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48