Identification

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
Thumb
Synonyms
  • Mitotan
  • Mitotane
  • Mitotano
  • Mitotanum
  • Piprine-DDD, O-
External IDs
CB 313 / NSC 38721
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LysodrenTablet500 mg/1OralLaboratoire HRA Pharma2009-01-06Not applicableUs
LysodrenTablet500 mgOralBristol Myers Squibb1979-12-31Not applicableCanada
LysodrenTablet500 mg/1OralE.R. Squibb & Sons, L.L.C.2009-06-012021-03-31Us
LysodrenTablet500 mgOralLaboratoire HRA Pharma2004-04-28Not applicableEu
International/Other Brands
Lisodren (Bristol-Myers Squibb) / Lysodren / Opeprim (Yakult Honsha)
Categories
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.

TargetActionsOrganism
ACytochrome P450 11B1, mitochondrial
inducer
Human
UAdrenodoxin, mitochondrial
unknown
Human
UEstrogen receptor alphaNot AvailableHuman
UProgesterone receptorNot AvailableHuman
UAndrogen receptor
antagonist
Human
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
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be increased when combined with Mitotane.
(S)-WarfarinThe metabolism of (S)-Warfarin can be increased when combined with Mitotane.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be increased when combined with Mitotane.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be increased when combined with Mitotane.
5-androstenedioneThe metabolism of 5-androstenedione can be increased when combined with Mitotane.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine 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.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Mitotane.
AcenocoumarolThe 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
PhaseStatusPurposeConditionsCount
1CompletedTreatmentProstate Cancer1
2TerminatedTreatmentRecurrent Adrenocortical Carcinoma / Stage III Adrenocortical Carcinoma / Stage IV Adrenocortical Carcinoma1
3Active Not RecruitingTreatmentStage I Adrenocortical Carcinoma / Stage II Adrenocortical Carcinoma / Stage III Adrenocortical Carcinoma / Stage IV Adrenocortical Carcinoma1
3CompletedTreatmentCarcinoma, Adrenal Cortical1
3RecruitingTreatmentENSAT Stage I Adrenal Cortex Carcinoma / ENSAT Stage II Adrenal Cortex Carcinoma / ENSAT Stage III Adrenal Cortex Carcinoma1
3Unknown StatusTreatmentAdrenocortical Carcinoma1

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-MSNot Available
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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot 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
  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. [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
  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. [PubMed:3770229]
  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. [PubMed:11159707]
  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. [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
  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. [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
  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. [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
  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. [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
  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. [PubMed:16551731]
  2. 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
  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. [PubMed:16551731]
  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. [PubMed:5520073]

Drug created on June 13, 2005 07:24 / Updated on October 23, 2018 21:48