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.

Structure

Similar Structures

Synonyms

Mitotan
Mitotane
Mitotano
Mitotanum

External IDs

CB 313 / CB-313 / NSC 38721

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Lysodren	Tablet	500 mg/1	Oral	E.R. Squibb & Sons, L.L.C.	2009-06-01	2021-03-31
Lysodren	Tablet	500 mg	Oral	Laboratoire HRA Pharma	2004-04-28	Not applicable
Lysodren	Tablet	500 mg	Oral	Bristol Myers Squibb	1979-12-31	Not applicable
Lysodren	Tablet	500 mg/1	Oral	Laboratoire HRA Pharma	2009-01-06	Not applicable

International/Other Brands

Lisodren (Bristol-Myers Squibb) / 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.

Target	Actions	Organism
ACytochrome P450 11B1, mitochondrial	inducer	Humans
UAdrenodoxin, mitochondrial	unknown	Humans
UEstrogen receptor alpha	Not Available	Humans
UProgesterone receptor	Not Available	Humans
UAndrogen receptor	antagonist	Humans

Absorption

About 40% oral Lysodren is absorbed

Volume of distribution

Not Available

Protein binding

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.
7-ethyl-10-hydroxycamptothecin	The metabolism of 7-ethyl-10-hydroxycamptothecin can be increased when combined with Mitotane.
9-aminocamptothecin	The metabolism of 9-aminocamptothecin 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.

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/1
Tablet	Oral	500 mg

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

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

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

Details1. Cytochrome P450 11B1, mitochondrial

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

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]

Details2. Adrenodoxin, mitochondrial

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

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]

Details3. Estrogen receptor alpha

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

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]

Details4. Progesterone receptor

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

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]

Details5. Androgen receptor

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

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

Details1. Cytochrome P450 3A4

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

Carriers

Details1. Sex hormone-binding globulin

Kind: Protein
Organism: Humans
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]

Details2. Corticosteroid-binding globulin

Kind: Protein
Organism: Humans
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]

Details3. Thyroxine-binding globulin

Kind: Protein
Organism: Humans
Pharmacological action: No
Actions: Inducer

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

CYTOMEL (liothyronine) FDA label [File]

Drug created on June 13, 2005 07:24 / Updated on April 22, 2019 17:13

Mitotane

Identification

Structure for Mitotane (DB00648)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

References

References

References

References

Enzymes

Carriers

References

References

References