Mitotane

Mitotane, sold under the brand name Lysodren, is a steroidogenesis inhibitor and cytostatic antineoplastic medication which is used in the treatment of adrenocortical carcinoma and Cushing's syndrome.^[3][4][5][6] It is a derivative of the early insecticide DDT and an isomer of p,p'-DDDTooltip dichlorodiphenyldichloroethane (4,4'-dichlorodiphenyldichloroethane) and is also known as 2,4'-(dichlorodiphenyl)-2,2-dichloroethane (o,p'-DDD).^[7]

Mitotane

Clinical data
Trade names	Lysodren
Other names	1,1-(Dichlorodiphenyl)-2,2-dichloroethane; o,p'-DDD
AHFS/Drugs.com	Monograph
MedlinePlus	a608050
License data	US DailyMed: Mitotane
Routes of administration	By mouth
ATC code	L01XX23 (WHO)
Legal status
Legal status	CA: ℞-only[1] EU: Rx-only[2] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	40%
Protein binding	6%
Elimination half-life	18–159 days
Identifiers
IUPAC name (RS)-1-chloro-2-[2,2-dichloro-1-(4-chlorophenyl)-ethyl]-benzene
CAS Number	53-19-0 Y
PubChem CID	4211
IUPHAR/BPS	6957
DrugBank	DB00648 Y
ChemSpider	4066 Y
UNII	78E4J5IB5J
KEGG	D00420 Y
ChEMBL	ChEMBL1670 Y
CompTox Dashboard (EPA)	DTXSID9020372
ECHA InfoCard	100.000.152
Chemical and physical data
Formula	C14H10Cl4
Molar mass	320.03 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
Melting point	76 to 78 °C (169 to 172 °F)
SMILES Clc1ccccc1C(c2ccc(Cl)cc2)C(Cl)Cl
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 Y Key:JWBOIMRXGHLCPP-UHFFFAOYSA-N Y
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Medical uses

Mitotane has been produced by Bristol Myers Squibb but it is marketed as an orphan drug for adrenocortical carcinoma due to the small number of patients in need of it. Its main use is in those patients who have persistent disease despite surgical resection, those who are not surgical candidates, or those who have metastatic disease. In a 2007 retrospective study of 177 patients from 1985 to 2005 showed a significant increase in the recurrence-free interval after radical surgery followed by mitotane when compared to surgery alone.^[8] The drug is also sometimes used in the treatment of Cushing's syndrome.^[5]

Side effects

The use of mitotane is unfortunately limited by side effects,^[9] which, as reported by Schteingart et al., include anorexia and nausea (88%), diarrhea (38%), vomiting (23%), decreased memory and ability to concentrate (50%), rash (23%), gynecomastia (50%), arthralgia (19%), and leukopenia (7%).^[10]

Pharmacology

Pharmacodynamics

Mitotane is an inhibitor of the adrenal cortex. It acts as an inhibitor of cholesterol side-chain cleavage enzyme (P450scc, CYP11A1), and also of 11β-hydroxylase (CYP11B1), 18-hydroxylase (aldosterone synthase, CYP11B2), and 3β-hydroxysteroid dehydrogenase (3β-HSD) to a lesser extent.^[3][9] In addition, mitotane has direct and selective cytotoxic effects on the adrenal cortex, via an unknown mechanism, and thereby induces permanent adrenal atrophy similarly to DDD.^[11][12]

Chemistry

Analogues of mitotane include aminoglutethimide, amphenone B, and metyrapone.

History

Mitotane was introduced in 1960 for the treatment of adrenocortical carcinoma.^[5]

Society and culture

Generic names

Mitotane is the generic name of the medication and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.^[6][13]

Brand names

Mitotane is sold under the brand name Lysodren.^[6]

Veterinary use

Mitotane is also used to treat Cushing's disease (pituitary-dependent Cushing's syndrome) in dogs. The medication is used in the controlled destruction of adrenal tissue, leading to a decrease in cortisol production.^[14]