Mitotane

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; US: WARNING; EU: Rx-only; 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 ;
PubChem CID	4211;
IUPHAR/BPS	6957;
DrugBank	DB00648 ;
ChemSpider	4066 ;
UNII	78E4J5IB5J;
KEGG	D00420 ;
ChEMBL	ChEMBL1670 ;
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 ; Key:JWBOIMRXGHLCPP-UHFFFAOYSA-N ;
	(verify)

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.^[4]^[5]^[6]^[7] 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).^[8]

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.^[9] The drug is also sometimes used in the treatment of Cushing's syndrome.^[6]

Side effects

The use of mitotane is unfortunately limited by side effects,^[10] 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%).^[11]

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.^[4]^[10] 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.^[12]^[13]

Chemistry

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

History

Mitotane was introduced in 1960 for the treatment of adrenocortical carcinoma.^[6]

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.^[7]^[14]

Brand names

Mitotane is sold under the brand name Lysodren.^[7]

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.^[15]

References

^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
^ "Product monograph brand safety updates". Health Canada. 7 July 2016. Retrieved 3 April 2024.
^ "Lysodren EPAR". European Medicines Agency. 12 June 2002. Retrieved 27 June 2024.
^ ^a ^b Cavagnini F, Giraldi FP (18 May 2010). "Adrenal Causes of Hypercortisolism". In Jameson JL, De Groot LJ (eds.). Endocrinology - E-Book: Adult and Pediatric. Elsevier Health Sciences. pp. 1888–. ISBN 978-1-4557-1126-0.
^ Hahner S, Fassnacht M (April 2005). "Mitotane for adrenocortical carcinoma treatment". Current Opinion in Investigational Drugs. 6 (4): 386–394. PMID 15898346.
^ ^a ^b ^c Dang C, Trainer PJ (1 October 2010). "Medical Management of Cushing's Syndrome". In Bronstein MD (ed.). Cushing's Syndrome: Pathophysiology, Diagnosis and Treatment. Springer Science & Business Media. pp. 156–. ISBN 978-1-60327-449-4.
^ ^a ^b ^c Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 382–. ISBN 978-1-4757-2085-3.
^ "Mitotane". PubChem. U.S. National Library of Medicine.
^ Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, et al. (June 2007). "Adjuvant mitotane treatment for adrenocortical carcinoma". The New England Journal of Medicine. 356 (23): 2372–2380. doi:10.1056/NEJMoa063360. hdl:2318/37317. PMID 17554118.{{cite journal}}: CS1 maint: overridden setting (link)
^ ^a ^b Tzanela M, Vassiliadi DA, Tsagarakis S (24 March 2014). "Coincidental adrenal masses and adrenal cancer". In Harris PE, Bouloux PM (eds.). Endocrinology in Clinical Practice (Second ed.). CRC Press. pp. 216–. ISBN 978-1-84184-951-5.
^ Schteingart DE, Motazedi A, Noonan RA, Thompson NW (September 1982). "Treatment of adrenal carcinomas". Archives of Surgery. 117 (9): 1142–1146. doi:10.1001/archsurg.1982.01380330010004. PMID 7115060.
^ Sojka WS, Raizer J (28 September 2011). "Neurologic Complications of Hormonal Chemotherapies". In Lee EQ, Schiff D, Wen PY (eds.). Neurologic Complications of Cancer Therapy. Demos Medical Publishing. pp. 179–. ISBN 978-1-61705-019-0.
^ Kannan CR (6 December 2012). "Cushing's Syndrome". The Adrenal Gland. Springer Science & Business Media. pp. 160–. ISBN 978-1-4613-1001-3.
^ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 697–. ISBN 978-3-88763-075-1.
^ Nichols R. "Canine Cushing's Syndrome: Diagnosis and Treatment Part 1: Typical, Atypical, and Pseudo-Cushing's Disease" (PDF). Archived from the original (PDF) on 21 October 2007.

External links

"Mitotane – information sheet". Government of Canada. 16 October 2017.
"RISK MANAGEMENT SCOPE for Benzene, 1-chloro-2-[2,2-dichloro-1-(4-chlorophenyl)ethyl]- (Mitotane)]" (PDF). Environment Canada & Health Canada. July 2013. Archived from the original (PDF) on 10 August 2014.

[FDA-AllBoxedWarnings-1] "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.

[2] "Product monograph brand safety updates". Health Canada. 7 July 2016. Retrieved 3 April 2024.

[3] "Lysodren EPAR". European Medicines Agency. 12 June 2002. Retrieved 27 June 2024.

[JamesonGroot2010-4] Cavagnini F, Giraldi FP (18 May 2010). "Adrenal Causes of Hypercortisolism". In Jameson JL, De Groot LJ (eds.). Endocrinology - E-Book: Adult and Pediatric. Elsevier Health Sciences. pp. 1888–. ISBN 978-1-4557-1126-0.

[pmid15898346-5] Hahner S, Fassnacht M (April 2005). "Mitotane for adrenocortical carcinoma treatment". Current Opinion in Investigational Drugs. 6 (4): 386–394. PMID 15898346.

[Bronstein2010-6] Dang C, Trainer PJ (1 October 2010). "Medical Management of Cushing's Syndrome". In Bronstein MD (ed.). Cushing's Syndrome: Pathophysiology, Diagnosis and Treatment. Springer Science & Business Media. pp. 156–. ISBN 978-1-60327-449-4.

[Elks2014-7] Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 382–. ISBN 978-1-4757-2085-3.

[PubChem-8] "Mitotane". PubChem. U.S. National Library of Medicine.

[:0-9] Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, et al. (June 2007). "Adjuvant mitotane treatment for adrenocortical carcinoma". The New England Journal of Medicine. 356 (23): 2372–2380. doi:10.1056/NEJMoa063360. hdl:2318/37317. PMID 17554118.{{cite journal}}: CS1 maint: overridden setting (link)

[HarrisBouloux2014-10] Tzanela M, Vassiliadi DA, Tsagarakis S (24 March 2014). "Coincidental adrenal masses and adrenal cancer". In Harris PE, Bouloux PM (eds.). Endocrinology in Clinical Practice (Second ed.). CRC Press. pp. 216–. ISBN 978-1-84184-951-5.

[11] Schteingart DE, Motazedi A, Noonan RA, Thompson NW (September 1982). "Treatment of adrenal carcinomas". Archives of Surgery. 117 (9): 1142–1146. doi:10.1001/archsurg.1982.01380330010004. PMID 7115060.

[MPHMD2011-12] Sojka WS, Raizer J (28 September 2011). "Neurologic Complications of Hormonal Chemotherapies". In Lee EQ, Schiff D, Wen PY (eds.). Neurologic Complications of Cancer Therapy. Demos Medical Publishing. pp. 179–. ISBN 978-1-61705-019-0.

[Kannan2012-13] Kannan CR (6 December 2012). "Cushing's Syndrome". The Adrenal Gland. Springer Science & Business Media. pp. 160–. ISBN 978-1-4613-1001-3.

[IndexNominum2000-14] Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 697–. ISBN 978-3-88763-075-1.

[15] Nichols R. "Canine Cushing's Syndrome: Diagnosis and Treatment Part 1: Typical, Atypical, and Pseudo-Cushing's Disease" (PDF). Archived from the original (PDF) on 21 October 2007.

[4]