Chemistry:Mitotane

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Short description: Chemical compound
Mitotane
Mitotane.svg
Mitotane-(2S)-enantiomer-from-xtal-3D-bs-17.png
Clinical data
Trade namesLysodren
Other names1,1-(Dichlorodiphenyl)-2,2-dichloroethane; o,p'-DDD
AHFS/Drugs.comMonograph
MedlinePlusa608050
License data
Pregnancy
category
  • C
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability40%
Protein binding6%
Elimination half-life18–159 days
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC14H10Cl4
Molar mass320.03 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
Melting point76 to 78 °C (169 to 172 °F)
  (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.[1][2][3][4] It is a derivative of the early insecticide DDT and an isomer of p,p'-DDD (4,4'-dichlorodiphenyldichloroethane) and is also known as 2,4'-(dichlorodiphenyl)-2,2-dichloroethane (o,p'-DDD).[5]

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.[6] The drug is also sometimes used in the treatment of Cushing's syndrome.[3]

Side effects

The use of mitotane is unfortunately limited by side effects,[7] which, as reported by Schteinberg 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%).[8]

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.[1][7] 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.[9][10]

Chemistry

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

History

Mitotane was introduced in 1960 for the treatment of adrenocortical carcinoma.[3]

Society and culture

Generic names

Mitotane is the generic name of the drug and its INN, USAN, BAN, and JAN.[4][11]

Brand names

Mitotane has been sold under the brand name Lysodren.[4]

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.[12]

References

  1. ↑ 1.0 1.1 "Adrenal Causes of Hypercortisolism". Endocrinology - E-Book: Adult and Pediatric. Elsevier Health Sciences. 18 May 2010. pp. 1888–. ISBN 978-1-4557-1126-0. https://books.google.com/books?id=W4dZ-URK8ZoC&pg=PA1888. 
  2. ↑ "Mitotane for adrenocortical carcinoma treatment". Current Opinion in Investigational Drugs 6 (4): 386–394. April 2005. PMID 15898346. 
  3. ↑ 3.0 3.1 3.2 "Medical Management of Cushing's Syndrome". Cushing's Syndrome: Pathophysiology, Diagnosis and Treatment. Springer Science & Business Media. 1 October 2010. pp. 156–. ISBN 978-1-60327-449-4. https://books.google.com/books?id=5_ulQAM9OZYC&pg=PA156. 
  4. ↑ 4.0 4.1 4.2 The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. 14 November 2014. pp. 382–. ISBN 978-1-4757-2085-3. https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA382. 
  5. ↑ "Mitotane". PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4211. 
  6. ↑ "Adjuvant mitotane treatment for adrenocortical carcinoma". The New England Journal of Medicine 356 (23): 2372–2380. June 2007. doi:10.1056/NEJMoa063360. PMID 17554118. 
  7. ↑ 7.0 7.1 "Coincidental adrenal masses and adrenal cancer". Endocrinology in Clinical Practice (Second ed.). CRC Press. 24 March 2014. pp. 216–. ISBN 978-1-84184-951-5. https://books.google.com/books?id=tZE-AwAAQBAJ&pg=PA216. 
  8. ↑ "Treatment of adrenal carcinomas". Archives of Surgery 117 (9): 1142–1146. September 1982. doi:10.1001/archsurg.1982.01380330010004. PMID 7115060. 
  9. ↑ "Neurologic Complications of Hormonal Chemotherapies". Neurologic Complications of Cancer Therapy. Demos Medical Publishing. 28 September 2011. pp. 179–. ISBN 978-1-61705-019-0. https://books.google.com/books?id=52qyu5XPqM4C&pg=PA179. 
  10. ↑ "Cushing's Syndrome". The Adrenal Gland. Springer Science & Business Media. 6 December 2012. pp. 160–. ISBN 978-1-4613-1001-3. https://books.google.com/books?id=WqXSBwAAQBAJ&pg=PA160. 
  11. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 697–. ISBN 978-3-88763-075-1. https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA697. 
  12. ↑ "Canine Cushing's Syndrome: Diagnosis and Treatment Part 1: Typical, Atypical, and Pseudo-Cushing's Disease". http://www.michvma.org/documents/MVC%20Proceedings/Nichols2.pdf. 

Further reading

  • "Effect of o,p-dichlorodiphenyldichloroethane and perthane in vitro on glutathione reductase activity in the adrenals of dogs and guinea pigs". Bulletin of Experimental Biology and Medicine 85 (2): 152–154. 1978. doi:10.1007/BF00800110. 

External links



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