Mitotane

Mitotane
Names
Trade namesLysodren
Other names1,1-(Dichlorodiphenyl)-2,2-dichloroethane; o,p'-DDD
IUPAC name
  • (RS)-1-chloro-2-[2,2-dichloro-1-(4-chlorophenyl)-ethyl]-benzene
Clinical data
Main usesAdrenocortical carcinoma, Cushing's syndrome[1]
Side effectsLoss of appetite, nausea, diarrhea, sleepiness, rash[1]
Pregnancy
category
  • C
Routes of
use		By mouth
External links
AHFS/Drugs.comMonograph
US NLMMitotane
MedlinePlusa608050
Legal
License data
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetics
Bioavailability40%
Protein binding6%
Elimination half-life18–159 days
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)
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 checkY
  • Key:JWBOIMRXGHLCPP-UHFFFAOYSA-N checkY

Mitotane, sold under the brand name Lysodren among others, is a medication used to treat adrenocortical carcinoma and Cushing's syndrome.[1] It is taken by mouth.[1] During treatment corticosteroids are often needed.[1]

Common side effects include loss of appetite, nausea, diarrhea, sleepiness, and rash.[1] Other complications may include bleeding from the cancers, brain damage, and adrenal insufficiency.[1] Use during pregnancy may harm the baby.[2] It works by blocking the adrenal cortex.[3]

Mitotane was introduced for medical use in 1960.[4] In the United Kingdom 100 tablets of 0.5 mg costs the NHS about £590 as of 2021.[3] This amount in the United States is about 1,100 USD.[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.[4]

Dosage

It is take at a dose of 1 mg two to three times per day and may be increased up to 2 mg three times per day.[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.[9][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.[10][11]

Chemistry

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

History

Mitotane was introduced in 1960 for the treatment of adrenocortical carcinoma.[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).[12]

Society and culture

Generic names

Mitotane is the generic name of the drug and its INN, USAN, BAN, and JAN.[13][14]

Brand names

Mitotane has been sold under the brand name Lysodren.[13]

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

  1. 1 2 3 4 5 6 7 "Mitotane Monograph for Professionals". Drugs.com. Archived from the original on 4 March 2016. Retrieved 18 November 2021.
  2. ↑ "Mitotane (Lysodren) Use During Pregnancy". Drugs.com. Archived from the original on 28 November 2020. Retrieved 18 November 2021.
  3. 1 2 3 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 979. ISBN 978-0857114105.
  4. 1 2 3 Marcello D. Bronstein (1 October 2010). Cushing's Syndrome: Pathophysiology, Diagnosis and Treatment. Springer Science & Business Media. pp. 156–. ISBN 978-1-60327-449-4.
  5. ↑ "Lysodren Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 17 January 2021. Retrieved 18 November 2021.
  6. ↑ Terzolo M, Angeli A, Fassnacht M, Daffara F, Tauchmanova L, Conton PA, Rossetto R, Buci L, Sperone P, Grossrubatscher E, Reimondo G, Bollito E, Papotti M, Saeger W, Hahner S, Koschker AC, Arvat E, Ambrosi B, Loli P, Lombardi G, Mannelli M, Bruzzi P, Mantero F, Allolio B, Dogliotti L, Berruti A (2007). "Adjuvant mitotane treatment for adrenocortical carcinoma". N Engl J Med. 356 (23): 2372–2380. doi:10.1056/NEJMoa063360. hdl:2318/37317. PMID 17554118.
  7. 1 2 Philip E. Harris; Pierre-Marc G. Bouloux (24 March 2014). Endocrinology in Clinical Practice, Second Edition. CRC Press. pp. 216–. ISBN 978-1-84184-951-5.
  8. ↑ Schteinberg DE, Motazedi A, NoonanRA, Thompson NW (1982). "Treatment of Adrenal Carcinomas". Arch. Surg. 117 (9): 1142–1149. doi:10.1001/archsurg.1982.01380330010004. PMID 7115060.
  9. ↑ J. Larry Jameson; Leslie J. De Groot (18 May 2010). Endocrinology - E-Book: Adult and Pediatric. Elsevier Health Sciences. pp. 1888–. ISBN 978-1-4557-1126-0.
  10. ↑ Eudocia Quant Lee, MD, MPH; David Schiff, MD; Patrick Y. Wen, MD (28 September 2011). Neurologic Complications of Cancer Therapy. Demos Medical Publishing. pp. 179–. ISBN 978-1-61705-019-0.{{cite book}}: CS1 maint: multiple names: authors list (link)
  11. ↑ C.R. Kannan (6 December 2012). The Adrenal Gland. Springer Science & Business Media. pp. 160–. ISBN 978-1-4613-1001-3.
  12. ↑ "Information from PubChem". Archived from the original on 2013-06-19. Retrieved 2021-04-07.
  13. 1 2 J. Elks (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 382–. ISBN 978-1-4757-2085-3.
  14. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 697–. ISBN 978-3-88763-075-1.
  15. ↑ Canine Cushing’s Syndrome: Diagnosis and Treatment Archived 2007-10-21 at the Wayback Machine
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