Mitotane

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Mitotane
Mitotane.svg
Mitotane-(2S)-enantiomer-from-xtal-3D-bs-17.png
Clinical data
Trade names Lysodren
Other names1,1-(Dichlorodiphenyl)-2,2-dichloroethane; o,p'-DDD
AHFS/Drugs.com Monograph
MedlinePlus a608050
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 40%
Protein binding 6%
Elimination half-life 18–159 days
Identifiers
  • (RS)-1-chloro-2-[2,2-dichloro-1-(4-chlorophenyl)-ethyl]-benzene
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.152 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C14H10Cl4
Molar mass 320.03 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
Melting point 76 to 78 °C (169 to 172 °F)
  • Clc1ccccc1C(c2ccc(Cl)cc2)C(Cl)Cl
  • 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 Yes check.svgY
  • Key:JWBOIMRXGHLCPP-UHFFFAOYSA-N Yes check.svgY
   (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. [3] [4] [5] [6] It is a derivative of the early insecticide DDT and an isomer of p,p'-DDD Tooltip dichlorodiphenyldichloroethane (4,4'-dichlorodiphenyldichloroethane) and is also known as 2,4'-(dichlorodiphenyl)-2,2-dichloroethane (o,p'-DDD). [7]

Contents

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]

Therapy with mitotane is initiated using an escalating regimen. The extent or intensity of the therapy is gradually increased. This depends on how well the individual patient tolerates the drug and the extent to which it affects the patient's performance status (according to the ECOG/Karnofsky Performance Status). Monitoring of the mitotane concentration in the blood is recommended. The general target value is ≥ 14 mg/L. [9]

Mitotane therapy is initiated using an escalating regimen. In all patients receiving mitotane therapy, glucocorticoid replacement is recommended, except for patients with persistent cortisol excess. In these cases, at least twice the standard replacement dose is generally required. This is due to the increased steroid excretion and the rise in cortisol-binding globulin. Mitotane-induced side effects must be monitored regularly and treated appropriately, avoiding over-, under-, or inappropriate treatment. Furthermore, initiating supportive therapy is advisable to improve mitotane tolerance. Ideally, this should be done before severe toxicity develops. Mitotane causes significant drug interactions due to strong induction of CYP3A4. Therefore, it is crucial to check all concomitant medications for CYP3A4 interactions and replace them with an alternative if necessary and available. Other healthcare providers should be advised not to initiate any other drug therapies without prior consultation. [9]

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. [3] [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] Mitotane has also been reported to interact with tubulin and inhibit its polymerization. [14]

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 INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and JAN Tooltip Japanese Accepted Name. [6] [15]

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. [16]

References

  1. ↑ "Product monograph brand safety updates". Health Canada . 7 July 2016. Retrieved 3 April 2024.
  2. ↑ "Lysodren EPAR". European Medicines Agency. 12 June 2002. Retrieved 27 June 2024.
  3. 1 2 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.
  4. ↑ Hahner S, Fassnacht M (April 2005). "Mitotane for adrenocortical carcinoma treatment". Current Opinion in Investigational Drugs. 6 (4): 386–394. PMID   15898346.
  5. 1 2 3 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.
  6. 1 2 3 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.
  7. ↑ "Mitotane". PubChem. U.S. National Library of Medicine.
  8. ↑ 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)
  9. 1 2 Martin Fassnacht, Stylianos Tsagarakis, Massimo Terzolo, Antoine Tabarin, Anju Sahdev, John Newell-Price, Iris Pelsma, Ljiljana Marina, Kerstin Lorenz, Irina Bancos, Wiebke Arlt, Olaf M Dekkers: European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. In: European Journal of Endocrinology. Volume 189, Issue 1, July 2023, ISSN 0804-4643, Pages G1–G42, https://doi.org/10.1093/ejendo/lvad066 [retrieved July 6, 2024]
  10. 1 2 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.
  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.
  13. ↑ Kannan CR (6 December 2012). "Cushing's Syndrome". The Adrenal Gland. Springer Science & Business Media. pp. 160–. ISBN   978-1-4613-1001-3.
  14. ↑ Baksheeva VE, La Rocca R, Allegro D, Derviaux C, Pasquier E, Roche P, et al. (2025). "NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure–Activity Insights". Journal of Medicinal Chemistry. 68 (16): 17485–17498. doi:10.1021/acs.jmedchem.5c01008. PMC   12406199 . PMID   40815226.
  15. ↑ Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 697–. ISBN   978-3-88763-075-1.
  16. ↑ 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.

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