Trilostane

Overview

Trilostane, sold under the brand name Vetoryl among others, is a medication which has been used in the treatment of Cushing's syndrome, Conn's syndrome, and postmenopausal breast cancer in humans. It was withdrawn for use in humans in the United States in the 1990s but was subsequently approved for use in veterinary medicine in the 2000s to treat Cushing's syndrome in dogs. It is taken by mouth.[1–7] WP

Uses, dosage and effects

Medical uses

Trilostane has been used in the treatment of Cushing's syndrome (hypercortisolism), Conn's syndrome (hyperaldosteronism), and postmenopausal breast cancer in humans. When used to treat breast cancer, trilostane is administered in combination with a corticosteroid to prevent glucocorticoid deficiency.[2][5] WP

Veterinary uses

Trilostane is used for the treatment of Cushing's syndrome in dogs. The safety and effectiveness of trilostane for this indication were shown in several studies. Success was measured by improvements in both blood test results and physical symptoms (normalized appetite and activity level, and decreased panting, thirst, and urination).[8][9] WP

Risks and side effects

Contraindications

Trilostane should not be used in pregnant women.[5] WP

Trilostane should not be given to a dog that: WP

• Has kidney or liver disease[10][11] WP
• Takes certain medications used to treat cardiovascular disease[12] WP
• Is pregnant, nursing or intended for breeding[10][11] WP

Side effects

Side effects of trilostane in conjunction with a corticosteroid in humans include gastrointestinal side effects like gastritis, nausea, vomiting, and diarrhea. Nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the incidence of diarrhea with trilostane. Serious gastrointestinal side effects of trilostane alone or in combination with an NSAID like peptic ulcer, erosive gastritis, gastric perforation, hematemesis, and melena may occur in some individuals. Reversible granulocytopenia and transient oral paresthesia may occur with trilostane.[5] WP

Pharmacology

Pharmacodynamics

Trilostane is a steroidogenesis inhibitor. It is specifically an inhibitor of 3β-hydroxysteroid dehydrogenase (3β-HSD). As a result of this action, trilostane blocks the conversion of Δ⁵-3β-hydroxysteroids, including pregnenolone, 17α-hydroxypregnenolone, dehydroepiandrosterone (DHEA), and androstenediol, into Δ⁴-3-ketosteroids, including progesterone, 17α-hydroxyprogesterone, androstenedione, and testosterone, respectively. Consequently, trilostane inhibits the production of all classes of steroid hormones, including androgens, estrogens, progestogens, glucocorticoids, and mineralocorticoids.[5][13] WP

The mechanism of action of trilostane in Cushing's syndrome and Conn's syndrome is by inhibiting the production of corticosteroids such as cortisol and aldosterone in the adrenal glands. Trilostane has also been used as an abortifacient due to its inhibition of progesterone synthesis.[5][14][15][16] WP

Trilostane is not an aromatase inhibitor and hence does not inhibit the conversion of androgens like androstenedione and testosterone into estrogens like estrone and estradiol. However, trilostane may nonetheless inhibit estrogen synthesis by inhibiting androgen synthesis.[5] WP

In addition to steroidogenesis inhibition, trilostane has been found to act as a noncompetitive antiestrogen, via direct and presumably allosteric interactions with the estrogen receptor. The effectiveness of trilostane in postmenopausal breast cancer may relate to this apparent antiestrogenic activity. Trilostane has also been found to act as an agonist of the androgen receptor. As such, its use in men with prostate cancer may warrant caution.[5][17][18][19] WP

Pharmacokinetics

Trilostane is metabolized in the liver. The major metabolite of trilostane is 17-ketotrilostane. The conversion of trilostane into 17-ketotrilostane is reversible, suggesting that trilostane and 17-ketotrilostane undergo interconversion in the body. 17-Ketotrilostane circulates at 3-fold higher levels than trilostane and is more active than trilostane as a 3β-HSD inhibitor. The elimination half-lives of trilostane and 17-ketotrilostane are both 1.2 hours, with both compounds cleared from the blood within 6 to 8 hours of a dose of trilostane. 17-Ketotrilostane is excreted by the kidneys.[5] WP

History

History

Trilostane was withdrawn from human use in the United States market in April 1994. It continued to be available in the United Kingdom for use in humans under the brand name Modrenal for the treatment of Cushing's disease and breast cancer in humans, but was eventually discontinued in this country as well.[6][8][20–23] WP

Trilostane was approved in the United States in 2008 for the treatment of Cushing's disease (hyperadrenocorticism) in dogs under the brand name Vetoryl. It was available by prescription in the United Kingdom for dogs under the Vetoryl brand name for some time before it was approved in the United States. The drug is also used to treat the skin disorder Alopecia X in dogs.[10][14][20][24][25] WP

Trilostane was the first drug approved to treat both pituitary- and adrenal-dependent Cushing's in dogs. Only one other drug, Anipryl (veterinary brand name) selegiline, is FDA-approved to treat Cushing's disease in dogs, but only to treat uncomplicated, pituitary-dependent Cushing's. The only previous treatment for the disease was the use of mitotane (brand name Lysodren) off-label.[9][26][27] WP⚠ Wikipedia itself has flagged this text: citation needed.

A number of compounding pharmacies in the United States sell trilostane for dogs. Since the United States approval of Vetoryl in December 2008, compounding pharmacies are no longer able to use a bulk drug product for compounding purposes, but must prepare the compounded drug from Vetoryl.[24][28] WP⚠ Wikipedia itself has flagged this text: citation needed.

Legal status

Legal status

In March 2024, the Committee for Veterinary Medicinal Products (CVMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the veterinary medicinal product Trilocur, oral suspension for dogs. The applicant for this veterinary medicinal product is Emdoka. In March 2024, the CVMP adopted a positive opinion, recommending the granting of a marketing authorization for the veterinary medicinal product Trilorale, oral suspension for dogs. The applicant for this veterinary medicinal product is Axience. Trilocur and Trilorale were approved for medical use in the European Union in May 2024.[29–32] WP

Generic names

Trilostane is the generic name of the drug and its INN (International Nonproprietary Name), USAN (United States Adopted Name), BAN (British Approved Name), and JAN (Japanese Accepted Name). Its developmental code name was WIN-24,540.[1][2] WP

Brand names

Trilostane has been marketed under a number of brand names including Desopan, Modrastane, Modrenal, Trilox, Vetoryl, Oncovet TL and Winstan.[1][2] WP

Availability

Trilostane is available for veterinary use in countries throughout the world.[33] WP

Chemistry

Formula

C20H27NO3 PC

CAS number

13647-35-3 PC

Molar mass (g/mol)

329.4 PC

IUPAC name (computed by PubChem)

(1S,2R,6R,8S,11S,12S,15S,16S)-5,15-dihydroxy-2,16-dimethyl-7-oxapentacyclo[9.7.0.02,8.06,8.012,16]octadec-4-ene-4-carbonitrile PC

SMILES

C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@@H]2O)CC[C@]45[C@@]3(CC(=C([C@H]4O5)O)C#N)C PC

InChIKey

KVJXBPDAXMEYOA-CXANFOAXSA-N PC

PubChem CID

656583

Harm reduction information

No harm reduction data is on file for this compound yet. That means no dose, timing or combination data from PsychonautWiki or TripSit. Please don't guess a dose from similar compounds. If you have taken it and feel unwell, contact emergency services or a poison control center.

User reports

Pop culture

No references added yet.

Sources

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2. Other Morton IK, Hall JM. Concise Dictionary of Pharmacological Agents: Properties and Synonyms. 6 December 2012
3. Other Negwer M. Organic-chemical Drugs and Their Synonyms: (an International Survey). 1987
4. Other Milne GW. Drugs: Synonyms and Properties: Synonyms and Properties. 8 May 2018
5. Journal / agency Puddefoot JR, Barker S, Vinson GP. Trilostane in advanced breast cancer. Expert Opinion on Pharmacotherapy. December 2006. doi:10.1517/14656566.7.17.2413 · PMID 17109615
6. Journal / agency Tung D, Ciallella J, Hain H, Cheung PH, Saha S. Possible therapeutic effect of trilostane in rodent models of inflammation and nociception. Current Therapeutic Research, Clinical and Experimental. December 2013. doi:10.1016/j.curtheres.2013.09.004 · PMID 24465047 · PMC3898193
7. Other Cushing's Disease in Dogs Part 3: Current & Investigative Options for Therapy. 24 February 2016
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9. Journal / agency Treating Cushing's Disease in Dogs
10. Other Vetoryl-Contraindications
11. Other Dechra US Datasheet-Vetoryl
12. Other Cushing's Disease in Dogs. 2 February 2015
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14. Other Reusch CE. Trilostane-5 Years of Clinical Experience for the Treatment of Cushing's Disease. 2006
15. Other Reusch CE. Trilostane-A Review of a Success Story. 2010
16. Journal / agency le Roux PA, Tregoning SK, Zinn PM, van der Spuy ZM. Inhibition of progesterone secretion with trilostane for mid-trimester termination of pregnancy: randomized controlled trials. Human Reproduction. June 2002. doi:10.1093/humrep/17.6.1483 · PMID 12042266
17. Journal / agency Puddefoot JR, Barker S, Glover HR, Malouitre SD, Vinson GP. Non-competitive steroid inhibition of oestrogen receptor functions. International Journal of Cancer. September 2002. doi:10.1002/ijc.10547 · PMID 12209583
18. Journal / agency Beatson GT. On the Treatment of Inoperable Cases of Carcinoma of the Mamma: Suggestions for a New Method of Treatment, with Illustrative Cases. Transactions. Medico-Chirurgical Society of Edinburgh. 1896. PMID 29584099 · PMC5518378
19. Journal / agency Takizawa I, Nishiyama T, Hara N, Hoshii T, Ishizaki F, Miyashiro Y, Takahashi K. Trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, has an agonistic activity on androgen receptor in human prostate cancer cells. Cancer Letters. November 2010. doi:10.1016/j.canlet.2010.05.015 · PMID 20831980
20. Other Cook AK. Trilostane: A therapeutic consideration for canine hyperadrenocorticism. 1 February 2008
21. Other Trilostane consumer information. 4 January 2009
22. Other Modrenal consumer information
23. Other Modrenal
24. Journal / agency Vetoryl approval information. 5 December 2008
25. Journal / agency Cerundolo R, Lloyd DH, Persechino A, Evans H, Cauvin A. Treatment of canine Alopecia X with trilostane. Veterinary Dermatology. October 2004. doi:10.1111/j.1365-3164.2004.00403.x · PMID 15500480
26. Other Anipryl consumer information
27. Journal / agency Reine NJ. Medical management of pituitary-dependent hyperadrenocorticism: mitotane versus trilostane. Clinical Techniques in Small Animal Practice. February 2007. doi:10.1053/j.ctsap.2007.02.003 · PMID 17542193
28. Journal / agency VETORYL (trilostane) Capsules Letter - Pharmacy Professionals. 11 September 2009
29. Journal / agency Trilocur EPAR. 13 March 2024
30. Journal / agency Trilorale EPAR. 13 March 2024
31. Other Trilocur PI. 7 May 2024
32. Other Trilorale PI. 7 May 2024
33. Other Vetoryl Capsules (Trilostane) for Animal Use

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