Trilostane

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Trilostane
Clinical data
Trade namesVetoryl, others
Other namesWIN-24,540; 4α,5-Epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile
Routes of
administration		By mouth[1]
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismLiver
Metabolites17-Ketotrilostane[1]
Elimination half-lifeTrilostane: 1.2 hours[1]
17-Ketotrilostane: 1.2 hours[1]
Identifiers
  • (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
JSmol)
  • N#C\C4=C(/O)[C@H]5O[C@]35[C@]([C@@H]2[C@H]([C@H]1[C@]([C@@H](O)CC1)(C)CC2)CC3)(C)C4
  • InChI=1S/C20H27NO3/c1-18-7-6-14-12(13(18)3-4-15(18)22)5-8-20-17(24-20)16(23)11(10-21)9-19(14,20)2/h12-15,17,22-23H,3-9H2,1-2H3/t12-,13-,14-,15-,17+,18-,19+,20+/m0/s1 checkY
  • Key:KVJXBPDAXMEYOA-CXANFOAXSA-N checkY
  (verify)

Trilostane, sold under the brand name Vetoryl among others, is a medication which has been used in the treatment of

withdrawn for use in humans in the United States in the 1990s[8] but was subsequently approved for use in veterinary medicine in the 2000s to treat Cushing's syndrome in dogs.[9] It is taken by mouth.[1]

Medical uses

Trilostane has been used in the treatment of

postmenopausal breast cancer in humans.[5][1] When used to treat breast cancer, trilostane is administered in combination with a corticosteroid to prevent glucocorticoid deficiency.[1]

Contraindications

Trilostane should not be used in pregnant women.[1]

Trilostane should not be given to a dog that:

Side effects

granulocytopenia and transient oral paresthesia may occur with trilostane.[1]

Pharmacology

Pharmacodynamics

Steroidogenesis
. Trilostane inhibits 3β-HSD.

Trilostane is a

17α-hydroxyprogesterone, androstenedione, and testosterone, respectively.[1] Consequently, trilostane inhibits the production of all classes of steroid hormones, including androgens, estrogens, progestogens, glucocorticoids, and mineralocorticoids.[1]

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.[14][15] Trilostane has also been used as an abortifacient due to its inhibition of progesterone synthesis.[1][16]

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.[1] However, trilostane may nonetheless inhibit estrogen synthesis by inhibiting androgen synthesis.[1]

In addition to steroidogenesis inhibition, trilostane has been found to act as a

allosteric interactions with the estrogen receptor.[1][17][18] The effectiveness of trilostane in postmenopausal breast cancer may relate to this apparent antiestrogenic activity.[1][17][18] Trilostane has also been found to act as an agonist of the androgen receptor.[19] As such, its use in men with prostate cancer may warrant caution.[1]

Pharmacokinetics

Trilostane is

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.[1] 17-Ketotrilostane is excreted by the kidneys.[1]

Chemistry

Trilostane, also known as 4α,5-epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile, is a

3β-androstanediol, and dihydrotestosterone.[4]

Synthesis

Trilostane is prepared from testosterone in a four-step synthesis.[citation needed]

History

Trilostane was

withdrawn from human use in the United States market in April 1994.[20][21][8] 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.[8][22][23][24]

Trilostane was approved in the United States in 2008 for the treatment of Cushing's disease (hyperadrenocorticism) in dogs under the brand name Vetoryl.[25] 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.[10] The drug is also used to treat the skin disorder Alopecia X in dogs.[20][26][27]

Trilostane was the first drug approved to treat both

adrenal-dependent Cushing's in dogs.[citation needed] 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.[28] The only previous treatment for the disease was the use of mitotane (brand name Lysodren) off-label.[29][30]

A number of

compounding pharmacies in the United States sell trilostane for dogs.[citation needed] Since the United States approval of Vetoryl in December 2008,[25] compounding pharmacies are no longer able to use a bulk drug product for compounding purposes, but must prepare the compounded drug from Vetoryl.[31]

Society and culture

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.[2] The applicant for this veterinary medicinal product is Emdoka.[2] 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.[3] The applicant for this veterinary medicinal product is Axience.[3] Trilocur and Trilorale were approved for medical use in the European Union in May 2024.[32][33]

Generic names

Trilostane is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[4][5] Its developmental code name was WIN-24,540.[4][5]

Brand names

Trilostane has been marketed under a number of brand names including Desopan, Modrastane, Modrenal, Trilox, Vetoryl, Oncovet TL and Winstan.[4][5]

Availability

Trilostane is available for veterinary use in countries throughout the world.[34]

Veterinary uses

Trilostane is used for the treatment of Cushing's syndrome in dogs. The

effectiveness of trilostane for this indication were shown in several studies.[24][29] Success was measured by improvements in both blood test results and physical symptoms (normalized appetite and activity level, and decreased panting, thirst, and urination).[24][29]

References

  1. ^
    S2CID 23940491
    .
  2. ^ a b c "Trilocur EPAR". European Medicines Agency. 13 March 2024. Retrieved 20 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. ^ a b c "Trilorale EPAR". European Medicines Agency. 13 March 2024. Retrieved 20 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ^
    ISBN 978-1-4757-2085-3
    .
  5. ^
    ISBN 978-94-011-4439-1
    .
  6. ISBN 978-0-89573-552-2
    . 5870 (6516) C20H2:NOs 13647-35-3 42,5-Epoxy-173-hydroxy-3-oxo-50-androstane-22carbonitrile = (22,42,52,173)-4,5-Epoxy-17-hydroxy-3-oxoandrostane-2-carbonitrile (e) S Desopan, Modrastane, Modrenal, Trilostane", Trilox, Win 24 540, Winstan U Adrenocortical suppressant (steroid biosynthesis inhibitor)
  7. ISBN 978-1-351-78989-9
    .
  8. ^
    PMID 24465047
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  9. ^ "Cushing's Disease in Dogs Part 3: Current & Investigative Options for Therapy". Today's Veterinary Practice. 24 February 2016. Retrieved 4 January 2021.
  10. ^ a b c "Vetoryl-Contraindications". NOAH Compendium of Animal Health-National Office of Animal Health UK. Archived from the original on 17 February 2013. Retrieved 3 April 2011.
  11. ^ a b "Dechra US Datasheet-Vetoryl" (PDF). Dechra US. Archived from the original (PDF) on 22 March 2012. Retrieved 3 April 2011. (PDF)
  12. ^ "Cushing's Disease in Dogs". NASC LIVE. 2 February 2015. Retrieved 4 January 2021.
  13. PMID 21295836
    .
  14. ^ Reusch CE (2006). "Trilostane-5 Years of Clinical Experience for the Treatment of Cushing's Disease" (PDF). Ohio State University Endocrinology Symposium. pp. 17–19. Retrieved 5 April 2011.[permanent dead link] (PDF)
  15. ^ Reusch CE (2010). "Trilostane-A Review of a Success Story". World Small Animal Veterinary Association (WSAVA). Retrieved 5 April 2011.
  16. PMID 12042266
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  17. ^
    S2CID 25779906
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  18. ^
    PMID 29584099
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  19. PMID 20831980
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  20. ^ a b Cook AK (1 February 2008). "Trilostane: A therapeutic consideration for canine hyperadrenocorticism". DVM 360. Archived from the original on 17 February 2013. Retrieved 5 April 2011.
  21. ^ "Trilostane consumer information". Drugs.com. 4 January 2009. Archived from the original on 12 February 2008. Retrieved 3 April 2011.
  22. ^ "Modrenal consumer information". Drugs.com UK. Archived from the original on 14 October 2012. Retrieved 3 April 2011.
  23. ^ "Modrenal". electronic Medicines Compendium UK. Retrieved 3 April 2011.
  24. ^
    PMID 15080470.[permanent dead link] (PDF
    )
  25. ^ a b "Vetoryl approval information". Food and Drug Administration. 5 December 2008. Retrieved 3 April 2011.
  26. ^ Hillier A (2006). "Alopecia: Is an Endocrine Disorder Responsible?" (PDF). Ohio State University Endocrinology Symposium. p. 12 of 67. Retrieved 8 April 2011.[permanent dead link] (PDF)
  27. PMID 15500480. Archived from the original (PDF) on 1 May 2014. Retrieved 16 May 2011. (PDF
    )
  28. ^ "Anipryl consumer information". Drugs.com Vet. Retrieved 3 April 2011.
  29. ^ a b c "Treating Cushing's Disease in Dogs". US Food and Drug Administration. Retrieved 3 April 2011.
  30. PMID 17542193
    .
  31. ^ "VETORYL (trilostane) Capsules Letter - Pharmacy Professionals". Food and Drug Administration. 11 September 2009. Retrieved 3 April 2011.
  32. ^ "Trilocur PI". Union Register of medicinal products. 7 May 2024. Retrieved 18 June 2024.
  33. ^ "Trilorale PI". Union Register of medicinal products. 7 May 2024. Retrieved 18 June 2024.
  34. ^ "Vetoryl Capsules (Trilostane) for Animal Use".
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