Chemical compound
Trilostane
Trade names Vetoryl, others Other names WIN-24,540; 4α,5-Epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile
Routes of administration
By mouth
[1]
ATC code
Legal status
Metabolism
Liver
Metabolites 17-Ketotrilostane
[1]
Elimination half-life Trilostane: 1.2 hours
[1] 17-Ketotrilostane: 1.2 hours
[1]
(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
CAS Number
PubChem
CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (
EPA )
ECHA InfoCard
100.033.743
Formula C 20 H 27 N O 3
Molar mass 329.440 g·mol−1 3D model (
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
Y Key:KVJXBPDAXMEYOA-CXANFOAXSA-N
Y
(verify)
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.
[2]
[3]
[4]
[5]
[1] It was
withdrawn for use in humans in the
United States in the 1990s
[6] but was subsequently approved for use in
veterinary medicine in the 2000s to treat Cushing's syndrome in dogs.
[7] It is taken
by mouth .
[1]
Medical uses
Trilostane has been used in the treatment of
Cushing's syndrome (hypercortisolism),
Conn's syndrome (hyperaldosteronism), and
postmenopausal
breast cancer in humans.
[3]
[1] When used to treat breast cancer, trilostane is administered in combination with a
corticosteroid to prevent
glucocorticoid deficiency .
[1]
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.
[8]
[9] 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]
Contraindications
Trilostane should not be used in
pregnant women.
[1]
Trilostane should not be given to a dog that:
Side effects
Side effects of trilostane in conjunction with a corticosteroid in humans include
gastrointestinal side effects like
gastritis ,
nausea ,
vomiting , and
diarrhea .
[1]
Nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the incidence of diarrhea with trilostane.
[1] 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.
[1] Reversible
granulocytopenia and transient oral
paresthesia may occur with trilostane.
[1]
Pharmacology
Pharmacodynamics
Steroidogenesis . Trilostane inhibits 3β-HSD.
Trilostane is a
steroidogenesis inhibitor .
[1] It is specifically an
inhibitor of
3β-hydroxysteroid dehydrogenase (3β-HSD).
[1]
[13] 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.
[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
noncompetitive
antiestrogen , via direct and presumably
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
metabolized in the
liver .
[1] The major
metabolite of trilostane is 17-ketotrilostane.
[1] The conversion of trilostane into 17-ketotrilostane is
reversible , suggesting that trilostane and 17-ketotrilostane undergo interconversion in the body.
[1] 17-Ketotrilostane circulates at 3-fold higher levels than trilostane and is more active than trilostane as a 3β-HSD inhibitor.
[1] 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.
[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
synthetic
androstane
steroid and a
derivative of
5α-reduced androstane derivatives like
3α-androstanediol ,
3β-androstanediol , and
dihydrotestosterone .
[2]
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]
[6] 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]
[22]
[23]
[8]
Trilostane was approved in the United States in 2008 for the treatment of Cushing's disease (hyperadrenocorticism) in dogs under the brand name Vetoryl.
[24] 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]
[25]
[26]
Trilostane was the first drug approved to treat both
pituitary - and
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.
[27] The only previous treatment for the disease was the use of
mitotane (brand name Lysodren)
off-label .
[9]
[28]
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,
[24] compounding pharmacies are no longer able to use a bulk drug product for compounding purposes, but must prepare the compounded drug from Vetoryl.
[29]
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.
[30] The applicant for this veterinary medicinal product is Emdoka.
[30] 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.
[31] The applicant for this veterinary medicinal product is Axience.
[31]
Generic names
Trilostane is the
generic name of the drug and its
INN Tooltip International Nonproprietary Name ,
USAN Tooltip United States Adopted Name ,
BAN Tooltip British Approved Name , and
JAN Tooltip Japanese Accepted Name .
[2]
[3] Its developmental code name was WIN-24,540 .
[2]
[3]
Brand names
Trilostane has been marketed under a number of brand names including Desopan, Modrastane, Modrenal, Trilox, Vetoryl, Oncovet TL and Winstan.
[2]
[3]
Availability
Trilostane is available for veterinary use in many countries throughout the world.
[32]
References
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b
c
d
e
f
g
h
i
j
k
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m
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ISBN
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^ Negwer M (1987).
Organic-chemical Drugs and Their Synonyms: (an International Survey) . VCH Publishers.
ISBN
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^ Milne GW (8 May 2018).
Drugs: Synonyms and Properties: Synonyms and Properties . Taylor & Francis. pp. 34–.
ISBN
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^
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PMC
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PMID
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^
"Cushing's Disease in Dogs Part 3: Current & Investigative Options for Therapy" . Today's Veterinary Practice . 2016-02-24. Retrieved 2021-01-04 .
^
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"Trilostane treatment in dogs with pituitary-dependent hyperadrenocorticism" . Australian Veterinary Journal . 81 (10): 600–607.
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PMID
15080470 . [
permanent dead link ] (
PDF )
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^
a
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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 .
^
a
b
"Dechra US Datasheet-Vetoryl" (PDF) . Dechra US. Archived from
the original (PDF) on 22 March 2012. Retrieved 3 April 2011 . (
PDF )
^
"Cushing's Disease in Dogs" . NASC LIVE . 2 February 2015. Retrieved 2021-01-04 .
^ de Gier J, Wolthers CH, Galac S, Okkens AC, Kooistra HS (April 2011). "Effects of the 3β-hydroxysteroid dehydrogenase inhibitor trilostane on luteal progesterone production in the dog". Theriogenology . 75 (7): 1271–1279.
doi :
10.1016/j.theriogenology.2010.11.041 .
PMID
21295836 .
^ 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 )
^ Reusch CE (2010).
"Trilostane-A Review of a Success Story" . World Small Animal Veterinary Association (WSAVA). Retrieved 5 April 2011 .
^ le Roux PA, Tregoning SK, Zinn PM, van der Spuy ZM (June 2002).
"Inhibition of progesterone secretion with trilostane for mid-trimester termination of pregnancy: randomized controlled trials" . Human Reproduction . 17 (6): 1483–1489.
doi :
10.1093/humrep/17.6.1483 .
PMID
12042266 .
^
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"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 . 15 : 153–179.
PMC
5518378 .
PMID
29584099 .
^ Takizawa I, Nishiyama T, Hara N, Hoshii T, Ishizaki F, Miyashiro Y, Takahashi K (November 2010). "Trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, has an agonistic activity on androgen receptor in human prostate cancer cells". Cancer Letters . 297 (2): 226–230.
doi :
10.1016/j.canlet.2010.05.015 .
PMID
20831980 .
^
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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 .
^
"Trilostane consumer information" . Drugs.com. 4 January 2009. Archived from
the original on 12 February 2008. Retrieved 3 April 2011 .
^
"Modrenal consumer information" . Drugs.com UK. Archived from
the original on 14 October 2012. Retrieved 3 April 2011 .
^
"Modrenal" . electronic Medicines Compendium UK. Retrieved 3 April 2011 .
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^ 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 )
^ Cerundolo R, Lloyd DH, Persechino A, Evans H, Cauvin A (October 2004).
"Treatment of canine Alopecia X with trilostane" (PDF) . Veterinary Dermatology . 15 (5). European Society of Veterinary Dermatology: 285–293.
doi :
10.1111/j.1365-3164.2004.00403.x .
PMID
15500480 . Archived from
the original (PDF) on 1 May 2014. Retrieved 16 May 2011 . (
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^ Reine NJ (February 2007). "Medical management of pituitary-dependent hyperadrenocorticism: mitotane versus trilostane". Clinical Techniques in Small Animal Practice . 22 (1): 18–25.
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^
"VETORYL (trilostane) Capsules Letter - Pharmacy Professionals" . Food and Drug Administration. 11 September 2009. Retrieved 3 April 2011 .
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b
"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.
^
"Vetoryl Capsules (Trilostane) for Animal Use" .
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