Trilostane

Clinical data
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	H02CA01 (WHO) QH02CA01 (WHO)
Legal status
Legal status	CA: ℞-only US: ℞-only EU: Rx-only[2][3][4][5]
Pharmacokinetic data
Metabolism	Liver
Metabolites	17-Ketotrilostane[1]
Eliminationhalf-life	Trilostane: 1.2 hours[1] 17-Ketotrilostane: 1.2 hours[1]
Identifiers
IUPAC name (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	13647-35-3 Y
PubChemCID	656583
IUPHAR/BPS	6850
DrugBank	DB01108 Y
ChemSpider	570949 Y
UNII	L0FPV48Q5R
KEGG	D01180 Y
ChEBI	CHEBI:32260 Y
ChEMBL	ChEMBL1200907 Y
CompTox Dashboard(EPA)	DTXSID9023706
ECHA InfoCard	100.033.743
Chemical and physical data
Formula	C20H27NO3
Molar mass	329.440 g·mol−1
3D model (JSmol)	Interactive image
SMILES 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 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 nameVetoryl among others, is a medication which has been used in the treatment ofCushing's syndrome,Conn's syndrome, andpostmenopausalbreast cancer in humans.^{[6][7][8][9][1]} It waswithdrawn for use in humans in theUnited States in the 1990s^[10] but was subsequently approved for use inveterinary medicine in the 2000s to treat Cushing's syndrome in dogs.^[11] It is takenby mouth.^[1]

Trilostane has been used in the treatment ofCushing's syndrome (hypercortisolism),Conn's syndrome (hyperaldosteronism), andpostmenopausalbreast cancer in humans.^[7][1] When used to treat breast cancer, trilostane is administered in combination with acorticosteroid to preventglucocorticoid deficiency.^[1]

Trilostane should not be used inpregnant women.^[1]

Trilostane should not be given to a dog that:

• Haskidney orliver disease^[12][13]
• Takes certain medications used to treatcardiovascular disease^[14]
• Ispregnant,nursing or intended for breeding^[12][13]

Side effects of trilostane in conjunction with a corticosteroid in humans includegastrointestinal side effects likegastritis,nausea,vomiting, anddiarrhea.^[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 likepeptic ulcer,erosive gastritis,gastric perforation,hematemesis, andmelena may occur in some individuals.^[1] Reversiblegranulocytopenia and transient oralparesthesia may occur with trilostane.^[1]

Trilostane is asteroidogenesis inhibitor.^[1] It is specifically aninhibitor of3β-hydroxysteroid dehydrogenase (3β-HSD).^[1][15] As a result of this action, trilostane blocks the conversion of Δ⁵-3β-hydroxysteroids, includingpregnenolone,17α-hydroxypregnenolone,dehydroepiandrosterone (DHEA), andandrostenediol, into Δ⁴-3-ketosteroids, includingprogesterone,17α-hydroxyprogesterone,androstenedione, andtestosterone, respectively.^[1] Consequently, trilostane inhibits theproduction of all classes ofsteroid hormones, includingandrogens,estrogens,progestogens,glucocorticoids, andmineralocorticoids.^[1]

Themechanism of action of trilostane in Cushing's syndrome and Conn's syndrome is by inhibiting the production of corticosteroids such ascortisol andaldosterone in theadrenal glands.^[16][17] Trilostane has also been used as anabortifacient due to its inhibition of progesterone synthesis.^[1][18]

Trilostane is not anaromatase inhibitor and hence does not inhibit the conversion of androgens like androstenedione and testosterone into estrogens likeestrone andestradiol.^[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 anoncompetitiveantiestrogen, via direct and presumablyallosteric interactions with theestrogen receptor.^[1][19][20] The effectiveness of trilostane in postmenopausal breast cancer may relate to this apparent antiestrogenic activity.^[1][19][20] Trilostane has also been found to act as anagonist of theandrogen receptor.^[21] As such, its use in men withprostate cancer may warrant caution.^[1]

Trilostane ismetabolized in theliver.^[1] The majormetabolite of trilostane is 17-ketotrilostane.^[1] The conversion of trilostane into 17-ketotrilostane isreversible, 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] Theelimination 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 isexcreted by thekidneys.^[1]

Trilostane, also known as 4α,5-epoxy-3,17β-dihydroxy-5α-androst-2-ene-2-carbonitrile, is asyntheticandrostanesteroid and aderivative of5α-reduced androstane derivatives like3α-androstanediol,3β-androstanediol, anddihydrotestosterone.^[6]

Trilostane is prepared fromtestosterone in a four-stepsynthesis.^{[citation needed]}

Trilostane waswithdrawn from human use in theUnited States market in April 1994.^[22][23][10] It continued to be available in theUnited Kingdom for use in humans under the brand name Modrenal for the treatment ofCushing's disease andbreast cancer in humans, but was eventually discontinued in this country as well.^{[10][24][25][26]}

Trilostane was approved in the United States in 2008 for the treatment of Cushing's disease (hyperadrenocorticism) in dogs under the brand name Vetoryl.^[27] 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.^[12] The drug is also used to treat the skin disorderAlopecia X in dogs.^[22][28][29]

Trilostane was the first drug approved to treat bothpituitary- andadrenal-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.^[30] The only previous treatment for the disease was the use ofmitotane (brand name Lysodren)off-label.^[31][32]

A number ofcompounding pharmacies in the United States sell trilostane for dogs.^{[citation needed]} Since the United States approval of Vetoryl in December 2008,^[27] compounding pharmacies are no longer able to use a bulk drug product for compounding purposes, but must prepare the compounded drug from Vetoryl.^[33]

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.^[34][35]

Trilostane is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andJANTooltip Japanese Accepted Name.^[6][7] Its developmental code name wasWIN-24,540.^[6][7]

Trilostane has been marketed under a number of brand names including Desopan, Modrastane, Modrenal, Trilox, Vetoryl, Oncovet TL and Winstan.^[6][7]

Trilostane is available for veterinary use in countries throughout the world.^[36]

Trilostane is used for the treatment of Cushing's syndrome in dogs. Thesafety andeffectiveness of trilostane for this indication were shown in several studies.^[26][31] Success was measured by improvements in bothblood test results and physical symptoms (normalizedappetite and activity level, and decreased panting,thirst, andurination).^[26][31]

• 3β-Hydroxysteroid dehydrogenase inhibitors
• 11β-Hydroxylase inhibitors
• Androgens
• Androstanes
• Antiestrogens
• Cholesterol side-chain cleavage enzyme inhibitors
• Nitriles
• Oxidoreductase inhibitors
• Withdrawn drugs
• Dog medications

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