Tibolone

Identification

Generic Name

Tibolone

DrugBank Accession Number

DB09070

Background

Tibolone is a synthetic steroid hormone drug, which is mainly non-selective in its binding profile, acting as an agonist primarily at estrogen receptors (ER), with a preference for ER alpha ¹¹.

Tibolone (Livial, Org OD 14), produced by Organon (West Orange, NJ), is a synthetic steroid that possesses estrogenic, androgenic and progestogenic properties. It has been used in Europe for almost 2 decades, primarily for the prevention of postmenopausal osteoporosis and the treatment of post-menopausal symptoms ⁴. Tibolone is approved in 90 countries to manage menopausal symptoms and in 45 countries to prevent the development of osteoporosis ¹².

In June 2006, Organon Pharmaceuticals announced the receipt of a Not Approvable Letter from the U.S. Food and Drug Administration (FDA), advising the company that the New Drug Application (NDA) for tibolone had not been approved ⁵.

Interestingly, the use of tibolone in the treatment cardiovascular disease has been studied with inconclusive results ². Tibolone has been to have anti-resorptive effects on bone ¹¹.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Tibolone (DB09070)

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Weight

Average: 312.453
Monoisotopic: 312.208930142

Chemical Formula

C₂₁H₂₈O₂

Synonyms

• 17-hydroxy-7alpha-methyl-19-nor-17alpha-pregn-5(10)-en-20-yn-3-one
• tibolona
• Tibolone
• tibolonum

External IDs

• ORG OD 14

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Pharmacology

Indication

For the relief of post-menopausal symptoms and for the prevention of osteoporosis ⁷.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Treatment of	Vasomotor symptoms associated with menopause		••••••••••••	••••••••••••••	• •••• ••••••••••••••	••••••

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Pharmacodynamics

Tibolone prevents bone loss and treating post-menopausal symptoms without stimulating the endometrial tissues, which may lead to malignancy. Typical, drugs that treat post-menopausal symptoms such as estrogen, have a proliferative effect on the endometrium, increasing the risk of endometrial carcinoma ⁸. The effects on the bone, brain and vaginal tissues can be explained by the estrogenic activity of tibolone. It is important to note that activity is not expressed in the endometrium. Tibolone behaves differently from estrogen plus progesterone combinations on the breast. Therefore, tibolone can be characterized as a selective estrogen activity regulator ¹.

Tibolone has been demonstrated to be an effective agent in treating symptoms associated with menopause. A 16 week trial in 1189 women examined the effect of tibolone 2.5 mg once daily on climacteric symptoms. Women treated with tibolone showed improvement from baseline in typical menopausal symptoms including hot flashes, sweating, insomnia, and anxiety ¹⁴.

Mechanism of action

This drug's effects are owed to the activity of its metabolites in various tissues ⁴.

Upon ingestion, tibolone is quickly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has progestogenic and androgenic effects. The specific tissue-selective effects of tibolone occur due to the metabolism, regulation of enzymes and receptor activation that varies in different tissues of the body.

The bone-conserving effects occur due to estradiol receptor activation, while the progesterone and androgen receptors are not involved in this process. Breast tissue of monkeys is not found to be stimulated after tibolone administration, as occurs with estrogen plus progesterone used in combination. This is explained by the fact that tibolone and its metabolites inhibit sulphatase and 17 beta-hydroxysteroid dehydrogenase (HSD) type I and stimulate sulphotransferase and 17 beta-HSD type II. The combined effects of this process prevent the conversion to active estrogens.

In the uterus, the progestogenic activity of the Delta(4)-metabolite and the effect on estrogen-inactivating enzymes prevent estrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone has been shown to regulate estrogenic activity in several tissue types by influencing the availability of estrogenic compounds for the estradiol receptor in a selective manner ².

Additionally, tibolone modulates cellular homeostasis in the breast by preventing breast tissue proliferation and stimulating cell apoptosis. Tibolone does not stimulate the endometrium because of the action of its highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulfatase (inhibition)-sulfotransferase (stimulation) system. The estrogenic metabolites of tibolone have direct, favorable effects on the cardiovascular system and, in animal models, this drug has shown no adverse consequences.

The tissue-selective effects of tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone-preserving effects of tibolone are the result of estradiol receptor activation, while other steroid receptors, mainly the progesterone and androgen receptors, are not involved in this process.

In a study of monkeys, breast tissue was not stimulated, which occurs with estrogen and progesterone, because tibolone and its metabolites inhibit sulfatase and 17 beta-hydroxysteroid _dehydrogenase (HSD) type I and stimulate _sulfotransferase and 17 beta-HSD type II. The simultaneous effects of this process halt conversion to active estrogens. Additionally, tibolone affects cellular homeostasis in the breast by preventing proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium due to the action of the highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulphatase (inhibition)-sulphotransferase (stimulation) pathway ¹.

The levels of tibolone metabolites and the alteration of hormonal activities vary according to the tissue type. In endometrial tissue the Δ4-isomer functions as a progestagen, however, in the brain and liver, it shows androgenic effects. In breast tissue, the primary actions of tibolone are strong inhibition of sulfatase activity and weak inhibition of 17β-hydroxysteroid dehydrogenase activity, which leads to blocking the conversion estrone sulfate to E2 ⁴.

Target	Actions	Organism
AEstrogen receptor alpha	antagonist agonist	Humans

Absorption

Tibolone is extensively and rapidly absorbed after oral administration ¹⁴. The parent drug undergoes extensive metabolism, with. Greater than 80% of a radioactive dose excreted from the body as metabolites, which suggests very low plasma concentrations of tibolone. Plasma concentrations of the metabolites appear within 30 minutes and peak within 1–1.5 hours.2,7 The plasma concentrations of the hydroxymetabolites are higher than those of the ∆4-isomer. Food does not appear to have an effect on the absorption of this drug ¹⁴.

Volume of distribution

Not Available

Protein binding

Tibolone is 96% bound to plasma proteins, most likely albumin.¹⁶

Metabolism

Tibolone is metabolized mainly in the liver ⁴.

The cytochrome P450 isoenzyme system is involved in minor hydroxylation of tibolone ¹⁴.

Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has both progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulfated form ¹.

Route of elimination

Excreted in the urine and feces in the form of sulfated metabolites.^4,14 About 40% of the drug is excreted as metabolites in urine.¹⁶

The predominant route of elimination of tibolone is via the feces:¹⁴ about 60% of the drug is excreted as metabolites in feces.¹⁶

Half-life

The elimination half-life is approximately 45 h ⁴.

Clearance

Elimination of tibolone is not dependent renal function ¹⁴.

Adverse Effects

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Toxicity

>2000 mg/kg ^MSDS

The Million Women Study (MWS), which had a prospective observational design, studied the use of hormone replacement therapy. The results indicated that the increase in the incidence of breast cancer with estrogen and progestogen (compared to estrogen alone) was greater than the reduction in occurrence of endometrial cancer associated with adding progestogen to estrogen therapy. The MWS also reported a marked increase in the incidence of breast cancer with tibolone and with implanted and transdermal estrogen-only preparations ⁶.

Tibolone treatment in rodent studies showed an increased association with the development of a range of tumors in long-term oral carcinogenicity studies. These tumors included pituitary adenomas, mammary carcinomas and fibroadenomas, hepatic adenomas, uterine carcinoma, stromal polyps and stromal sarcoma, and carcinomas of the urinary bladder and testes. Tibolone failed to show any evidence of genotoxicity in studies for gene mutations, chromosomal damage as well as DNA damage ⁹.

Other adverse effects these include dizziness, headache, nausea, abdominal pain, rashes, pruritus, weight gain, edema, and migraine ¹⁶.

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Abciximab	Tibolone may increase the anticoagulant activities of Abciximab.
Aceclofenac	Aceclofenac may increase the thrombogenic activities of Tibolone.
Acenocoumarol	Tibolone may increase the anticoagulant activities of Acenocoumarol.
Acetohexamide	The therapeutic efficacy of Acetohexamide can be decreased when used in combination with Tibolone.
Adalimumab	Tibolone may increase the thrombogenic activities of Adalimumab.

Food Interactions

• Avoid St. John's Wort. St. John's Wort induces CYP3A4, increasing the metabolism of estrogens and progesterone and therefore reducing the efficacy of tibolone.
• Take with or without food.

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Categories

ATC Codes

G03CX01 — Tibolone

• G03CX — Other estrogens
• G03C — ESTROGENS
• G03 — SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM
• G — GENITO URINARY SYSTEM AND SEX HORMONES

Drug Categories

• Anabolic Agents
• Antineoplastic Agents, Hormonal
• Cardiovascular Agents
• Estrogen Receptor Modulators
• Estrogens
• Estrogens, Antiestrogens, and Estrogen Agonist-Antagonists
• Fused-Ring Compounds
• Genito Urinary System and Sex Hormones
• Hormone Antagonists
• Hormones
• Hormones, Hormone Substitutes, and Hormone Antagonists
• Norpregnanes
• Norsteroids
• Sex Hormones and Modulators of the Genital System
• Steroids

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as oxosteroids. These are steroid derivatives carrying a C=O group attached to steroid skeleton.

Kingdom

Organic compounds

Super Class

Lipids and lipid-like molecules

Class

Steroids and steroid derivatives

Sub Class

Oxosteroids

Direct Parent

Oxosteroids

Alternative Parents

3-oxosteroids / 17-hydroxysteroids / Cyclohexenones / Ynones / Tertiary alcohols / Cyclic alcohols and derivatives / Acetylides / Organic oxides / Hydrocarbon derivatives

Substituents

17-hydroxysteroid / 3-oxosteroid / Acetylide / Alcohol / Aliphatic homopolycyclic compound / Carbonyl group / Cyclic alcohol / Cyclic ketone / Cyclohexenone / Hydrocarbon derivative

Molecular Framework

Aliphatic homopolycyclic compounds

External Descriptors

terminal acetylenic compound, 17beta-hydroxy steroid (CHEBI:32223)

Affected organisms

Not Available

Chemical Identifiers

UNII

FF9X0205V2

CAS number

5630-53-5

InChI Key

WZDGZWOAQTVYBX-XOINTXKNSA-N

InChI

InChI=1S/C21H28O2/c1-4-21(23)10-8-18-19-13(2)11-14-12-15(22)5-6-16(14)17(19)7-9-20(18,21)3/h1,13,17-19,23H,5-12H2,2-3H3/t13-,17-,18+,19-,20+,21+/m1/s1

IUPAC Name

(1S,9R,10R,11S,14R,15S)-14-ethynyl-14-hydroxy-9,15-dimethyltetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadec-2(7)-en-5-one

SMILES

[H][C@@]12CC[C@@](O)(C#C)[C@@]1(C)CC[C@]1([H])C3=C(CC(=O)CC3)C[C@@]([H])(C)[C@@]21[H]

References

General References

1. Kloosterboer HJ: Tissue-selectivity: the mechanism of action of tibolone. Maturitas. 2004 Aug 30;48 Suppl 1:S30-40. doi: 10.1016/j.maturitas.2004.02.012. [Article]
2. Campisi R, Marengo FD: Cardiovascular effects of tibolone: a selective tissue estrogenic activity regulator. Cardiovasc Drug Rev. 2007 Summer;25(2):132-45. doi: 10.1111/j.1527-3466.2007.00007.x. [Article]
3. Steckelbroeck S, Oyesanmi B, Jin Y, Lee SH, Kloosterboer HJ, Penning TM: Tibolone metabolism in human liver is catalyzed by 3alpha/3beta-hydroxysteroid dehydrogenase activities of the four isoforms of the aldo-keto reductase (AKR)1C subfamily. J Pharmacol Exp Ther. 2006 Mar;316(3):1300-9. doi: 10.1124/jpet.105.091587. Epub 2005 Dec 8. [Article]
4. Tibolone for Postmenopausal Women: Systematic Review of Randomized Trials [Link]
5. Tibolone Approval Status [Link]
6. WHO DRUG INFORMATION [Link]
7. Livial [Link]
8. Postmenopausal hormonal therapy: Current status [Link]
9. LIVIAL- Drug sheet NZ [Link]
10. Tibolone Drug Monograph [Link]
11. Tibolone inhibits bone resorption without secondary positive effects on cartilage degradation [Link]
12. The Effects of Tibolone in Older Postmenopausal Women [Link]
13. Tibolone Metabolism in Human Liver Is Catalyzed by 3α/3β-Hydroxysteroid Dehydrogenase Activities of the Four Isoforms of the Aldo-Keto Reductase (AKR)1C Subfamily [Link]
14. Tibolone: A Unique Version of Hormone Replacement Therapy [Link]
15. Cardiovascular Effects of Tibolone: A Selective Tissue Estrogenic Activity Regulator [Link]
16. Drug and Liver prelims [Link]

External Links

KEGG Drug

D01639

PubChem Compound

444008

PubChem Substance

347827821

ChemSpider

392038

RxNav

38260

ChEBI

32223

ChEMBL

CHEMBL2103774

ZINC

ZINC000003812889

Wikipedia

Tibolone

MSDS

Download (91.5 KB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Prevention	Cholesterol, HDL	1
4	Completed	Treatment	Menopausal Depression	1
4	Completed	Treatment	Menopausal Syndromes	1
4	Completed	Treatment	Menopause	2
4	Completed	Treatment	Osteopenia (Disorder)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	2.500 mg
Tablet	Oral
Tablet, film coated	Oral	2.5 mg
Tablet	Oral	2.5 mg

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	<0.1 g/L	MSDS

Predicted Properties

Property	Value	Source
Water Solubility	0.00722 mg/mL	ALOGPS
logP	2.69	ALOGPS
logP	3.1	Chemaxon
logS	-4.6	ALOGPS
pKa (Strongest Acidic)	16.27	Chemaxon
pKa (Strongest Basic)	-1.7	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	2	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	37.3 Å2	Chemaxon
Rotatable Bond Count	0	Chemaxon
Refractivity	91.73 m3·mol-1	Chemaxon
Polarizability	36.77 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	Yes	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
LC-MS/MS Spectrum - LC-ESI-qTof , Positive	LC-MS/MS	splash10-0002-0971000000-09912161a9fdfe89ed83
MS/MS Spectrum - , positive	LC-MS/MS	splash10-0002-0971000000-09912161a9fdfe89ed83
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-03di-0029000000-b8d3ce8417a17751fafc
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-03di-0009000000-8bc956f7e53c5b64d359
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004j-0982000000-9923925cef5bf0f01981
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-03di-0019000000-f9f61e2187c2d3f848a6
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-001r-0091000000-3228ee39c140e60332c5
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01tl-1920000000-9dfbeead7295b24d00ac
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	185.5748773	predicted	DarkChem Lite v0.1.0
[M-H]-	174.0738	predicted	DeepCCS 1.0 (2019)
[M+H]+	187.4292773	predicted	DarkChem Lite v0.1.0
[M+H]+	176.46938	predicted	DeepCCS 1.0 (2019)
[M+Na]+	186.4949773	predicted	DarkChem Lite v0.1.0
[M+Na]+	182.38191	predicted	DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.

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Details1. Estrogen receptor alpha

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

Agonist

General Function

Zinc ion binding

Specific Function

Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissu...

Gene Name

ESR1

Uniprot ID

P03372

Uniprot Name

Estrogen receptor

Molecular Weight

66215.45 Da

References

1. Escande A, Servant N, Rabenoelina F, Auzou G, Kloosterboer H, Cavailles V, Balaguer P, Maudelonde T: Regulation of activities of steroid hormone receptors by tibolone and its primary metabolites. J Steroid Biochem Mol Biol. 2009 Aug;116(1-2):8-14. doi: 10.1016/j.jsbmb.2009.03.008. Epub 2009 Apr 2. [Article]

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Drug created at May 14, 2015 15:49 / Updated at February 20, 2024 23:55