Identification

Name
Tibolone
Accession Number
DB09070
Type
Small Molecule
Groups
Approved, Investigational
Description

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].

Structure
Thumb
Synonyms
  • 17-hydroxy-7alpha-methyl-19-nor-17alpha-pregn-5(10)-en-20-yn-3-one
  • tibolona
  • tibolonum
External IDs
ORG OD 14
Categories
UNII
FF9X0205V2
CAS number
5630-53-5
Weight
Average: 312.453
Monoisotopic: 312.208930142
Chemical Formula
C21H28O2
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]

Pharmacology

Indication

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

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].

TargetActionsOrganism
AEstrogen receptor alpha
antagonist
agonist
Human
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
Not Available
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].

The predominant route of elimination of tibolone is via the feces, although some excretion occurs via the urine [14].

Half life

The elimination half-life is approximately 45 h [4].

Clearance

Elimination of tibolone is not dependent renal function [14].

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 [L1728].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinTibolone may increase the anticoagulant activities of (R)-warfarin.
(S)-WarfarinTibolone may increase the anticoagulant activities of (S)-Warfarin.
3,5-diiodothyropropionic acidThe therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Tibolone.
4-hydroxycoumarinTibolone may increase the anticoagulant activities of 4-hydroxycoumarin.
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Tibolone.
AbciximabTibolone may increase the anticoagulant activities of Abciximab.
AbituzumabTibolone may increase the thrombogenic activities of Abituzumab.
AceclofenacAceclofenac may increase the thrombogenic activities of Tibolone.
AcenocoumarolTibolone may increase the anticoagulant activities of Acenocoumarol.
Acetylsalicylic acidTibolone may increase the anticoagulant activities of Acetylsalicylic acid.
Food Interactions
Not Available

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. [PubMed:15337246]
  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. [PubMed:17614936]
  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. [PubMed:16339391]
  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]
External Links
KEGG Drug
D01639
PubChem Compound
444008
PubChem Substance
347827821
ChemSpider
392038
ChEBI
32223
ChEMBL
CHEMBL2103774
Wikipedia
Tibolone
ATC Codes
G03CX01 — Tibolone
MSDS
Download (91.5 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Unknown StatusTreatmentDepression / Major Depressive Disorder (MDD)1
2CompletedTreatmentCancer, Breast / Menopause / Postmenopausal Bone Loss1
3CompletedOtherPostmenopausal Women1
3CompletedTreatmentCancer, Breast1
3CompletedTreatmentCancer, Breast / Climacteric Symptoms1
3CompletedTreatmentOsteoporosis1
3CompletedTreatmentSexual Dysfunctions1
4CompletedPreventionCholesterol, HDL1
4CompletedTreatmentMenopause2
4CompletedTreatmentOsteopenia1
4CompletedTreatmentOne to five years postmenopausal / Osteoporosis1
4CompletedTreatmentVasomotor Symptoms1
4Not Yet RecruitingTreatmentAmenorrhea / Endometriosis / Quality of Life1
4RecruitingTreatmentMenopausal Depression1
4RecruitingTreatmentMenopausal Syndromes1
4TerminatedTreatmentPerimenopausal Depression1
Not AvailableCompletedTreatmentFlow-mediated Dilation Evaluation of the Brachial Artery1
Not AvailableCompletedTreatmentMenopause1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubility<0.1 g/LMSDS
Predicted Properties
PropertyValueSource
Water Solubility0.00722 mg/mLALOGPS
logP2.69ALOGPS
logP3.1ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)16.27ChemAxon
pKa (Strongest Basic)-1.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area37.3 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity91.73 m3·mol-1ChemAxon
Polarizability36.77 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0002-0971000000-09912161a9fdfe89ed83

Taxonomy

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
3-oxosteroid / Hydroxysteroid / Oxosteroid / 17-hydroxysteroid / Cyclohexenone / Ynone / Cyclic alcohol / Tertiary alcohol / Ketone / Cyclic ketone
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
terminal acetylenic compound, 17beta-hydroxy steroid (CHEBI:32223)

Targets

Kind
Protein
Organism
Human
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. [PubMed:19464167]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Sulfuric ester hydrolase activity
Specific Function
Conversion of sulfated steroid precursors to estrogens during pregnancy.
Gene Name
STS
Uniprot ID
P08842
Uniprot Name
Steryl-sulfatase
Molecular Weight
65491.72 Da
References
  1. Tibolone: A Unique Version of Hormone Replacement Therapy [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Steroid delta-isomerase activity
Specific Function
3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. The 3-beta-HSD enzymatic system pl...
Gene Name
HSD3B1
Uniprot ID
P14060
Uniprot Name
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1
Molecular Weight
42251.25 Da
References
  1. Tibolone: A Unique Version of Hormone Replacement Therapy [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Steroid delta-isomerase activity
Specific Function
3-beta-HSD is a bifunctional enzyme, that catalyzes the oxidative conversion of Delta(5)-ene-3-beta-hydroxy steroid, and the oxidative conversion of ketosteroids. The 3-beta-HSD enzymatic system pl...
Gene Name
HSD3B2
Uniprot ID
P26439
Uniprot Name
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 2
Molecular Weight
42051.845 Da
References
  1. Tibolone: A Unique Version of Hormone Replacement Therapy [Link]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Substrate
General Function
Sulfotransferase activity
Specific Function
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of catecholamines, phenolic drugs and neurotransmitters. Has also estroge...
Gene Name
SULT1A1
Uniprot ID
P50225
Uniprot Name
Sulfotransferase 1A1
Molecular Weight
34165.13 Da
References
  1. Cardiovascular Effects of Tibolone: A Selective Tissue Estrogenic Activity Regulator [Link]

Drug created on May 14, 2015 09:49 / Updated on November 02, 2018 06:58