Identification

Name
Tixocortol
Accession Number
DB09091
Type
Small Molecule
Groups
Approved, Withdrawn
Description

Tixocortol is a 21-thiol derivative of hydrocortisone classified as a class A corticosteroid. It is a synthetic steroid with topical anti-inflammatory properties without the systemic glucocorticoid and mineralocorticoid activities and toxicity.[11]

Structure
Thumb
Synonyms
Not Available
Product Ingredients
IngredientUNIICASInChI Key
Tixocortol pivalate6K28E35M3B55560-96-8BISFDZNIUZIKJD-XDANTLIUSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Rectovalone 250mg/100mlSuspension250 mgRectalAxcan Pharma1991-12-311998-07-16Canada
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
T.R.U.E. Test Thin-Layer Rapid Use Patch TestTixocortol pivalate (2 ug/48h) + 2,2'-Dibenzothiazyl disulfide (20 ug/48h) + 2-mercaptobenzothiazole (61 ug/48h) + 4-(Isopropylamino)diphenylamine (10 ug/48h) + Bacitracin (486 ug/48h) + Balsam of Peru (648 ug/48h) + Benzocaine (378 ug/48h) + Benzylparaben (162 ug/48h) + Bisphenol A diglycidyl ether (32 ug/48h) + Bromothalonil (4 ug/48h) + Bronopol (203 ug/48h) + Budesonide (0.8 ug/48h) + Butylparaben (162 ug/48h) + Chlorquinaldol (77 ug/48h) + Cinchocaine hydrochloride (66 ug/48h) + Cinnamaldehyde (41 ug/48h) + Cinnamyl alcohol (63 ug/48h) + Clioquinol (77 ug/48h) + Cobalt chloride hexahydrate (4 ug/48h) + Diazolidinylurea (446 ug/48h) + Potassium dichromate (15.7 ug/48h) + Dipentamethylenethiuram disulfide (5.5 ug/48h) + Diphenylguanidine (68 ug/48h) + Disperse Blue 106 (41 ug/48h) + Disulfiram (5.5 ug/48h) + Ditiocarb Zinc (68 ug/48h) + Ethyl hydroxybenzoate (162 ug/48h) + Ethylenediamine (18 ug/48h) + Eugenol (41 ug/48h) + Evernia prunastri (81 ug/48h) + Formaldehyde (146 ug/48h) + Geraniol (81 ug/48h) + Hydrocortisone butyrate (16 ug/48h) + Hydroxycitronellal (63 ug/48h) + Imidurea (486 ug/48h) + Isoeugenol (17 ug/48h) + Lanolin alcohols (810 ug/48h) + Methylchloroisothiazolinone (3 ug/48h) + Methylparaben (162 ug/48h) + Morpholinylmercaptobenzothiazole (20 ug/48h) + N,N'-diphenyl-1,4-phenylenediamine (25 ug/48h) + N-Cyclohexyl-N'-phenyl-1,4-phenylenediamine (25 ug/48h) + Neomycin sulfate (486 ug/48h) + Nickel sulfate hexahydrate (36 ug/48h) + P-Tert-Butylphenol-Formaldehyde Resin (Low Molecular Weight) (36 ug/48h) + Parthenolide (2 ug/48h) + Propylparaben (162 ug/48h) + Quaternium-15 (81 ug/48h) + Rosin (972 ug/48h) + Sodium aurotiosulfate (23 ug/48h) + Tetracaine hydrochloride (66 ug/48h) + Tetramethylthiuram monosulfide (5.5 ug/48h) + Thimerosal (6 ug/48h) + Thiohexam (20 ug/48h) + Thiram (5.5 ug/48h) + Zinc Dibutyldithiocarbamate (68 ug/48h) + alpha-Amyl cinnamaldehyde (17 ug/48h) + p-Phenylenediamine (65 ug/48h)KitSmartPractice Denmark ApS2012-03-01Not applicableUs
Categories
UNII
ZX3KEK657Z
CAS number
61951-99-3
Weight
Average: 378.53
Monoisotopic: 378.18648062
Chemical Formula
C21H30O4S
InChI Key
YWDBSCORAARPPF-VWUMJDOOSA-N
InChI
InChI=1S/C21H30O4S/c1-19-7-5-13(22)9-12(19)3-4-14-15-6-8-21(25,17(24)11-26)20(15,2)10-16(23)18(14)19/h9,14-16,18,23,25-26H,3-8,10-11H2,1-2H3/t14-,15-,16-,18+,19-,20-,21-/m0/s1
IUPAC Name
(1S,2R,10S,11S,14R,15S,17S)-14,17-dihydroxy-2,15-dimethyl-14-(2-sulfanylacetyl)tetracyclo[8.7.0.0²,⁷.0¹¹,¹⁵]heptadec-6-en-5-one
SMILES
[H][C@@]12CC[C@](O)(C(=O)CS)[C@@]1(C)C[C@H](O)[C@@]1([H])[C@@]2([H])CCC2=CC(=O)CC[C@]12C

Pharmacology

Indication

Tixocortol is indicated for the treatment of rhinitis as a nasal suspension or aerosol. It is also used in the form of lozenges for the treatment of pharyngitis and in the form of enemas or rectal solution for the treatment of ulcerative colitis. Tixocortol can be used orally in a suspension or powder for the treatment of inflammatory conditions.[10] It is also the substance used for the screening of contact allergies to class A steroids.[2]

Pharmacodynamics

Tixocortol presents the characteristic of local action which reduces significantly the side effects of systemic glucocorticoids. Reports have demonstrated that gastrointestinal administration of tixocortol generates a decrease in abdominal pain, bleeding, and frequency of stools which resulted in an amelioration in the malabsorption laboratory tests. All the effects were independent of suppression of the pituitary-adrenal axis, which was shown by the absence of significant depression of cortisol.[1] Administration of tixocortol as a nasal spray has been shown to respect nasal drainage by the ciliary beats of the pituitary mucosa.[3] The actions of tixocortol have no effect on leukocyte count, blood glucose level, sodium urinary excretion, and immunosupressive activity on lymphocytes.[9]

Mechanism of action

The mechanism of action of tixocortol is similar to other corticosteroids regarding the binding sites and prostaglandin synthesis but the local properties of tixocortol are given by the immediate liver metabolism and transformation withing red blood cells. All the immediate transformations of tixocortol classified it as part of the nonsystemic steroids.[11]

TargetActionsOrganism
AGlucocorticoid receptor
binder
Human
AHistone deacetylase 2
stimulator
Human
Absorption

The absorption of tixocortol is the same as in other steroids including hydrocortisone.[11] Oral administration of tixocortol presents a 10-20% bioavailability with a significantly lower plasma Cmax than cortisol. The fast metabolism, larger volume of distribution and low bioavailability donates tixocortol with the absence of systemic activity.[4]

Volume of distribution

Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger volume of distribution compared to cortisol of 21.7 L/kg.[4]

Protein binding

The presence of the C-17 in the corticosteroids is a protein binding site.[8]

Metabolism

Tixocortol is rapidly modified within red blood cells and it is immediately metabolized by a first-pass liver metabolism.[11] The metabolites of tixocortol are mainly represented by the formation of sulfo- and glucurono-conjugates which are later hydrolyzed from the conjugate forming neutral steroids. The metabolic transformations are the reduction of the 3-keto and delta 4 system, reduction of the C-20 carbonyl group, oxidation of the C-11 alcohol and cleavage of the side chain at C-17. The specific metabolic pathways of the C-21 thiol ester function were its transformation into methylthio, methylsulfonyl and methylsulfonyl derivatives and reductive cleavage of the C-21-S bond leading to 21-methyl structures. None of the metabolites have affinity for glucocorticoid receptors. This and the extensive metabolism explains the exclusive local activities of tixocortol.[5]

Route of elimination

Tixocortol has a rapid elimination after continuous metabolism. Urine analysis of oral administration of tixocortol demonstrate a complete lack of unchanged drug.[5]

Half life

Tixocortol presents a shorter half-life than cortisol.[6]

Clearance

Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger clearance rate compared to cortisol of 33.3 L h/kg.[4]

Toxicity

Diverse studies performed on tixocortol proved that this drug is non-toxic and non-immunosupressive. This low toxicity and abscence of immuno supression gave tixocortol the potential to be a lead for topical or local anti-inflammatory treatments.[7] Nevertheless, toxicortol is a potent cutaneous sensitizer, causing a local allergy.[3]

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe therapeutic efficacy of (R)-warfarin can be increased when used in combination with Tixocortol.
(S)-WarfarinThe therapeutic efficacy of (S)-Warfarin can be increased when used in combination with Tixocortol.
1-TestosteroneThe risk or severity of edema formation can be increased when 1-Testosterone is combined with Tixocortol.
1,10-PhenanthrolineThe therapeutic efficacy of 1,10-Phenanthroline can be decreased when used in combination with Tixocortol.
16-BromoepiandrosteroneThe risk or severity of edema formation can be increased when 16-Bromoepiandrosterone is combined with Tixocortol.
19-norandrostenedioneThe risk or severity of edema formation can be increased when 19-norandrostenedione is combined with Tixocortol.
1alpha-Hydroxyvitamin D5The therapeutic efficacy of 1alpha-Hydroxyvitamin D5 can be decreased when used in combination with Tixocortol.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Tixocortol.
4-hydroxycoumarinThe therapeutic efficacy of 4-hydroxycoumarin can be increased when used in combination with Tixocortol.
4-HydroxytestosteroneThe risk or severity of edema formation can be increased when 4-Hydroxytestosterone is combined with Tixocortol.
Food Interactions
Not Available

References

General References
  1. Friedman BS, Metcalfe DD: Effects of tixocortol pivalate on gastrointestinal disease in systemic mastocytosis: a preliminary study. Clin Exp Allergy. 1991 Mar;21(2):183-8. [PubMed:2043986]
  2. Rasanen L, Tuomi ML, Ylitalo L: Reactivity of tixocortol pivalate-positive patients in intradermal and oral provocation tests. Br J Dermatol. 1996 Dec;135(6):931-4. [PubMed:8977714]
  3. Bircher AJ, Hirsbrunner P, Tschopp K, Wildermuth V: Allergic contact dermatitis from tixocortol pivalate in a nasal spray masquerading as infectious complication of sinusitis. ORL J Otorhinolaryngol Relat Spec. 1995 Jan-Feb;57(1):54-6. [PubMed:7700614]
  4. Chanoine F, Junien JL: Comparative pharmacokinetic studies of tixocortol pivalate and cortisol in the rat. J Steroid Biochem. 1984 Oct;21(4):453-9. [PubMed:6492803]
  5. Chanoine F, Grenot C, Sellier N, Barrett WE, Thompson RM, Fentiman AF, Nixon JR, Goyer R, Junien JL: Isolation and identification of major metabolites of tixocortol pivalate in human urine. Drug Metab Dispos. 1987 Nov-Dec;15(6):868-76. [PubMed:2893715]
  6. Lelievre V, Bertin B, Chanoine F, Bure J, Junien JL: Correlation between binding activity, inhibition of lymphoblastic transformation and metabolism of tixocortol 21 pivalate in mouse thymocytes. Agents Actions. 1987 Aug;21(3-4):262-5. [PubMed:3500591]
  7. Uphill PF: A comparison of the effects of tixocortol pivalate (JO 1016), beclomethasone dipropionate and hydrocortisone acetate on the activation of lymphocytes. Arzneimittelforschung. 1981;31(3):459-62. [PubMed:6784735]
  8. Rietschel R. and Fowler J. (2008). Fisher's contact dermatitis. BC Decker.
  9. Rainsford K. and Velo G. (1989). New developments in antirheumatic therapy. Kluwer Academic Publishers.
  10. Chemotechnique diagnostics [Link]
  11. Clinical experience with tixocortol pivalate [Link]
External Links
PubChem Compound
162955
PubChem Substance
310265018
ChemSpider
143053
ChEBI
63560
Wikipedia
Tixocortol
ATC Codes
A07EA05 — TixocortolR01AD07 — TixocortolR01AD57 — Tixocortol, combinations
MSDS
Download (26.7 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
SuspensionRectal250 mg
Kit
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)50-55ºC'MSDS'
boiling point (°C)607ºC at 760 mmHg'MSDS'
water solubilityInsoluble'MSDS'
logP4.48'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.0428 mg/mLALOGPS
logP2.42ALOGPS
logP2.32ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)9.57ChemAxon
pKa (Strongest Basic)-2.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area74.6 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity103.53 m3·mol-1ChemAxon
Polarizability41.96 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
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

Taxonomy

Description
This compound belongs to the class of organic compounds known as gluco/mineralocorticoids, progestogins and derivatives. These are steroids with a structure based on a hydroxylated prostane moiety.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Pregnane steroids
Direct Parent
Gluco/mineralocorticoids, progestogins and derivatives
Alternative Parents
20-oxosteroids / 3-oxo delta-4-steroids / 17-hydroxysteroids / 11-beta-hydroxysteroids / Delta-4-steroids / Cyclohexenones / Tertiary alcohols / Alpha-hydroxy ketones / Secondary alcohols / Cyclic alcohols and derivatives
show 3 more
Substituents
Progestogin-skeleton / 20-oxosteroid / 3-oxo-delta-4-steroid / 3-oxosteroid / 17-hydroxysteroid / 11-hydroxysteroid / 11-beta-hydroxysteroid / Hydroxysteroid / Oxosteroid / Delta-4-steroid
show 16 more
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
3-oxo steroid, 11beta-hydroxy steroid, 17alpha-hydroxy steroid, 20-oxo steroid, steroid sulfide (CHEBI:63560)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Binder
General Function
Zinc ion binding
Specific Function
Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modula...
Gene Name
NR3C1
Uniprot ID
P04150
Uniprot Name
Glucocorticoid receptor
Molecular Weight
85658.57 Da
References
  1. Barnes PJ: How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. 2006 Jun;148(3):245-54. doi: 10.1038/sj.bjp.0706736. [PubMed:16604091]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Stimulator
General Function
Transcription factor binding
Specific Function
Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an impo...
Gene Name
HDAC2
Uniprot ID
Q92769
Uniprot Name
Histone deacetylase 2
Molecular Weight
55363.855 Da
References
  1. Barnes PJ: How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. 2006 Jun;148(3):245-54. doi: 10.1038/sj.bjp.0706736. [PubMed:16604091]

Drug created on September 15, 2015 15:31 / Updated on November 02, 2018 08:46