Identification
- Summary
Atosiban is an inhibitor of oxytocin and vasopressin used to delay imminent preterm birth in pregnant adult women displaying specific clinical observations.
- Generic Name
- Atosiban
- DrugBank Accession Number
- DB09059
- Background
Atosiban is an inhibitor of the hormones oxytocin and vasopressin. It is used intravenously to halt premature labor. Although initial studies suggested it could be used as a nasal spray and hence would not require hospital admission, it is not used in that form. Atobisan was developed by the Swedish company Ferring Pharmaceuticals. It was first reported in the literature in 1985. Atosiban is licensed in proprietary and generic forms for the delay of imminent pre-term birth in pregnant adult women.
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Atosiban (DB09059)
- Weight
- Average: 994.19
Monoisotopic: 993.441208989 - Chemical Formula
- C43H67N11O12S2
- Synonyms
- Atosiban
- External IDs
- CAP-449
- CAP-476
- CAP-581
- F-314
- ORF 22164
- ORF-22164
- RW-22164
- RWJ 22164
- RWJ-22164
Pharmacology
- Indication
Atosiban is indicated for use in delaying imminent pre-term birth in pregnant adult women with:
- regular uterine contractions of at least 30 s duration at a rate of at least 4 per 30 min
- a cervical dilation of 1-3cm (0-3cm for nulliparas) and effacement of at least 50%
- a gestational age of 24-33 weeks
- a normal fetal heart rate
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Prevention of Premature births •••••••••••• ••••• •••••••••• •• • •••• •••••••• •••••••• • • • •• •••• ••• •••••••••••• •••••• ••••• ••••• ••••• ••••••••••• ••• •••• •• ••••• •• ••••••••• •••••• • • ••••••• •••••••••••• ••• •• •••••••• •••••••• ••••• ••••••••• - Contraindications & Blackbox Warnings
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Atosiban reduces the frequency of uterine contractions to delay pre-term birth in adult females and induces uterine quiescence 5,1.
- Mechanism of action
Atosiban is a synthetic peptide oxytocin antagonist 5,1. It resembles oxytocin with has modifications at the 1, 2, 4, and 8 positions. The N-terminus of the cysteine residue is deaminated to form 3-mercaptopropanic acid at position 1, at position 2 L-tyrosine is modified to D-tyrosine with an ethoxy group replacing the phenol , threonine replaces glutamine at postion 4, and ornithine replaces leucine at position 8.
It binds to membrane bound oxytocin receptors on the myometrium and prevents oxytocin-stimulated increases in inositol triphosphate production 1. This ultimately prevents release of stored calcium from the sarcoplasmic reticulum and subsequent opening of voltage gated calcium channels. This shutdown of cytosolic calcium increase prevents contractions of the uterine muscle, reducing the frequency of contractions and inducing uterine quiescence.
Atosiban has more recently been found to act as a biased ligand at oxytocin receptors 3,4. It acts as an antagonist of Gq coupling, explaining the inhibition of the inositol triphosphate pathway thought to be responsible for the effect on uterine contraction, but acts as an agonist of Gi coupling. This agonism produces a pro-inflammatory effect in the human amnion, activating pro-inflammatory signal tranducer NF-κB 4. It is thought that this reduces atosiban's effectiveness compared to agents which do not produce inflammation as inflammatory mediators are known to play a role in the induction of labour.
Target Actions Organism AOxytocin receptor antagonistHumans UVasopressin V1a receptor antagonistHumans UVasopressin V1b receptor antagonistHumans UVasopressin V2 receptor antagonistHumans - Absorption
In women receiving 300 μg/min by infusion for 6-12 h, average steady state concentrations of 442 ng/mL were reached within 1 h 5. Steady state concentrations increase proportionally to dosage.
- Volume of distribution
Atosiban has a mean volume of distribution of 41.8 L. Atosiban crosses the placenta and, at a dose of 300 μg/min, was found to have a 0.12 maternal/fetal concentration ratio 5.
- Protein binding
Atosiban is 46-48% bound to plasma proteins in pregnant women. It is not known to partition into red blood cells. Differences in the free fraction of drug between maternal and fetal compartments are unknown 5.
- Metabolism
There are two metabolites of atosiban created through the cleavage of the peptide bond between ornithine and proline which is thought to be facilitated by prior cleavage of the disulfide bridge 5,2. The larger fragment remains active as an antagonist of oxytocin receptors but is 10 times less potent than the parent molecule. At a dosage of 300 μg/min the ratio of parent molecule to the main metabolite was observed to be 1.4 at the second hour and 2.8 at the end of infusion 5.
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- Route of elimination
Small amounts of atosiban are found in the urine with 50 times the amount appearing as the large fragment metabolite (des-(Orn⁸, Gly⁹-NH2)-[Mpa¹, D-Tyr(Et)², Thr⁴]-oxytocin 5. The amount of drug excreted in the feces is not known.
- Half-life
Atosiban does not conform to either 1-compartment or 2-compartment kinetics. It has been determined to have an initial half life (tα) of 0.21 h and a terminal half life (tβ) of 1.7 h 5.
- Clearance
Atosiban has a mean clearance rate of 41.8 L/h 5.
- Adverse Effects
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No systemic toxicities were found in rat and dog studies at dosages equivalent to 10 times normal human exposure 5. It is thought that the risk of toxicity is low due to the short duration of action and short half life of atosiban 1.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- 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.
Drug Interaction Integrate drug-drug
interactions in your softwareAlbuterol The risk or severity of adverse effects can be increased when Salbutamol is combined with Atosiban. Arbutamine The risk or severity of adverse effects can be increased when Arbutamine is combined with Atosiban. Arformoterol The risk or severity of adverse effects can be increased when Arformoterol is combined with Atosiban. Celiprolol The risk or severity of adverse effects can be increased when Celiprolol is combined with Atosiban. Clenbuterol The risk or severity of adverse effects can be increased when Clenbuterol is combined with Atosiban. - Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Atosiban acetate 0P5DNO7CEF 914453-95-5 SVDWBHHCPXTODI-QIWYXCRTSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Atosiban Sun Injection, solution 6.75 mg/0.9ml Intravenous Sun Pharmaceutical Industries (Europe) B.V. 2020-12-22 Not applicable EU 
Atosiban Sun Injection, solution, concentrate 37.5 mg/5ml Intravenous Sun Pharmaceutical Industries (Europe) B.V. 2020-12-22 Not applicable EU Tractocile Injection, solution 6.75 mg/0.9ml Intravenous Ferring Pharmaceuticals 2016-09-08 Not applicable EU Tractocile Injection, solution, concentrate 37.5 mg/5ml Intravenous Ferring Pharmaceuticals 2016-09-08 Not applicable EU
Categories
- ATC Codes
- G02CX01 — Atosiban
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as oligopeptides. These are organic compounds containing a sequence of between three and ten alpha-amino acids joined by peptide bonds.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Carboxylic acids and derivatives
- Sub Class
- Amino acids, peptides, and analogues
- Direct Parent
- Oligopeptides
- Alternative Parents
- Cyclic peptides / Macrolactams / N-acyl-alpha amino acids and derivatives / Proline and derivatives / Alpha amino acid amides / Pyrrolidinecarboxamides / N-acylpyrrolidines / Phenol ethers / Phenoxy compounds / Alkyl aryl ethers show 13 more
- Substituents
- Alcohol / Alkyl aryl ether / Alpha-amino acid amide / Alpha-amino acid or derivatives / Alpha-oligopeptide / Amine / Amino acid or derivatives / Aromatic heteromonocyclic compound / Azacycle / Benzenoid show 34 more
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 081D12SI0Z
- CAS number
- 90779-69-4
- InChI Key
- VWXRQYYUEIYXCZ-OBIMUBPZSA-N
- InChI
- InChI=1S/C43H67N11O12S2/c1-5-23(3)35-41(63)53-36(24(4)55)42(64)50-29(20-32(45)56)38(60)51-30(43(65)54-17-8-10-31(54)40(62)49-27(9-7-16-44)37(59)47-21-33(46)57)22-68-67-18-15-34(58)48-28(39(61)52-35)19-25-11-13-26(14-12-25)66-6-2/h11-14,23-24,27-31,35-36,55H,5-10,15-22,44H2,1-4H3,(H2,45,56)(H2,46,57)(H,47,59)(H,48,58)(H,49,62)(H,50,64)(H,51,60)(H,52,61)(H,53,63)/t23-,24+,27-,28+,29-,30-,31-,35-,36-/m0/s1
- IUPAC Name
- (2S)-5-amino-2-{[(2S)-1-[(4R,7S,10S,13S,16R)-13-[(2S)-butan-2-yl]-7-(carbamoylmethyl)-16-[(4-ethoxyphenyl)methyl]-10-[(1R)-1-hydroxyethyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentaazacycloicosane-4-carbonyl]pyrrolidin-2-yl]formamido}-N-(carbamoylmethyl)pentanamide
- SMILES
- [H][C@]1(NC(=O)[C@@]([H])(NC(=O)[C@@H](CC2=CC=C(OCC)C=C2)NC(=O)CCSSC[C@H](NC(=O)[C@H](CC(N)=O)NC1=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCN)C(=O)NCC(N)=O)[C@@H](C)CC)[C@@H](C)O
References
- General References
- Lamont RF: The development and introduction of anti-oxytocic tocolytics. BJOG. 2003 Apr;110 Suppl 20:108-12. [Article]
- Fjellestad-Paulsen A, Lundin S: Metabolism of vasopressin, oxytocin and their analogues [Mpa1, D-Arg8]-vasopressin (dDAVP) and [Mpa1, D-Tyr(Et)2, Thr4, Orn8]-oxytocin (antocin) in human kidney and liver homogenates. Regul Pept. 1996 Nov 14;67(1):27-32. [Article]
- Reversi A, Rimoldi V, Marrocco T, Cassoni P, Bussolati G, Parenti M, Chini B: The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism. J Biol Chem. 2005 Apr 22;280(16):16311-8. doi: 10.1074/jbc.M409945200. Epub 2005 Feb 10. [Article]
- Kim SH, MacIntyre DA, Hanyaloglu AC, Blanks AM, Thornton S, Bennett PR, Terzidou V: The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(alphai) signalling. Mol Cell Endocrinol. 2016 Jan 15;420:11-23. doi: 10.1016/j.mce.2015.11.012. Epub 2015 Nov 14. [Article]
- EMA: Tractocile Product Information [Link]
- External Links
- KEGG Drug
- D03008
- ChemSpider
- 4470550
- BindingDB
- 50177595
- 59639
- ChEBI
- 135899
- ChEMBL
- CHEMBL382301
- ZINC
- ZINC000169362009
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Atosiban
- MSDS
- Download (24 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Treatment Implantation Failure 1 4 Completed Treatment Premature Labour 1 4 Completed Treatment Subfertility 1 4 Recruiting Treatment Premature Births 1 3 Completed Treatment Obstetric Labour, Premature 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Parenteral 6.75 mg/0.9ml Injection, solution, concentrate Intravenous Injection, solution Parenteral Injection, solution 6.75 MG/0.9ML Injection, solution, concentrate Intravenous; Parenteral 37.5 MG/5ML Injection, solution, concentrate Intravenous; Parenteral 75 MG/10ML Injection, solution, concentrate Intravenous 75 mg/10ml Injection, solution Injection, solution Intravenous 6.75 mg/0.9ml Injection, solution Intravenous; Parenteral 6.75 MG/0.9ML Injection, solution, concentrate Intravenous 37.5 MG/5ML Solution Intravenous 37.500 mg Solution, concentrate Intravenous 37.5 mg Solution Parenteral 37.500 mg Solution Intravenous 6.75 mg Solution Parenteral 6.750 mg Injection Intravenous Injection, solution Intravenous; Parenteral 7.5 MG/ML Injection, solution, concentrate Intravenous; Parenteral 7.5 MG/ML Solution Intravenous 6.750 mg Solution 7.5 mg/1ml Injection, solution 7.5 mg/1ml Solution Intravenous 37.5 mg Solution Parenteral 37.5 mg Solution Parenteral 6.75 mg Injection, solution 7.5 mg/ml Injection, solution, concentrate 7.5 mg/ml Injection, solution Intravenous - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.0517 mg/mL ALOGPS logP -0.17 ALOGPS logP -4.6 Chemaxon logS -4.3 ALOGPS pKa (Strongest Acidic) 11.28 Chemaxon pKa (Strongest Basic) 9.59 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 13 Chemaxon Hydrogen Donor Count 11 Chemaxon Polar Surface Area 365.67 Å2 Chemaxon Rotatable Bond Count 18 Chemaxon Refractivity 250.62 m3·mol-1 Chemaxon Polarizability 101.49 Å3 Chemaxon Number of Rings 3 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 273.10178 predictedDeepCCS 1.0 (2019) [M+H]+ 274.92667 predictedDeepCCS 1.0 (2019) [M+Na]+ 280.5626 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Antagonist
- Curator comments
- Used as an antagonist but displays properties of a biased ligand (see Mechanism of Action ). Ki = 397 nmol/L.
- General Function
- Vasopressin receptor activity
- Specific Function
- Receptor for oxytocin. The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system.
- Gene Name
- OXTR
- Uniprot ID
- P30559
- Uniprot Name
- Oxytocin receptor
- Molecular Weight
- 42770.99 Da
References
- Lamont RF: The development and introduction of anti-oxytocic tocolytics. BJOG. 2003 Apr;110 Suppl 20:108-12. [Article]
- Kim SH, MacIntyre DA, Hanyaloglu AC, Blanks AM, Thornton S, Bennett PR, Terzidou V: The oxytocin receptor antagonist, Atosiban, activates pro-inflammatory pathways in human amnion via G(alphai) signalling. Mol Cell Endocrinol. 2016 Jan 15;420:11-23. doi: 10.1016/j.mce.2015.11.012. Epub 2015 Nov 14. [Article]
- Reversi A, Rimoldi V, Marrocco T, Cassoni P, Bussolati G, Parenti M, Chini B: The oxytocin receptor antagonist atosiban inhibits cell growth via a "biased agonist" mechanism. J Biol Chem. 2005 Apr 22;280(16):16311-8. doi: 10.1074/jbc.M409945200. Epub 2005 Feb 10. [Article]
- Akerlund M, Bossmar T, Brouard R, Kostrzewska A, Laudanski T, Lemancewicz A, Serradeil-Le Gal C, Steinwall M: Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women. Br J Obstet Gynaecol. 1999 Oct;106(10):1047-53. [Article]
- Fabry I, De Paepe P, Kips J, Vermeersch S, Van Bortel L: Different effects of tocolytic medication on blood pressure and blood pressure amplification. Eur J Clin Pharmacol. 2011 Jan;67(1):11-7. doi: 10.1007/s00228-010-0926-y. Epub 2010 Nov 16. [Article]
- de Heus R, Mulder EJ, Derks JB, Visser GH: Acute tocolysis for uterine activity reduction in term labor: a review. Obstet Gynecol Surv. 2008 Jun;63(6):383-8; quiz 405. doi: 10.1097/OGX.0b013e31816ff75b. [Article]
- EMA: Tractocile Product Information [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- Curator comments
- Ki = 4.7 nmol/L.
- General Function
- Vasopressin receptor activity
- Specific Function
- Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system. Has been involved in social behavi...
- Gene Name
- AVPR1A
- Uniprot ID
- P37288
- Uniprot Name
- Vasopressin V1a receptor
- Molecular Weight
- 46799.105 Da
References
- Akerlund M, Bossmar T, Brouard R, Kostrzewska A, Laudanski T, Lemancewicz A, Serradeil-Le Gal C, Steinwall M: Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women. Br J Obstet Gynaecol. 1999 Oct;106(10):1047-53. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- Curator comments
- Ki = 256 nmol/L.
- General Function
- Vasopressin receptor activity
- Specific Function
- Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate a phosphatidyl-inositol-calcium second messenger system.
- Gene Name
- AVPR1B
- Uniprot ID
- P47901
- Uniprot Name
- Vasopressin V1b receptor
- Molecular Weight
- 46970.345 Da
References
- Akerlund M, Bossmar T, Brouard R, Kostrzewska A, Laudanski T, Lemancewicz A, Serradeil-Le Gal C, Steinwall M: Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women. Br J Obstet Gynaecol. 1999 Oct;106(10):1047-53. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antagonist
- Curator comments
- Ki = 3195 nmol/L.
- General Function
- Vasopressin receptor activity
- Specific Function
- Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption.
- Gene Name
- AVPR2
- Uniprot ID
- P30518
- Uniprot Name
- Vasopressin V2 receptor
- Molecular Weight
- 40278.57 Da
References
- Akerlund M, Bossmar T, Brouard R, Kostrzewska A, Laudanski T, Lemancewicz A, Serradeil-Le Gal C, Steinwall M: Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women. Br J Obstet Gynaecol. 1999 Oct;106(10):1047-53. [Article]
Drug created at May 11, 2015 21:47 / Updated at February 21, 2021 18:52