Atosiban

Identification

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Name
Atosiban
Accession Number
DB09059
Type
Small Molecule
Groups
Approved, Investigational
Description

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.

Structure
Thumb
Synonyms
  • Atosiban
External IDs
CAP-449 / CAP-476 / CAP-581 / F-314 / ORF 22164 / ORF-22164 / RW-22164 / RWJ 22164 / RWJ-22164
Product Ingredients
IngredientUNIICASInChI Key
Atosiban acetate0P5DNO7CEF914453-95-5SVDWBHHCPXTODI-QIWYXCRTSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TractocileInjection, solution, concentrate37.5 mg/5mlIntravenousFerring Pharmaceuticals2000-01-20Not applicableEu
TractocileInjection, solution6.75 mg/0.9mlIntravenousFerring Pharmaceuticals2000-01-20Not applicableEu
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories
UNII
081D12SI0Z
CAS number
90779-69-4
Weight
Average: 994.19
Monoisotopic: 993.441208989
Chemical Formula
C43H67N11O12S2
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

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
Associated Therapies
Pharmacodynamics

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.

TargetActionsOrganism
AOxytocin receptor
antagonist
Humans
UVasopressin V1a receptor
antagonist
Humans
UVasopressin V1b receptor
antagonist
Humans
UVasopressin V2 receptor
antagonist
Humans
Additional Data Available
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Contraindications

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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.

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.

Toxicity

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.

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

Interactions

Drug Interactions
DrugInteraction
AbediterolThe risk or severity of adverse effects can be increased when Abediterol is combined with Atosiban.
ArbutamineThe risk or severity of adverse effects can be increased when Arbutamine is combined with Atosiban.
ArformoterolThe risk or severity of adverse effects can be increased when Arformoterol is combined with Atosiban.
BambuterolThe risk or severity of adverse effects can be increased when Bambuterol is combined with Atosiban.
BatefenterolThe risk or severity of adverse effects can be increased when Batefenterol is combined with Atosiban.
BitolterolThe risk or severity of adverse effects can be increased when Bitolterol is combined with Atosiban.
CeliprololThe risk or severity of adverse effects can be increased when Celiprolol is combined with Atosiban.
ClenbuterolThe risk or severity of adverse effects can be increased when Clenbuterol is combined with Atosiban.
DobutamineThe risk or severity of adverse effects can be increased when Dobutamine is combined with Atosiban.
DoxofyllineThe risk or severity of adverse effects can be increased when Doxofylline is combined with Atosiban.
Additional Data Available
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Food Interactions
Not Available

References

General References
  1. Lamont RF: The development and introduction of anti-oxytocic tocolytics. BJOG. 2003 Apr;110 Suppl 20:108-12. [PubMed:12763125]
  2. 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. [PubMed:8952002]
  3. 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. [PubMed:15705593]
  4. 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. [PubMed:26586210]
  5. EMA: Tractocile Product Information [Link]
External Links
KEGG Drug
D03008
ChemSpider
4470550
BindingDB
50177595
ChEBI
135899
ChEMBL
CHEMBL382301
Wikipedia
Atosiban
ATC Codes
G02CX01 — Atosiban
MSDS
Download (24 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentHealthy Volunteers1
1Not Yet RecruitingTreatmentRepeated Implantation Failure1
2CompletedTreatmentIn Vitro Fertilisation (IVF) Treatment1
2CompletedTreatmentPremature Labour1
2RecruitingTreatmentPremature Labour1
3Active Not RecruitingTreatmentObstetric Labour, Premature1
3Not Yet RecruitingTreatmentLabor Preterm Multiple1
3TerminatedTreatmentObstetric Labour, Premature1
3WithdrawnTreatmentThreatened Preterm Labor1
4CompletedTreatmentPremature Labour1
4CompletedTreatmentSubfertility1
4RecruitingTreatmentImplantation Failure1
Not AvailableCompletedTreatmentPremature Births1
Not AvailableCompletedTreatmentRepeated Implantation Failure1
Not AvailableRecruitingTreatmentInfertility, Female1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionIntravenous6.75 mg/0.9ml
Injection, solution, concentrateIntravenous37.5 mg/5ml
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0517 mg/mLALOGPS
logP-0.17ALOGPS
logP-4.6ChemAxon
logS-4.3ALOGPS
pKa (Strongest Acidic)11.28ChemAxon
pKa (Strongest Basic)9.59ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count13ChemAxon
Hydrogen Donor Count11ChemAxon
Polar Surface Area365.67 Å2ChemAxon
Rotatable Bond Count18ChemAxon
Refractivity250.62 m3·mol-1ChemAxon
Polarizability101.49 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
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

Classification
Not classified

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
  1. Lamont RF: The development and introduction of anti-oxytocic tocolytics. BJOG. 2003 Apr;110 Suppl 20:108-12. [PubMed:12763125]
  2. 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. [PubMed:26586210]
  3. 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. [PubMed:15705593]
  4. 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. [PubMed:10519430]
  5. 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
  1. 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. [PubMed:10519430]
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
  1. 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. [PubMed:10519430]
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
  1. 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. [PubMed:10519430]

Drug created on May 11, 2015 15:47 / Updated on July 13, 2019 00:51