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| Targets |
Vasopressin V1 receptor
Terlipressin (25 nM; 24-72 hours; IEC-6 cells) treatment dramatically increases the viability, proliferation, and apoptosis of IEC-6 cells[1]. Terlipressin prevents IEC-6 cells from secreting TNF-α and 15-F2t-isoprostane after they are subjected to oxygen and glucose deprivation and then reoxygenated. Through the PI3K signaling pathway, terlipressin administration after OGD reduces OGD/R-induced cell damage[1]. |
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| ln Vitro |
Terlipressin (25 nM; 24-72 hours; IEC-6 cells) treatment dramatically increases the viability, proliferation, and apoptosis of IEC-6 cells[1].
Terlipressin prevents IEC-6 cells from secreting TNF-α and 15-F2t-isoprostane after they are subjected to oxygen and glucose deprivation and then reoxygenated. Through the PI3K signaling pathway, terlipressin administration after OGD reduces OGD/R-induced cell damage[1]. In an in vitro model of oxygen-glucose deprivation/re-oxygenation (OGD/R) using rat intestinal epithelial cells (IEC-6), incubation with 25 nM Terlipressin following OGD significantly improved cell viability compared to the OGD/R-only group. Terlipressin (25 nM) treatment attenuated OGD/R-induced cell apoptosis. While Terlipressin did not affect cell cycle dynamics or proliferation within the first 24 hours post-reoxygenation, it significantly increased IEC-6 cell proliferation at 48 and 72 hours after OGD. Terlipressin (25 nM) significantly inhibited the OGD/R-induced secretion of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and the oxidative stress marker 15-F2t-isoprostane from IEC-6 cells. The protective effects of Terlipressin on cell viability, proliferation, apoptosis, and cytokine secretion were completely abolished by co-administration of the specific phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (2 μM), indicating that the action of Terlipressin is mediated through the PI3K signaling pathway. [1] |
| ln Vivo |
Terlipressin treatment dramatically reduces IR-induced liver apoptosis, necrosis, and inflammation in a mouse model of nonlethal hepatic ischemia-reperfusion (IR)[3].
(Clinical Case Description) A 67-year-old male patient with multiple comorbidities (diabetes, hypertension, hepatitis C-related liver cirrhosis, chronic kidney disease, history of infective endocarditis) and pre-existing QT interval prolongation was administered Terlipressin (1 ampoule IV every 6 hours) for acute esophageal variceal bleeding. Approximately 6 hours after the first dose (and following a second dose), the patient developed refractory torsade de pointes (TdP), a polymorphic ventricular tachycardia, leading to multiple episodes of cardiac arrest. Treatment with defibrillation, lidocaine, magnesium sulfate, and transcutaneous pacing provided only temporary relief. The ventricular arrhythmia was ultimately terminated and did not recur after the insertion of a transvenous pacemaker for overdrive pacing (at 110 bpm) and, crucially, after the discontinuation of Terlipressin. The patient's ECGs reverted to his baseline prolonged QT pattern after pacemaker removal, with no further arrhythmia. This temporal association strongly suggested Terlipressin as the inciting cause of the life-threatening arrhythmia in this susceptible patient. [2] |
| Cell Assay |
Cell Line: IEC-6 cells induced by oxygen and glucose deprivation/re-oxygenation (OGD/R)
Concentration: 25 nM Incubation Time: 24 hours, 48 hours, 72 hours Result: Significantly increased the proliferation of IEC-6 cells. Cell Viability Assay (MTT): IEC-6 cells were seeded in 96-well plates. After OGD/R treatment with or without Terlipressin, MTT reagent was added to each well and incubated for 4 hours at 37°C. The medium was then replaced with dimethyl sulfoxide, and the optical density was measured at 490 nm using a microplate reader to assess cell viability. [1] Cell Proliferation Assay (CCK-8): IEC-6 cell proliferation was assessed at baseline and at 24, 48, and 72 hours post-treatment. Cells were seeded in plates, and at each time point, CCK-8 reagent was added to the culture medium, incubated for 1 hour, and the absorbance at 450 nm was measured using a spectrophotometer. [1] Apoptosis Assay (Flow Cytometry): Following treatments, IEC-6 cells were harvested, washed, and stained with fluorescein isothiocyanate (FITC) Annexin V and propidium iodide (PI) using an apoptosis detection kit. Stained cells were analyzed by flow cytometry within 1 hour. Cells positive for Annexin V (with or without PI) were considered apoptotic, and the apoptosis index was calculated. [1] Cell Cycle Analysis (Flow Cytometry): After treatments, IEC-6 cells were harvested, fixed with ethanol, treated with RNase, and stained with PI. The DNA content was analyzed by flow cytometry, and the percentage of cells in different cell cycle phases (G1, S) was determined using analysis software. [1] Cytokine Measurement (Immunoassay): After re-oxygenation, the culture medium was collected and centrifuged. The concentrations of TNF-α and 15-F2t-isoprostane in the supernatant were quantified using commercial enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturer's instructions. [1] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion
In HRS-1 patients, following intravenous administration of 1 mg terlipressin acetate, the median Cmax, AUC24h, and Cave at steady state for terlipressin were 70.5 ng/mL, 123 ng × hr/mL, and 14.2 ng/mL, respectively. The median Cmax, AUC24h, and Cave for lisiopressin were 1.2 ng/mL, 11.2 ng × hr/mL, and 0.5 ng/mL, respectively. Both terlipressin and lisiopressin exhibited linear pharmacokinetic characteristics in healthy subjects. Plasma concentrations of terlipressin increased proportionally to the administered dose. Less than 1% of terlipressin and less than 0.1% of lysine vasopressin were excreted in the urine of healthy subjects. The volume of distribution for terlipressin was 6.3 L, and for lysine vasopressin, it was 1370 L. Terlipressin has a clearance rate of 27.4 L/hr, while lysine vasopressin has a clearance rate of 318 L/hr. In HRS-1 patients, terlipressin clearance increases with body weight, while body weight has no effect on lysine vasopressin clearance. Metabolism/Metabolites: The N-terminal glycyl residue of terlipressin is cleaved by various tissue peptidases, releasing its pharmacologically active metabolite, lysine vasopressin (LV). After its formation, LV undergoes various peptidase-mediated metabolic pathways in tissues throughout the body. Terlipressin is not metabolized in blood or plasma. Because peptidases are ubiquitous in human tissues, the metabolism of terlipressin is unlikely to be affected by disease states or other drugs. Biological Half-Life: The terminal half-life of terlipressin is 0.9 hours, and that of lysine vasopressin is 3.0 hours. |
| Toxicity/Toxicokinetics |
(Adverse Drug Reactions - Cardiac) Terlipressin use may be associated with cardiac adverse reactions. Adverse reactions were categorized according to the referenced core safety profile. The frequency of torsades de pointes (TdP) and heart failure was categorized as “unknown” (cannot be estimated based on available data), indicating that they are very rare. Other listed cardiac adverse reactions include bradycardia, atrial fibrillation, premature ventricular contractions, tachycardia, chest pain, myocardial infarction, fluid overload with pulmonary edema, left ventricular failure, hypertension, and peripheral effects such as vasoconstriction, ischemia, and cyanosis. [2] The described case report describes a serious case of terlipressin-induced refractory torsades de pointes in a patient with multiple risk factors (previous QTc interval prolongation, renal and hepatic impairment, recent infective endocarditis). [2]
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| References | |
| Additional Infomation |
Pharmacodynamics
Terlipressin mimics the biological effects of endogenous vasopressin, but it exhibits greater selectivity for V1 receptors and a longer half-life than vasopressin. These pharmacokinetic and molecular properties of terlipressin offer several advantages, such as prevention of rebound hypotension after discontinuation and ease of use in patients with limited intravenous access. Terlipressin increases arterial pressure (diastolic, systolic, and mean arterial pressure) and decreases heart rate in patients with hepatorenal syndrome type 1 (HRS-1). In HRS-1 patients, cardiovascular effects are observed within 5 minutes of a single administration of 0.85 mg terlipressin and last for at least 6 hours. The maximum changes in blood pressure and heart rate occur between 1.2 and 2 hours after administration. Terlipressin is an analogue of vasopressin. This study suggests that terlipressin may directly protect intestinal epithelial cells from ischemia/reperfusion-like injury in vitro by activating the PI3K signaling pathway, reducing inflammation, oxidative stress and apoptosis, and promoting late-stage cell proliferation. [1] Terlipressin (gliprexine) is a commonly used drug in the emergency department and is effective for acute esophageal variceal bleeding. Contraindications include allergy to terlipressin and pregnancy. Due to its significant vasoconstrictive effect, it should be used with caution in patients with low cardiac output. This case highlights that terlipressin should be included among the drugs to be avoided in patients with prolonged QTc intervals. It reminds clinicians to assess the QT interval before administering terlipressin. [2] This report does not fully elucidate the mechanism by which terlipressin induces torsades de pointes (TdP). Some studies suggest that this may involve the direct effect of the drug on the transmural dispersion or variability of ventricular repolarization, rather than simply by further prolonging the QT interval. [2] |
| Molecular Formula |
C52H74N16O15S2
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|---|---|
| Molecular Weight |
1227.3722
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| Exact Mass |
1226.496
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| Elemental Analysis |
C, 50.89; H, 6.08; N, 18.26; O, 19.55; S, 5.22
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| CAS # |
14636-12-5
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| Related CAS # |
Terlipressin diacetate; 1884420-36-3; Terlipressin acetate; 914453-96-6
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| PubChem CID |
72081
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
1824.0±65.0 °C at 760 mmHg
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| Flash Point |
1056.9±34.3 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
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| Index of Refraction |
1.664
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| LogP |
-6.75
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| Hydrogen Bond Donor Count |
16
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| Hydrogen Bond Acceptor Count |
19
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| Rotatable Bond Count |
25
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| Heavy Atom Count |
85
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| Complexity |
2380
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| Defined Atom Stereocenter Count |
8
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| SMILES |
S1C([H])([H])[C@@]([H])(C(N2C([H])([H])C([H])([H])C([H])([H])[C@@]2([H])C(N([H])[C@]([H])(C(N([H])C([H])([H])C(N([H])[H])=O)=O)C([H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H])=O)=O)N([H])C([C@]([H])(C([H])([H])C(N([H])[H])=O)N([H])C([C@]([H])(C([H])([H])C([H])([H])C(N([H])[H])=O)N([H])C([C@]([H])(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])N([H])C([C@]([H])(C([H])([H])C2C([H])=C([H])C(=C([H])C=2[H])O[H])N([H])C([C@]([H])(C([H])([H])S1)N([H])C(C([H])([H])N([H])C(C([H])([H])N([H])C(C([H])([H])N([H])[H])=O)=O)=O)=O)=O)=O)=O)=O
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| InChi Key |
BENFXAYNYRLAIU-QSVFAHTRSA-N
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| InChi Code |
InChI=1S/C52H74N16O15S2/c53-17-5-4-9-31(45(76)60-23-41(57)72)63-51(82)38-10-6-18-68(38)52(83)37-27-85-84-26-36(61-44(75)25-59-43(74)24-58-42(73)22-54)50(81)65-34(20-29-11-13-30(69)14-12-29)48(79)64-33(19-28-7-2-1-3-8-28)47(78)62-32(15-16-39(55)70)46(77)66-35(21-40(56)71)49(80)67-37/h1-3,7-8,11-14,31-38,69H,4-6,9-10,15-27,53-54H2,(H2,55,70)(H2,56,71)(H2,57,72)(H,58,73)(H,59,74)(H,60,76)(H,61,75)(H,62,78)(H,63,82)(H,64,79)(H,65,81)(H,66,77)(H,67,80)/t31-,32-,33-,34-,35-,36-,37-,38-/m0/s1
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| Chemical Name |
(2S)-1-[(4R,7S,10S,13S,16S,19R)-19-[[2-[[2-[(2-aminoacetyl)amino]acetyl]amino]acetyl]amino]-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-13-benzyl-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]-N-[(2S)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]pyrrolidine-2-carboxamide
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| Synonyms |
Glycylpressin; Remestyp; Terlipressin
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~81.5 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.04 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.04 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (2.04 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.8148 mL | 4.0738 mL | 8.1475 mL | |
| 5 mM | 0.1630 mL | 0.8148 mL | 1.6295 mL | |
| 10 mM | 0.0815 mL | 0.4074 mL | 0.8148 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Treatment of hepatorenal syndrome with terlipressin infusion adjusted to hemodynamic response
CTID: null
Phase: Phase 4 Status: Completed
Date: 2012-02-08
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