Liraglutide is a lipopeptide that is an analogue of human GLP-1 in which the lysine residue at position 27 is replaced by arginine and a hexadecanoyl group attached to the remaining lysine via a glutamic acid spacer. Used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It has a role as a neuroprotective agent and a glucagon-like peptide-1 receptor agonist. It is a polypeptide and a lipopeptide.
Other Experimental PropertiesClear, colorless solution /Victoza/
Physikochemische Eigenschaften
Schmelzpunkt
182 °C · >182°C (dec.)
storage temp.
Refrigerator
Löslichkeit
DMSO (Slightly), Water (Slightly)
Aggregatzustand
Solid
Farbe
White to Off-White
InChIKey
YSDQQAXHVYUZIW-VTFFJMQZNA-N
Sicherheit und Regulatorisches
Sicherheitsangaben dienen nur zur Orientierung und ersetzen weder das Sicherheitsdatenblatt (SDB) des Lieferanten noch geltende Vorschriften oder eine fachliche Bewertung.
GHS-Klassifizierung
GHS Classification · 5 Einträge
This chemical does not meet GHS hazard criteria for 20% (1 of 5) of reports.
Warning
H351 (60%): Suspected of causing cancer [Warning Carcinogenicity]
P203, P280, P318, P405, and P501 (click each P-code to see the statement)
Aggregated GHS information provided per 5 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
Gefahrenhinweise
Fire PotentialThis product is not readily flammable.
FDA Requirements · 1 Eintrag
The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including liraglutide recombinant, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Liraglutide recombinant/
Hazard Classes and CategoriesCarc. 2 (60%)
Sicherheit und Schutzausrüstung
Fire Fighting ProceduresAvoid breathing vapors and flue gases - seek fresh air. Fire Fighting Extinguishing Media: In case of fire use foam, waterspray, dry chemical or CO2.
Storage Conditions · 1 Eintrag
Prior to first use, Victoza should be stored in a refrigerator between 36 °F to 46 °F (2 °C to 8 °C). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze Victoza and do not use Victoza if it has been frozen. After initial use of the Victoza pen, the pen can be stored for 30 days at controlled room temperature (59 °F to 86 °F; 15 °C to 30 °C) or in a refrigerator (36 °F to 46 °F; 2 °C to 8 °C). Keep the pen cap on when not in use. Victoza should be protected from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the Victoza pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy.
Chemie und Industrie
Pharmakologische Informationen
ATC Code · 3 Einträge
A - Alimentary tract and metabolism
QA - Alimentary tract and metabolism
A10BJ02
Protein Binding>98%.
Pharmacodynamics · 1 Eintrag
Liraglutide is a once-daily GLP-1 derivative for the treatment of type 2 diabetes. The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at position 26 of the GLP-1 molecule, enabling it to bind reversibly to albumin within the subcutaneous tissue and bloodstream and be released slowly over time. Binding with albumin results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to GLP-1. The effect of liraglutide is the increased secretion of insulin and decreased secretion of glucagon in response to glucose as well as slower gastric emptying. Liraglutide also does not adversely affect glucagon secretion in response to low blood sugar.
Mechanism of Action · 5 Einträge
Liraglutide is an acylated synthetic glucagon-like peptide-1 analog. Liraglutide is an agonist of the glucagon-like peptide-1 receptor which is coupled to adenylate cyclase. The increase in cyclic AMP stimulates the glucose dependant release of insulin, inhibits the glucose dependant release of glucagon, and slows gastric emptying to increase control of blood sugar.
Liraglutide is an acylated, long-acting, human glucagon-like peptide-1 (GLP-1) receptor agonist; the synthetic (recombinant DNA origin) peptide precursor of liraglutide has 97% amino acid sequence homology to endogenous human GLP-1-(7-37). Liraglutide is prepared by attaching palmitic acid with a glutamic acid spacer on the lysine residue at position 26 of the peptide precursor. GLP-1-(7-37) represents less than 20% of total circulating endogenous GLP-1. Like GLP-1-(7-37), liraglutide activates the GLP-1 receptor in pancreatic beta cells. Liraglutide also increases intracellular cyclic 3',5'-adenosine monophosphate (cAMP) leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. In addition, liraglutide suppresses glucagon secretion in a glucose-dependent manner but does not impair normal glucagon response to hypoglycemia. Liraglutide delays gastric emptying, reducing the rate at which postprandial glucose appears in the circulation. As a result of these actions resulting in increased insulin secretion, suppression of glucagon secretion, and delays in gastric emptying, liraglutide effectively reduces fasting and postprandial plasma glucose concentrations in patients with type 2 diabetes mellitus.
Do not discharge large quantities of concentrated spills and residue into drains.
Use the same personal protective equipment ... . Mop up spillage with a cloth. Dam spill and collect with sand or other absorbent material and place in suitable waste containers.
Disposal Methods · 2 Einträge
SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
The product is not hazardous waste.
Preventive Measures · 2 Einträge
SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.
Work under effective process ventilation (e.g. local exhaust ventilation). There must be access to running water and eye wash.
Personal Protective Equipment (PPE) · 3 Einträge
Eye protection: Clean-up, manufacturing and packaging operations may require safety glasses or goggles if there is a risk of splashing.
Gloves and protective clothing: PVC gloves, nitril rubber or similar of greater protection are recommended for waste clean-up and manufacturing and packaging operations.
Respiratory protection: Not normally required.
Toxikologische Informationen
Interactions · 5 Einträge
A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of Victoza at steady state. Victoza lowered ethinylestradiol and levonorgestrel Cmax by 12% and 13%, respectively. There was no effect of Victoza on the overall exposure (AUC) of ethinylestradiol. Victoza increased the levonorgestrel AUC0-8 by 18%. Victoza delayed Tmax for both ethinylestradiol and levonorgestrel by 1.5 hr.
A single dose of digoxin 1 mg was administered 7 hours after the dose of Victoza at steady state. The concomitant administration with Victoza resulted in a reduction of digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximal concentration (Tmax) was delayed from 1 hr to 1.5 hr.
A single dose of lisinopril 20 mg was administered 5 minutes after the dose of Victoza at steady state. The co-administration with Victoza resulted in a reduction of lisinopril AUC by 15%; Cmax decreased by 27%. Lisinopril median Tmax was delayed from 6 hr to 8 hr with Victoza.
Victoza did not change the overall exposure (AUC) of griseofulvin following co-administration of a single dose of griseofulvin 500 mg with Victoza at steady state. Griseofulvin Cmax increased by 37% while median Tmax did not change.
For more Interactions (Complete) data for Liraglutide (8 total), please visit the HSDB record page.
Hepatotoxicity · 1 Eintrag
In large clinical trials, serum enzyme elevations were no more common with liraglutide therapy than with placebo or comparator agents, and no instances of clinically apparent liver injury were reported. Since licensure, there has been a single case report of autoimmune hepatitis arising in a patient taking liraglutide. She did not improve with stopping liraglutide and ultimately required long term corticosteroid therapy, suggesting that the autoimmune hepatitis was independent of the drug therapy or that liraglutide triggered an underlying condition. Other cases of hepatotoxicity due to liraglutide have not been published and the product label does not list liver injury as an adverse event. Thus, liver injury due to liraglutide must be quite rare.
Adverse EffectsThe most common adverse reactions associated with liraglutide administration include nausea, diarrhea, vomiting, decreased appetite, dyspepsia, and constipation. Immunogenic-related events have been reported in less than 0.8% of patients.
Milk Concentrations · 3 Einträge
EXPERIMENTAL: Liraglutide is distributed into milk in rats.
EXPERIMENTAL: Liraglutide is secreted into milk, but the amount of liraglutide that a pup would receive per day via breast milk is low (at most 3% of the maternal dose).
EXPERIMENTAL: Liraglutide is distributed into milk in rats. It is not known whether liraglutide is distributed into milk in humans; ... .
Toxicity Summary · 2 Einträge
IDENTIFICATION AND USE: Liraglutide is a clear colorless liquid formulated into solution for subcutaneous use. Liraglutide is a synthetic, long-acting human glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic). It is used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. HUMAN EXPOSURE AND TOXICITY: Overdoses have been reported in clinical trials and post-marketing use of liraglutide. Effects have included severe nausea and severe vomiting. Post-marketing reports also include acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema), and acute renal failure and worsening of chronic renal failure (which may require hemodialysis). Liraglutide also causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Therefore, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Finally, there are no adequate and well-controlled studies of liraglutide in pregnant women; however the drug did cause developmental toxicity in experimental animals. Therefore, liraglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ANIMAL STUDIES: Liraglutide had no adverse effects on fertility when given to male rats at doses up to 1.0 mg/kg/day. However, liraglutide caused developmental toxicity in both rats and rabbits. When female rats were given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day, the number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidences of fetal malformations in liraglutide-treated groups were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. In a rabbit developmental study, pregnant females were administered liraglutide subcutaneously at doses of 0.01, 0.025 and 0.05 mg/kg/day from gestation day 6 through day 18 inclusive. Fetal weight was decreased and the incidence of total major fetal abnormalities was increased at all dose levels tested. Single cases of microphthalmia were noted at all dose levels. In addition, there was an increase in the fetal incidence of connected parietals in the high dose group, and a single case of split sternum in the 0.025 and 0.05 mg/kg/day. Minor abnormalities considered to be treatment-related were an increase in the incidence of jugal(s) connected/fused to maxilla at all dose levels and an increase in the incidence of bilobed/bifurcated gallbladder at 0.025 and 0.50 mg/kg/day. Studies for the carcinogenicity potential of liraglutide were also conducted in mice and rats. In both species, a dose-related increase in benign thyroid C-cell adenomas and malignant C-cell carcinomas were observed. Also, there was a treatment-related increase in the incidence and severity of focal C-cell hyperplasia in both male and female rats. In addition, there was a treatment-related increase in fibrosarcomas on the dorsal skin and subcutis, the body surface used for drug injection, in male mice. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. Finally, liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. Liraglutide was negative in repeat-dose in vivo micronucleus tests in rats.
Human Toxicity Excerpts · 5 Einträge
/SIGNS AND SYMPTOMS/ Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with Victoza.
/SIGNS AND SYMPTOMS/ In postmarketing reports, acute renal failure and worsening of chronic renal failure (which may require hemodialysis) have been reported with liraglutide. Some of these events occurred in patients without known underlying renal disease. Most of these events occurred in patients experiencing nausea, vomiting, diarrhea, or dehydration. Some of these events occurred in patients receiving liraglutide in combination with one or more agents known to affect renal function or hydration status. Liraglutide has not been found to be directly nephrotoxic in preclinical or clinical studies. Renal effects usually have been reversible with supportive treatment and discontinuance of potentially causative agents, including liraglutide. Clinicians should use caution when initiating liraglutide or escalating dosage in patients with renal impairment.
/SIGNS AND SYMPTOMS/ There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with Victoza.
/SIGNS AND SYMPTOMS/ Overdoses have been reported in clinical trials and post-marketing use of Victoza. Effects have included severe nausea and severe vomiting.
For more Human Toxicity Excerpts (Complete) data for Liraglutide (13 total), please visit the HSDB record page.
Drug Induced Liver Injury · 6 Einträge
Drug Induced Liver Injury Rank (DILIrank 2.0)
Liraglutide
vLess-DILI-concern
4
Adverse reactions
DOI:10.1016/j.drudis.2016.02.015
Non-Human Toxicity Excerpts · 5 Einträge
/LABORATORY ANIMALS: Acute Exposure/ Single dose studies were performed in mice and rats in standard design studies and in monkeys in a maximum tolerated dose (MTD) study. A single dose of 10 mg/kg was generally well tolerated by mice and rats without mortality. In monkeys, a single SC administration of 5 mg/kg was well tolerated without mortality. The observed reductions in body weight and food consumption can be regarded as pharmacologically mediated.
/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ The ultimate treatment goal of diabetes is to preserve and restore islet cell function. Treatment of certain diabetic animal models with incretins has been reported to preserve and possibly enhance islet function and promote islet cell growth. The studies reported here detail islet cell anatomy in animals chronically treated with the incretin analog, liraglutide. /The/ aim was to quantitatively and qualitatively analyze islet cells from diabetic animals treated with vehicle (control) or liraglutide to determine whether normal islet cell anatomy is maintained or enhanced with pharmaceutical treatment. We harvested pancreata from liraglutide and vehicle-treated Zucker Diabetic Fatty (ZDF) rats to examine islet structure and function and obtain isolated islets. Twelve-week-old male rats were assigned to 3 groups: (1) liraglutide-treated diabetic, (2) vehicle-treated diabetic, and (3) lean non-diabetic. Liraglutide was given SC twice daily for 9 weeks. As expected, liraglutide treatment reduced body weight by 15% compared to the vehicle-treated animals, eventually to levels that were not different from lean controls. At the termination of the study, blood glucose was significantly less in the liraglutide-treated rats compared to vehicle treated controls (485.8 + or - 22.5 and 547.2 + or - 33.1mg/dL, respectively). Insulin content/islet (measured by immunohistochemistry) was 34.2 + or - 0.7 pixel units in vehicle-treated rats, and 54.9 + or - 0.6 in the liraglutide-treated animals. Glucose-stimulated insulin secretion from isolated islets (measured as the stimulation index) was maintained in the liraglutide-treated rats, but not in the vehicle-treated. However, liraglutide did not preserve normal islet architecture. There was a decrease in the glucagon-positive area/islet and in the alpha-cell numbers/area with liraglutide treatment (6.5 cells/field), compared to vehicle (17.9 cells/field). There was an increase in beta-cell numbers, the beta- to alpha-cell ratio that was statistically higher in the liraglutide-treated rats (24.3 + or - 4.4) compared to vehicle (9.1 + or - 2.8). Disrupted mitochondria were more commonly observed in the alpha-cells (51.9+ or - 10.3% of cells) than in the beta-cells (27.2 + or - 4.4%) in the liraglutide-treated group. While liraglutide enhanced or maintained growth and function of certain islet cells, the overall ratio of alpha- to beta-cells was decreased and there was an absolute reduction in islet alpha-cell content. There was selective disruption of intracellular alpha-cell organelles, representing an uncoupling of the bihormonal islet signaling that is required for normal metabolic regulation. The relevance of the findings to long-term liraglutide treatment in people with diabetes is unknown and should be investigated in appropriately designed clinical studies.
Populations at Special Risk · 2 Einträge
Liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).
In postmarketing reports, acute renal failure and worsening of chronic renal failure (which may require hemodialysis) have been reported with liraglutide. Some of these events occurred in patients without known underlying renal disease. Most of these events occurred in patients experiencing nausea, vomiting, diarrhea, or dehydration. Some of these events occurred in patients receiving liraglutide in combination with one or more agents known to affect renal function or hydration status. Liraglutide has not been found to be directly nephrotoxic in preclinical or clinical studies. Renal effects usually have been reversible with supportive treatment and discontinuance of potentially causative agents, including liraglutide. Clinicians should use caution when initiating liraglutide or escalating dosage in patients with renal impairment.
Antidote and Emergency Treatment · 5 Einträge
Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. 2. Treat coma and seizures if the occur. 3. Obtain finger stick blood glucose levels every 1-2 hours until stabilized. /Antidiabetic agents/
Specific drugs and antidotes. 1. If the patient is hypoglycemic, administer concentrated glucose orally or IV. ... 3. Maintaining serum glucose concentrations above 90-100 mg/dL for the first 12 hours of therapy or longer is often necessary to prevent recurrent hypoglycemia. However, once hypoglycemia resolves (usually 12-24 hours after the ingestion) and the patient no longer requires dextrose infusions, serum glucose concentrations should be allowed to normalize. Follow serum glucose levels closely for several hours after the last dose of dextrose. ... /Antidiabetic agents/
Decontamination. 1. Oral agents. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. ... /Antidiabetic agents/
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
For more Antidote and Emergency Treatment (Complete) data for Liraglutide (6 total), please visit the HSDB record page.
Effects During Pregnancy and Lactation◉ Summary of Use during Lactation
Regulatorische Informationen
FDA Requirements · 1 Eintrag
The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including liraglutide recombinant, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Liraglutide recombinant/
Sicherheitsdaten
wgk
WGK 3
Speicherklasse
11 - Combustible Solids
Giftige Stoffe Daten
204656-20-2(Hazardous Substances Data)
Hazard Classifications
Repr. 2
Liraglutide is a glucagon-like peptide-1 (GLP-1) mimetic used for the treatment of Type 2 diabetes. Similar to the actions of endogenous GLP-1, liraglutide potentiates the post-prandial release of insulin, inhibits glucagon release and increases satiety. Recent epidemiological studies and clinical trials have suggested that treatment with GLP-1 mimetics may also diminish the risk of cardiovascular disease in diabetic patients. The mechanism responsible for this effect has yet to be determined; however, one possibility is that they might do so by a direct effect on vascular endothelium. Since low grade inflammation of the endothelium is an early event in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD), we determined the effects of liraglutide on inflammation in cultured human aortic endothelial cells (HAECs). Liraglutide reduced the inflammatory responses to TNFalpha and LPS stimulation, as evidenced by both reduced protein expression of the adhesion molecules VCAM-1 and E-Selectin, and THP-1 monocyte adhesion. This was found to result from increased cell Ca2+ and several molecules sensitive to Ca2+ with known anti inflammatory actions in endothelial cells, including CaMKKbeta, CaMKI, AMPK, eNOS and CREB. Treatment of the cells with STO-609, a CaMKK inhibitor, diminished both the activation of AMPK, CaMKI and the inhibition of TNFa and LPS-induced monocyte adhesion by liraglutide. Likewise, expression of an shRNA against AMPK nullified the anti-inflammatory effects of liraglutide. The results indicate that liraglutide exerts a strong anti-inflammatory effect on HAECs. They also demonstrate that this is due to its ability to increase intracellular Ca2+ and activate CAMKKbeta, which in turn activates AMPK.
In vivo, liraglutide lowers blood glucose and body weight in a number of diabetic and obese models using rodents, pigs and monkeys. The mechanism of action in vivo involved glucose-dependent increase in insulin secretion, lowered glucagon secretion, decreased gastric emptying, loss of body fat, lowered food intake, altered food preference, and maintained energy expenditure. The mechanism of action is consistent with a specific GLP-1 effect.
Liraglutide is a long-acting GLP-1 analogue, designed to bind to albumin as the main molecular mechanism of protraction. In vitro, this was shown in the receptor cAMP as well as binding assay where addition of albumin right-shifted the dose-response and/or binding curve. The apparent reduced potency of liraglutide underlines that only the free fraction of liraglutide is responsible for its pharmacological effect in vitro as well as in vivo. Furthermore, liraglutide in a pharmaceutical solution forms a micell-like heptamer which may contribute to the slow absorption from the subcutis.
Biological Half-Life · 3 Einträge
Terminal half life of 13 hours.
The terminal half-life of liraglutide seems to be similar in pigs (approximately 14 hr) and humans (approximately 15 hr) while shorter in mice, rats, rabbits and monkeys (4-8 hr). Several studies in monkeys, pigs and humans indicated that extravascular administration (SC and pulmonary) of liraglutide prolongs the terminal half-life as compared to intravenous (IV) administration. Furthermore, the terminal half-life seemed also to be prolonged by repeated dosing in rats, monkeys, pigs and humans. This tendency was not apparent for mice and rabbits.
elimination half-life ... approximately 13 hours
Metabolism/Metabolites · 3 Einträge
Liraglutide is less sensitive to metabolism than the endogenous GLP-1 and so is more slowly metabolized by dipeptidyl peptidase-4 and neutral endopeptidase to various smaller polypeptides which have not all been structurally determined. A portion of Liraglutide may be completely metabolized to carbon dioxide and water.
The metabolic and excretion patterns were highly similar across species with liraglutide being fully metabolised in the body by sequential cleavage of small peptide fragments and amino acids. The in vitro metabolism studies indicate that the initial metabolism involves cleavage of the peptide backbone with no degradation of the glutamate-palmitic acid side-chain. Mice, rats and monkeys displayed similar plasma profiles and showed no significant gender differences. A higher number of metabolites were observed in plasma from the animal species (especially the rat and monkey) as compared to human plasma. This disparity can partly be explained by differences in the sample preparation as human plasma samples were freeze dried prior to analysis causing a removal of volatile metabolites (including tritiated water). All detected metabolites were minor and obtained in low amount (<15%) and therefore no structural identification of these was performed. This is acceptable since the metabolites are only formed in low amounts and since the metabolites are expected to resemble endogenous substances with well-known metabolic pathways
During the initial 24 hours following administration of a single 3(H)-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized /SRP: in a manner similar to large proteins/ without a specific organ as a major route of elimination.
FDA Pharmacological Classification · 6 Einträge
839I73S42A
LIRAGLUTIDE
Established Pharmacologic Class [EPC] - GLP-1 Receptor Agonist
Chemical Structure [CS] - Glucagon-Like Peptide 1
Mechanisms of Action [MoA] - Glucagon-like Peptide-1 (GLP-1) Agonists
Liraglutide is a GLP-1 Receptor Agonist. The mechanism of action of liraglutide is as a Glucagon-like Peptide-1 (GLP-1) Agonist.
MeSH Pharmacological Classification · 2 Einträge
Compounds that stimulate the activity of GLUCAGON-LIKE PEPTIDE-1 RECEPTOR. Glucagon-like peptide-1 receptor agonists are used to treat TYPE 2 DIABETES and OBESITY.
Peptides which stimulate INSULIN release from the PANCREATIC BETA CELLS following oral nutrient ingestion, or postprandially.
Absorption, Distribution and Excretion · 6 Einträge
Bioavailability of liraglutide after subcutaneous injection is approximately 55% and maximum concentrations are reached after 11.7 hours.
6% excreted in urine and 5% excreted in feces.
13L.
1.2L/h.
The mean apparent volume of distribution after subcutaneous administration of Victoza 0.6 mg is approximately 13 L. The mean volume of distribution after intravenous administration of Victoza is 0.07 L/kg. Liraglutide is extensively bound to plasma protein (>98%).
Following a 3(H)-liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces radioactivity was excreted during the first 6-8 days. The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L/hr with an elimination half-life of approximately 13 hours, making Victoza suitable for once daily administration.
Verwendung und Herstellung
Uses · 2 Einträge
MEDICATION
Hypoglycemic Agents
Methods of ManufacturingPreparation: L. B. Knudsen et al., World Intellectual Property Organization patent 9808871; idem et al., United States of America patent 6268343 (1998, 2001 both to Novo Nordisk).
Formulations/PreparationsParenteral: Injection, for subcutaneous use: 6 mg/mL Victoza, available as prefilled cartridge pen, (Novo Nordisk)
General Manufacturing InformationAcylated derivative of glucagen-like peptide
Anwendungen · 1 Eintrag
VerwendenLiraglutide is a new type of hypoglycemic drug that activates AMP-activated protein kinase thus enhancing insulin sensitivity. It not only has a significant hypoglycemic effect, but also has the functions of weight loss, blood pressure reduction, and improvement of blood lipid profile.Liraglutide, a human glucagon-like peptide-1 (GLP-1) receptor agonist, slows gastric emptying, increases satiety, and reduces patient eating, while reducing the brain's desire to eat and allowing the body to Increased energy expenditure plays a role in weight loss; it prevents the liver from producing too much glucose and promotes the pancreas to produce more insulin to lower blood sugar; in addition, liraglutide also has cardiovascular benefits and kidney protection.
Ergänzende Hinweise · 1 Eintrag
DefinitionChEBI: Liraglutide, a lipopeptide and polypeptide, is an analogue of human GLP-1 in which the lysine residue at position 27 is replaced by arginine and a hexadecanoyl group attached to the remaining lysine via a glutamic acid spacer. It is used alongside diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Liraglutide functions as a glucagon-like peptide-1 receptor agonist and serves as a neuroprotective agent.
Severe nausea, vomiting, or hypoglycemia may indicate an overdose of liraglutide, which is treated with symptom management. There is no rescue drug for a liraglutide overdose.
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A 104-week carcinogenicity study was conducted in male and female mice at doses of 0.03, 0.2, 1.0, 3.0 mg/kg/day administered by subcutaneous bolus injection. The human exposure multiple (based on plasma AUC0-24 comparison) values for the 0.03, 0.2, 1 and 3mg/kg/day doses were 0.2, 1.8, 10.0 and 45.0. Treatment resulted in an increased incidence of focal C-cell hyperplasia for males and females dosed at 1.0 and 3.0 mg/kg/day, and for females dosed at 0.2 mg/kg/day, incidence rates for the 0, 0.03, 0.2, 1.0 and 3.0 mg/kg/day groups respectively, were 0%, 0%, 1.5%, 16.4% and 38.0% for males, and 0%, 0%, 10.4%, 10.5% and 33.3% for females. There was also a dose-related increase in benign thyroid C-cell adenomas in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively. C-cell adenomas did not occur in control groups or in the 0.03 and 0.2 mg/kg/day groups. Treatment-related malignant C-cell carinomas occurred in 3% of females in the 3.0 mg/kg/day group. Thyroid C-cell tumors are rare findings during carcinogenicity testing in mice. In addition, there was a treatment-related increase in fibrosarcomas on the dorsal skin and subcutis, the body surface used for drug injection, in males in the 3mg/kg/day group. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 mg/mL) is 10-times higher than the concentration in the formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study (0.6 mg/mL). The NOAEL for this study is 0.03 mg/kg/day.
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A 104-week carcinogenicity study was conducted in male and female rats at doses of 0.075, 0.25 and 0.75 mg/kg/day administered by bolus subcutaneous injection with exposures 0.5, 2.2 and 7.6 times the human exposure level, respectively, based on plasma AUC0-24 comparison. There was a treatment-related increase in the incidence and severity of focal C-cell hyperplasia in the 0.25 and 0.75 mg/kg/day groups; incidence rates for the 0, 0.075, 0.25 and 0.75 mg/kg/day, respectively, were 22%, 29%, 40% and 48% for males, and 28%, 29%, 55% and 48% for females. In addition, there was a treatment-related increase in benign thyroid C-cell adenomas noted for males in the 0.25 and 0.75 mg/kg/day groups with incidences of 12%, 16%, 42% and 46% for females in all treated groups with incidences of 10%, 27%, 33% and 56% in the 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups with incidences of 2%, 8%, 6% and 14% and in females at 0.25 and 0.75 mg/kg/day with incidences of 0%, 0%, 4%, and 6% in 0 (control)(, 0.075, 0.25 and 0.75 mg/kg/day groups, respectively. Thyroid C-cell carcinomas are rare findings during carcinogenicity testing in rats. The NOAEL for this study is <0.075 mg/kg/day.
For more Non-Human Toxicity Excerpts (Complete) data for Liraglutide (16 total), please visit the HSDB record page.
