Tirzepatide comprises a 39 amino acid linear synthetic peptide conjugated to a C20 fatty diacid moiety. 1 Its protein sequence was based on the sequence of endogenous GIP, and its pharmacological action on GLP-1 receptors is comparable to endogenous GIP; however, the long half-life of tirzepatide allows for once-weekly dosing. 2 Tirzepatide was approved by the FDA on May 13, 2022, under the brand name MOUNJARO by the FDA for the treatment of adults with type 2 diabetes, making it the first and only GIP and GLP-1 receptor agonist for this indication. 5 Later, it was approved under a different brand name ZEPBOUND on November 8, 2023, for the chronic weight management in adults with obesity or overweight with at least one weight-related condition. 9 On September 15, 2022, tirzepatide was also approved by the European Commission. 7
Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. Dual GIP/GLP-1 agonists gained increasing attention as new therapeutic agents for glycemic and weight control as they demonstrated better glucose control and weight loss compared to selective GLP-1 receptor agonists in preclinical and clinical trials. 1
Tirzepatide is a dual GIP and GLP-1 receptor agonist used for the treatment of type II diabetes in adults as an adjunct to diet and exercise.
Tirzepatide is a synthetic peptide with glucose-lowering effects. It works to stimulate first- and second-phase insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner.1,4 Tirzepatide was also shown to delay gastric emptying, lower fasting and postprandial glucose concentration, decrease food intake,4 and reduce body weight in patients with type 2 diabetes.2 Tirzepatide can increase insulin sensitivity.4
As the peptide is conjugated to a C20 fatty diacid moiety through a hydrophilic linker at the lysine residue at position 20, the drug is highly bound to albumin in the plasma, which prolongs its half-life.2
Glucagon-like peptide-1 (GLP-1) receptors (GLP-1R) are expressed throughout the body, including pancreatic beta-cells and the gastrointestinal tract. They have been implicated in the pathophysiology of type II diabetes mellitus as GLP-1R signalling is involved in glucose control by enhancing glucose-stimulated insulin secretion, delaying gastric transit, decreasing plasma glucagon levels, and reducing body weight by activating anorexigenic pathways in the brain.1 Both glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 are peptide hormones involved in glucose homeostasis: they promote glucose-stimulated insulin secretion from the pancreatic beta-cells.2 However, GIP is the main incretin hormone that exerts insulinotropic effects in response to food intake.1,2
The exact mechanism of action of tirzepatide has not been fully elucidated; however, dual agonism at GIP and GLP-1R may contribute to the glycemic and weight control effects of the drug.2 Studies demonstrated that co-administration of GIP and a GLP-1R agonist more significantly increased insulin response and suppressed glucagon secretion compared to separate administration of either hormone alone.3 Tirzepatide binds to GIP and GLP-1R with high affinity.1,2 In vitro, tirzepatide has a comparable GIP receptor binding affinity to native GIP and five times lower GLP-1R affinity than that of native GLP-1.3 Tirzepatide potently activates the GLP-1R signalling pathway to stimulate glucose-dependent insulin secretion through activity at the GIP receptor (GIPR) or the GLP-1R.1 However, the role of GIPR agonism in the drug's mechanism of action requires further investigation, as the evidence of GIPR agonism on glycemic and weight control in preclinical and clinical studies are conflicting.2
TargetActionsOrganismA
Glucagon-like peptide 1 receptoragonist
HumansA
Gastric inhibitory polypeptideagonist
HumansOver the dose range of 1-5 mg, the Cmax of tirzepatide ranged from 108 to 397 ng/mL.1 The mean absolute bioavailability of tirzepatide following subcutaneous administration is 80%. Following subcutaneous administration, the Tmax ranged from eight to 72 hours. The steady-state plasma concentrations were achieved following four weeks of once-weekly subcutaneous administration.4
As tirzepatide delays gastric emptying, it has the potential to affect the absorption of concomitantly administered oral medications. The US prescribing information recommends the use of caution when co-administering tirzepatide with other oral medications.4
Following subcutaneous administration, the mean steady-state volume of distribution was 9.5 L.1 The mean apparent steady-state volume of distribution of tirzepatide following subcutaneous administration in patients with type 2 diabetes mellitus was approximately 10.3 L.4
Tirzepatide is 99% bound to plasma albumin.1,2,4
Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety, and amide hydrolysis.4
Tirzepatide is primarily excreted via urine and feces, mostly in the form of metabolites. Unchanged parent drug was not detectable in urine and feces.4
The half-life is approximately five days.2,4
The apparent population mean clearance of tirzepatide is 0.061 L/h.4 The mean steady-state apparent clearance of tirzepatide was 0.056 L/h.1
There is limited information regarding the LD50 and overdose of tirzepatide. In case of an overdosage, appropriate supportive treatment should be initiated with a sufficient amount of time for observation and treatment, as tirzepatide has a long half-life.4
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