What Is Linagliptin?

Ligliptin compound is the main component of a drug named Liglitinine, with the chemical name 8-[(3R) -3-amino-1-piperidinyl] -7- (2-butynyl-1 ) -3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl) methyl] -1H-purine-2,6-dione; the compound is clinically synthesized The drug is a new and effective selective dipeptidyl peptidase-4 (DPP-4) inhibitor, which can be used to treat type 2 diabetes.

Chinese name: Ligliptin
Foreign name: linagliptin
CAS number: 668270-12-0

Molecular formula: C25H28N8O2
Molecular weight: 472.54200
Melting point: 202ºC

Brief Introduction to Ligliptin Compounds

Litagliptin Basic Information

Chinese name:

Chinese alias: 8-[(3R) -3-amino-1-piperidinyl] -7- (2-butynyl) -3,7-dihydro-3-methyl-1-[(4-methyl Methyl-2-quinazolinyl) methyl] -1H-purine-2,6-dione; lilaritin; ^[1]

English name: linagliptin ^[1]

English alias: Trajenta; BI-1356-BS; Ondero; BI-1356; Linagliptin; Tradjenta; 8-[(3R) -3-aminopiperidin-1-yl] -7-but-2-ynyl-3-methyl-1 -[(4-methylquinazolin-2-yl) methyl] purine-2,6-dione; ^[1]

CAS number: 668270-12-0 ^[1]

Molecular formula: C25H28N8O2 ^[1]

Structural formula:

Molecular weight: 472.54200 ^[1]

Exact mass: 472.23400 ^[1]

PSA: 116.86000 ^[1]

LogP: 1.91270 ^[1]

Physical and Chemical Properties of Ligliptin

Density: 1.39

Melting point: 202ºC ^[1]

Boiling point: 661.189ºC at 760 mmHg ^[1]

Flash point: 353.675ºC ^[1]

Refractive index: 1.717 ^[1]

Ligliptin Synthesis Route

1) ^[2]

Ligliptin Atlas

1 Ligliptin 1) Carbon spectrum

2 Ligliptin 2) Proton spectrum

Ligliptin Pharmacology and Toxicology

Litagliptin pharmacological effects

Ligliptin is a dipeptidyl peptidase 4 (DPP-4) inhibitor. DPP-4 is able to degrade insulinotropic hormone-like polypeptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Litagliptin can increase the concentration of active enterotropic hormones, stimulate insulin release in a glucose-dependent manner, and reduce circulating glucagon levels. ^[3]

Both of these enterotropic hormones are involved in the physiological regulation of glucose homeostasis. Intestinal insulin secretion is maintained at a low basal level throughout the day and rises immediately after meals. Under normal or elevated glucose levels, GLP-1 and GIP can increase pancreatic -cell insulin biosynthesis and secretion. In addition, GLP-1 can also reduce the glucagon secretion of pancreatic alpha cells, and reduce liver glucose excretion. ^[3]

Ligagliptin pharmacodynamics

Ligliptin can reversibly bind to DPP-4, thereby increasing intestinal insulinotropic hormone concentration. Ligliptin promotes insulin secretion in a glucose-dependent manner, while reducing glucagon secretion, thereby better regulating the glucose balance in the body. In vitro, ligagliptin can selectively bind to DPP-4 and selectively inhibit DPP-4, but does not inhibit DPP-8 or DPP-9 activity at near therapeutic exposure levels.
Cardiac electrophysiology ^[3]

In a randomized, placebo-controlled, positive-control, 4-treatment group crossover study, 36 healthy subjects received 5 mg of lidagliptin, 100 mg of lidagliptin (20 times the recommended dose), and moxifloxacin And placebo. At the recommended dose of 5 mg or 100 mg, no increase in QTc was observed. At a 100 mg dose, the peak plasma concentration level of lidagliptin was approximately 38 times the peak concentration after the 5 mg dose was administered. ^[3]

Ligliptin Toxicology Study

Genetic toxicity ^[3]

The results of the Ligliptin Ames test, human lymphocyte chromosome aberration test, and in vivo micronucleus test were all negative.

Reproductive toxicity ^[3]

In the rat fertility and early embryonic developmental toxicity test, the dose of Liglitin was 10, 30, and 240 mg / kg (the exposure was about 943 times the clinical dose of 5 mg / day). No effects on early embryonic development, mating, Fertility and adverse effects of conception.

Carcinogenic ^[3]

In a two-year carcinogenicity test in rats, the doses of lidagliptin were 6, 18, and 60 mg / kg (high-dose exposure was approximately 418 times the clinical dose), and no increase in tumor incidence was seen. In a two-year carcinogenicity test in mice, the doses of lidagliptin were 8, 25, and 80 mg / kg, and the doses of male and female animals were as high as 80 mg / kg or 25 mg / kg, respectively. (35, 270 times), there was no increase in tumor incidence, but the increase in lymphoma incidence was seen in female mice at a dose of 80 mg / kg (the exposure was approximately 215 times the clinical dose).

Ligliptin pharmacokinetics

The characteristics of the pharmacokinetics of ligagliptin were studied in healthy subjects and two diabetic patients. After a single 5 mg oral dose in healthy subjects, peak plasma concentrations occurred approximately 1.5 hours (Tmax) after administration; the area under the average plasma curve (AUC) was 139 nmol · h / L, and the maximum plasma concentration (Cmax) was 8.9 nmol / L. The plasma concentration of lidagliptin is eliminated in at least two phases, and the terminal half-life is longer (> 100 hours), which is related to the saturable binding of lidagliptin to DPP-4. Longer half-life does not cause drug accumulation. After repeated oral administration of 5 mg dose of lidagliptin, it can be determined that the effective half-life of the accumulation of lidagliptin is about 12 hours. After once daily dosing, 5mg Ligliptin reached steady-state blood drug concentration after the third dose, and the Cmax and AUC reached at steady state increased 1.3 times compared to the first dose . The subject's own coefficient of variation and inter-subject coefficient of variation for both Ligliptin AUC were small (12.6% and 28.5%, respectively). In the dose range of 1 to 10 mg, the plasma AUC of lidagliptin increased in a manner below the dose ratio. The pharmacokinetics of lidagliptin in healthy subjects are usually similar to those in patients with type 2 diabetes. ^[3]

Ligliptin indications

Ligliptin is used in combination with metformin and sulfonylureas in combination with diet control and exercise, and can be used for blood glucose control in adults with type 2 diabetes. ^[3]

Ligliptin specifications

5mg

Ligliptin Dosage

Ligliptin Adult

The recommended dose is 5 mg once daily. This product can be taken at any time of the day, with or without meals. ^[3]

Ligliptin special population

Patients with renal insufficiency ^[3]

Patients with renal insufficiency do not need to adjust the dose.

Patients with liver dysfunction ^[3]

Patients with liver dysfunction do not need to adjust the dose.

Missed ^[3]

If missed doses, patients are advised not to take double doses at the next dose.

Ligliptin adverse reactions

1. Treated patients report 5% and often have more adverse reactions than patients treated with placebo including nasopharyngitis. ^[3]

2. Patients treated with sulfonylureas are more commonly reported than patients treated with placebo and sulfonylureas. ^[3]

3. Patients randomized to lidagliptin reported pancreatitis more often (1 per 538 person-years compared to zero for every 433 person-years). ^[3]

4. Other adverse reactions reported in clinical studies receiving Ligliptin include hypersensitivity reactions (such as urticaria, angioedema, local skin exfoliation, or bronchial hypersensitivity reactions) and myalgia. ^[3]

Ligliptin Taboo

It is contraindicated in patients with a history of allergies to ligagliptin, such as urticaria, angioedema, or bronchial hypersensitivity. ^[3]

Ligliptin considerations

This product cannot be used to treat patients with type 1 diabetes, nor can it be used to treat diabetic ketoacidosis. ^[3]

In combination with drugs known to cause hypoglycemia ^[3]

Insulin-promoting drugs and insulin are known to cause hypoglycemia. In a clinical trial, the combination of lidagliptin and insulinotropic drugs (for example, sulfonylureas) caused a lower incidence of hypoglycemia than placebo. Ligliptin combined with insulin can cause a higher incidence of hypoglycemia in patients with severe renal insufficiency. Therefore, when used in combination with lidagliptin, lower doses of insulin secretagogues or insulin are required to reduce the risk of hypoglycemia.
Large blood vessel results ^[3]

There is no clear evidence that clinical studies have established that lidagliptin or other hypoglycemic drugs can reduce the risk of large blood vessels.
Impact on the ability to drive and operate machinery No studies have been conducted on the impact on the ability to drive and operate machinery. However, patients should be reminded of the risk of hypoglycemia, especially when used in combination with sulfonylureas. ^[3]

Ligliptin Drug Interactions

In Vitro Evaluation of Litagliptin Drug Interactions

Ligliptin is a weak to medium inhibitor of CYP isoenzyme CYP3A4, but it does not inhibit other CYP isoenzymes, nor is it an inducer of CYP isoenzymes, including: CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11. ^[3]

Ligliptin is a P-glycoprotein (P-gp) substrate that inhibits P-glycoprotein-mediated digoxin transport at high concentrations. Based on these results and in vivo drug interaction studies, it is considered that ligagliptin is unlikely to interact with other P-gp substrates at therapeutic concentrations. ^[3]

In Vivo Evaluation of Litagliptin Drug Interactions

An inducer of CYP3A4 or P-gp (eg, rifampicin) reduces the exposure of rigagliptin to subtherapeutic levels, most likely to ineffective concentrations. For patients who need this type of drug, it is highly recommended to replace ligagliptin. In vivo studies have shown that drug interactions with CYP3A4, CYP2C9, CYP2C8, substrates of P-glycoproteins, and organic cation transporters (OCTs) are less likely to occur. Based on the results of the described pharmacokinetic studies, no dose adjustment recommendations for lidagliptin are available. ^[3]

Ligliptin overdose

If Ligliptin overdose, go to the hospital immediately. Common support measures should also be taken based on the patient's clinical situation (for example, removal of unabsorbed drugs from the gastrointestinal tract, clinical monitoring, and supportive care). Ligliptin is unlikely to be cleared by hemodialysis or peritoneal dialysis. ^[3]

In a controlled trial conducted in healthy subjects, a single dose of lidagliptin reached 600 mg (equivalent to 120 times the recommended daily dose), and there were no clinical adverse drug reactions related to the dose of the drug. There is no experience in humans using doses above 600 mg. ^[3]