Introduce

Linagliptin compound is the main component of the drug marketed as Linagliptin tablets, 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; Clinically, the drug synthesized from this compound is a new and effective selective dipeptidyl peptidase 4 (DPP-4) inhibitor, which can be used to treat type 2 diabetes[1].

Figure 1 Characteristics of Linagliptin

pharmacological action

Linagliptin is a dipeptidyl peptidase 4 (DPP-4) inhibitor, which can degrade intestinal insulinotropic hormones like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Linagliptin can increase the concentration of active intestinal insulinotropic hormone, stimulate insulin release in a glucose-dependent manner, and reduce circulating glucagon levels. Both intestinal insulinotropic hormones are involved in the physiological regulation of glucose homeostasis. The basal level of insulin secretion in the midgut is maintained at a low level throughout the day and immediately increases after meals. Under normal or elevated glucose levels, GLP-1 and GIP can increase the biosynthesis and secretion of insulin in pancreatic beta cells. In addition, GLP-1 can reduce glucagon secretion by pancreatic alpha cells and decrease hepatic glucose excretion.

Pharmacokinetics

The pharmacokinetic characteristics of linagliptin were studied in healthy subjects and two diabetes patients. After a single oral dose of 5mg in healthy subjects, the peak plasma concentration occurs approximately 1.5 hours after administration (Tmax); The average area under the plasma curve (AUC) is 139 nmol · h/L, and the maximum plasma concentration (Cmax) is 8.9 nmol/L. The plasma concentration of sitagliptin is eliminated in at least two phases, with a long terminal half-life (>100 hours), which is related to the saturable binding of sitagliptin with DPP-4. A long half-life does not cause drug accumulation. After multiple oral doses of 5mg of sitagliptin, it can be determined that the effective half-life of sitagliptin accumulation is approximately 12 hours. After daily administration, 5mg of sitagliptin reached steady-state blood concentration after the third administration, and the Cmax and AUC reached a steady state increased by 1.3 times compared to the first administration. The subject-specific coefficient of variation and inter-subject coefficient of variation of the AUC of linagliptin are both relatively small (12.6% and 28.5%, respectively). Within the dose range of 1-10mg, the plasma AUC of sitagliptin increases proportionally below the dose. The pharmacokinetics of linagliptin in healthy subjects is generally similar to that in patients with type 2 diabetes.

Toxicological research

Genetic toxicity

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

Reproductive toxicity

In the toxicity test of rat fertility and early embryo development, doses of sitagliptin were 10, 30, and 240 mg/kg (exposure levels were approximately 943 times the clinical dose of 5 mg/day), and no adverse effects were observed on early embryo development, mating, fertility, and conception.

Drug overdose

If there is an overdose of sitagliptin, seek medical attention immediately. Common supportive measures should also be taken based on the patient's clinical condition, such as clearing unabsorbed drugs from the gastrointestinal tract, conducting clinical monitoring, and supportive treatment. Linagliptin is unlikely to be cleared through hemodialysis or peritoneal dialysis. In a controlled trial conducted in healthy subjects, a single dose of 600mg (equivalent to 120 times the recommended daily dose) of sitagliptin was administered without any dose-related clinical adverse drug reactions. There is no experience of using doses above 600mg in humans.

conclusion

As an effective oral specific DPP Ⅳ inhibitor, Lilalitine can significantly reduce the level of HbA1c, reduce the secretion of postprandial glucagon, and improve the function of B cells, whether used alone or in combination with other anti-diabetes drugs. This product is well tolerated and has few adverse reactions. It is a promising new drug for the treatment of diabetes. However, further clinical research is needed to observe the contraindications, drug interactions, and adverse reactions of this product[2].