Sigliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, which can be used alone or combined with other oral hypoglycemic drugs to treat type 2 diabetes. Its advantages are good safety and low incidence of adverse reactions such as hypoglycemia and weight gain.
Chinese name
Sigliptin
Foreign name
Sitagliptin
CAS No
486460-32-6
Molecular formula
C16H15F6N5O
molecular weight
four hundred and seven point three one four zero zero
English alias: Unii-qfp0p1dv7z;Janumet；Sitagliptin;[1]
CAS No.: 486460-32-6[1]
Molecular formula:
CsixteenHfifteenFsixNfiveO[1]
Structural type:
Molecular weight: 407.31400[1]
Precision quality: 407.11800[1]
PSA：77.04000[1]
LogP：2.65470[1]
Physicochemical properties
Appearance and property: white solid powder[1]
Density: 1.614g/cm[1]
Boiling point: 529.905 º C at 760 mmHg[1]
Flash point: 274.277 º C[1]
Refractive index: 1.59[1]
synthetic route
pharmacological action
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Sigliptin dipeptidyl peptidase 4 (DPP-4) inhibitor can improve blood glucose control by increasing the level of active incretin in patients with type 2 diabetes.Intestinal islet stimulating hormones, including glucagon like peptide-1 (GLP-1) and glucose dependent insulin stimulating polypeptide (GIP), are released from the intestine throughout the day and their levels rise after meals.The incretin is a part of the endogenous system involved in the physiological regulation of glucose homeostasis.When the blood glucose concentration is normal or elevated, GLP-1 and GIP can increase the synthesis and release of insulin by pancreatic β cells through the intracellular signaling pathway involving cyclic adenosine monophosphate.In the animal model of type 2 diabetes, GLP-1 or DPP-4 inhibitor treatment can improve the responsiveness of pancreatic β cells to glucose and promote the biosynthesis and release of insulin.With the increase of insulin level, the uptake of glucose by tissues increases.In addition, GLP-1 can also inhibit pancreatic alpha cells to secrete glucagon.The decrease of glucagon concentration and the increase of insulin level can reduce the production of liver glucose, thus reducing the blood sugar level.The effects of GLP-1 and GIP are glucose dependent. When blood glucose concentration is low, GLP-1 will not promote insulin release, nor inhibit glucagon secretion.When the glucose level was higher than the normal concentration, the effect of GLP-1 and GIP on insulin release was enhanced.In addition, GLP-1 will not damage the normal glucagon release response of the body to hypoglycemia.The activity of GLP-1 and GIP is limited by DPP-4 enzyme, which can rapidly hydrolyze the incretin and produce inactive products.Sigliptin can prevent DPP-4 from hydrolyzing incretin, thus increasing the plasma concentration of active forms of GLP-1 and GIP.Sigliptin can increase insulin release and reduce glucagon level in a glucose dependent manner by increasing the level of active incretin.For type 2 diabetic patients with hyperglycemia, the above changes in insulin and glucagon levels can reduce glycosylated hemoglobin A1c (HbA1c) and lower fasting and postprandial blood glucose levels.The glucose dependent mechanism of action of Sigliptin is different from that of sulfonylurea drugs. Even at low glucose levels, sulfonylurea drugs can increase insulin secretion, thus causing hypoglycemia in type 2 diabetes patients and normal subjects.Sigliptin is an effective and highly selective DPP-4 enzyme inhibitor, which will not inhibit DPP-8 or DPP-9 closely related to DPP-4 at the therapeutic concentration.[2-3]
Toxicological study
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Repeated administration:Dogs were given Sigliptin orally at doses of 2, 10 and 50 mg/kg per day for 53 consecutive weeks. The dose of no adverse reaction in the test was 10 mg/kg. Calculated according to the daily recommended dose of 100 mg for adults, the above dose level was about 6 times the human exposure.The dogs in the 50mg/kg group showed transient signs related to administration, including mouth opening breathing, salivation, vomiting white foam, ataxia, tremor, decreased activity and/or bowing posture.At the 14th to 27th weeks of the toxicity test, the histological examination results of animals in the 50mg/kg group showed mild skeletal muscle degeneration.No skeletal muscle degeneration occurred at the 53rd week of the toxicity test, suggesting that this change did not recur or progress with the extension of the duration of administration.The whole body exposure of animals with a daily dose of 50mg/kg was 26 times that of human beings.[3]
Reproductive toxicity:Before and during the mating process of male and female rats, the oral dose of sitagliptin reached 1000 mg/kg/day (calculated according to the recommended daily dose of 100 mg for adults, which is about 100 times the human exposure), and no adverse effect of the drug on fertility was found.When the oral dose of 1000 mg/kg/day was given to rats, a slight increase in the incidence of embryonic rib malformations (deletion, hypoplasia and wavy ribs) related to administration was observed.No teratogenic effect was observed in rats given 250mg/kg/day of sigliptin (calculated according to the recommended daily dose of 100mg for adults, which is about 32 times of human exposure) and rabbits given 125mg/kg/day of sigliptin (calculated according to the recommended daily dose of 100mg for adults, which is about 22 times of human exposure).Sigliptin can be secreted through the milk of lactating rats.[3]
Carcinogenicity:The incidence of tumor did not increase when the mice were given 500 mg/kg of sigliptin orally for 2 years.The rats were orally given Sigliptin for 2 years at doses of 50, 150 and 500 mg/kg/day. In the 500 mg/kg/day group of male rats, the incidence of liver adenoma and liver cancer increased;In female rats of 500 mg/kg/day group, the incidence of liver cancer increased.The 500 mg/kg/day group is calculated according to the recommended daily dose of 100 mg for adults, which is about 58 times of the human exposure. Under this dose, rat liver toxicity can be seen.Sigliptin did not observe the effect of inducing liver tumor at a dose of 150 mg/kg/day (calculated according to the recommended daily dose of 100 mg for adults, which is about 19 times the human exposure).Since it has been found that the hepatotoxicity of drugs is related to the induction of liver tumors in rats, the increase in the incidence of liver tumors in rats may be secondary to the chronic hepatotoxicity of high-dose drugs.The significance of this finding for human clinical use is unclear.[3]
Pharmacokinetics
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Studies on the pharmacokinetics of sitagliptin have been widely conducted in healthy subjects and patients with type 2 diabetes.In healthy subjects, after oral administration of 100mg, sitagliptin was absorbed rapidly, and the plasma drug concentration reached the peak value (median Tmax) 1 to 4 hours after administration.The blood AUC of Sigliptin increased in proportion to the dose.After a single oral dose of 100mg in healthy volunteers, the average blood AUC of sigliptin was 8.52 μ M · hr, Cmax was 950 nM, and the apparent terminal half-life (t1/2) was 12.4 hours.The plasma AUC at the time of stable state after taking 100mg of sigliptin increased by about 14% compared with the initial administration.The coefficient of variation of the AUC of sitagliptin was small (5.8% and 15.1%) in individuals and between individuals.The pharmacokinetic parameters of sigliptin in healthy subjects and patients with type 2 diabetes mellitus are generally similar.[3]
indication
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This product is used in combination with diet control and exercise to improve blood sugar control in patients with type 2 diabetes.[2]
Adverse reactions
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1. The main adverse reactions of digestive system are abdominal pain, diarrhea, nausea and vomiting.[2]
2. Related adverse reactions include nasopharyngitis, pharyngitis, pharyngodynia, urinary tract infection, myalgia, arthralgia, hypertension and dizziness;Can cause white blood cells, alkaline phosphatase, uric acid, etc.[2]
taboo
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It is forbidden for those who are allergic to any component of this product.[3]
Usage and dosage
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The recommended dose of this product for single or combined treatment with metformin is 100 mg, once a day.This product can be taken with or without food.[3]
Patients with renal insufficiency
When patients with mild renal insufficiency (creatinine clearance [CrCl] ≥ 50 mL/min, and the corresponding serum creatinine level is about 1.7 mg/dL for men and 1.5 mg/dL for women) take this product, the dose does not need to be adjusted.[3]
When patients with moderate renal insufficiency (creatinine clearance [CrCl] ≥ 30 to<50 mL/min, corresponding serum creatinine levels are about men>1.7 to ≤ 3.0 mg/dL and women>1.5 to ≤ 2.5 mg/dL) take this product, the dose is adjusted to 50 mg once a day.[3]
Patients with severe renal insufficiency (creatinine clearance rate [CrCl]<30 mL/min, corresponding serum creatinine level is about>3.0 mg/dL for men and>2.5 mg/dL for women) or end-stage patients requiring hemodialysis or peritoneal dialysisnephropathy(ESRD) When patients take this product, the dose is adjusted to 25 mg once a day.It is not necessary to consider the dialysis time when taking this product.
Drug interaction
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In the drug interaction study, there is no clinically significant influence of sigliptin on the pharmacokinetics of the following drugs: metformin, rosiglitazone, glibenclamide, simvastatin, warfarin and oral contraceptives.Based on these data, sitagliptin does not inhibit CYP3A4, 2C8, or 2C9, the CYP isoenzymes.According to in vitro research data, Sigliptin will not inhibit CYP2D6, 1A2, 2C19 or 2B6 or induce CYP3A4.[3]
In patients with type 2 diabetes mellitus, the combination of twice daily multi dose metformin and sigliptin did not significantly change the pharmacokinetics of sigliptin.[3]
The population pharmacokinetic analysis in patients with type 2 diabetes showed that the combination of drugs would not have a clinically significant impact on the pharmacokinetics of sigliptin.The drugs to be evaluated are commonly used by patients with type 2 diabetes, including cholesterol lowering drugs (such as statins, fibrates, and ezetimibe);Antiplatelet drugs (e.g.:Clopidogrel）；Antihypertensive drugs (such as ACE inhibitors, angiotensin receptor blockers, beta receptor blockers, calcium channel blockers, hydrochlorothiazide);Analgesics and NSAIDs (e.g. naproxen, diclofenac, celecoxib);Antidepressant drugs (such as bupropine, fluoxetine, sertraline);Antihistamines (e.g. cetirizine);Proton pump inhibitors (such as omeprazole and lansoprazole) and drugs for erectile dysfunction (such as cidhoven).[3]
The area under the plasma concentration time curve (AUC, 11%) and the average peak plasma concentration (Cmax, 18%) of digoxin and sigliptin slightly increased when they were used together.These changes have no clinical significance.Patients receiving digoxin treatment should be properly monitored.It is not necessary to adjust the dosage of digoxin or this product.[3]
