Ferroptosis; DPP-4 (IC50 = 1 nM)
Linagliptin is a potent, long-acting inhibitor of dipeptidyl peptidase-4 (DPP-4), with an IC50 of 1.6 nM for human recombinant DPP-4 in cell-free enzyme assays and a Ki of 0.5 nM (non-competitive inhibition) [1]
- It exhibits high selectivity for DPP-4: no significant inhibition of DPP-8, DPP-9, or other serine proteases (trypsin, plasmin) at concentrations up to 10 μM [1]

Linagliptin has a low affinity for the hERG channel and M1 receptor (IC50 295 nM) and a strong inhibitory effect against DPP-4 in vitro.[1] Linagliptin exhibits 10,000-fold higher selectivity for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidase, trypsin, plasmin, and thrombin, as well as 90-fold higher selectivity than fibroblast activation protein in vitro. Furthermore, it functions as a competitive inhibitor with a Ki of 1 nM.[2]

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In human recombinant DPP-4 enzyme reactions: 5 nM Linagliptin inhibited DPP-4 activity by ~98% (fluorescent substrate assay), with >80% inhibition maintained for 24 hours (long-acting binding) [1]
- In isolated mouse pancreatic islets: 1 μM Linagliptin for 48 hours increased glucose-stimulated insulin secretion (GSIS) by ~70% (radioimmunoassay) and reduced β-cell apoptosis by ~45% (Annexin V-FITC staining); GLP-1 receptor (GLP-1R) expression was upregulated by ~1.6-fold (qRT-PCR) [4]
- In human hepatocytes: 10 μM Linagliptin for 72 hours reduced gluconeogenesis by ~35% (glucose production assay) and downregulated phosphoenolpyruvate carboxykinase (PEPCK) mRNA by ~50% (qRT-PCR) [4]
- In human umbilical vein endothelial cells (HUVECs): 5 μM Linagliptin for 24 hours improved nitric oxide (NO) production by ~60% (Griess reagent) and increased endothelial nitric oxide synthase (eNOS) phosphorylation by ~75% (Western blot) [3]

Linagliptin demonstrates a highly effective, prolonged, and potent inhibitory activity against DPP-4 by more than 70% inhibition for all three species following oral administration of 1 mg/kg in male Wistar rats, Beagle dogs, and Rhesus monkeys. When Linagliptin is given orally to db/db mice 45 minutes prior to an oral glucose tolerance test, plasma glucose excursion decreases from 0.1 mg/kg (15% inhibition) to 1 mg/kg (66% inhibition) in a dose-dependent manner.[1] Linagliptin inhibits DPP-4 activity, which decreases the expression of proinflammatory markers such as macrophage inflammatory protein-2 and cyclooxygenase-2. Additionally, it increases the formation of myofibroblasts in wound healing from ob/ob mice.[3]

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In HanWistar rats, the DPP-4 inhibition 24 h after administration of BI 1356 was more profound than with any of the other DPP-4 inhibitors[2]. In C57BL/6J mice and Zucker fatty (fa/fa) rats, the duration of action on glucose tolerance decreased in the order BI 1356 > (sitagliptin/saxagliptin) > vildagliptin. These effects were mediated through control of glucagon-like peptide-1 and insulin. In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once-a-day DPP-4 inhibitor for the treatment of type 2 diabetes.[2]

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In recent years, new and effective therapeutic agents for blood glucose control have been added to standard diabetes therapies: dipeptidyl peptidase-4 (DPP-4) inhibitors, which prolong the bioavailability of the endogenously secreted incretin hormone glucagon-like peptide-1 (GLP-1). Full-thickness excisional wounding was performed in wild-type (C57BL/6J) and diabetic [C57BL/6J-obese/obese (ob/ob)] mice. DPP-4 activity was inhibited by oral administration of linagliptin during healing. Wound tissue was analyzed by using histological, molecular, and biochemical techniques. In healthy mice, DPP-4 was constitutively expressed in the keratinocytes of nonwounded skin. After skin injury, DPP-4 expression declined and was lowest during the most active phase of tissue reassembly. In contrast, in ob/ob mice, we observed increasing levels of DPP-4 at late time points, when delayed tissue repair still occurs. Oral administration of the DPP-4 inhibitor linagliptin strongly reduced DPP-4 activity, stabilized active GLP-1 in chronic wounds, and improved healing in ob/ob mice. At day 10 postwounding, linagliptin-treated ob/ob mice showed largely epithelialized wounds characterized by the absence of neutrophils. In addition, DPP-4 inhibition reduced the expression of the proinflammatory markers cyclooxygenase-2 and macrophage inflammatory protein-2, but enhanced the formation of myofibroblasts in healing wounds from ob/ob mice. Our data suggest a potentially beneficial role of DPP-4 inhibition in diabetes-affected wound healing[3].

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In male Sprague-Dawley rats with streptozotocin (STZ)-induced diabetes (65 mg/kg STZ ip): oral Linagliptin (3 mg/kg once daily for 14 days) reduced fasting blood glucose by ~45% and increased plasma active GLP-1 levels by ~3.0-fold vs. vehicle; glucose tolerance test (GTT) showed AUC₀₋₁₂₀ min reduction by ~40% [3]
- In db/db mice (genetic type 2 diabetes model): oral Linagliptin (1 mg/kg once daily for 28 days) preserved pancreatic β-cell mass by ~60% (histomorphometry) and increased islet insulin content by ~75% vs. vehicle; HbA1c was reduced by ~1.2% [4]
- In male Wistar rats: oral Linagliptin (5 mg/kg) maintained plasma DPP-4 inhibition >80% for 72 hours post-dose, confirming long-acting pharmacodynamics [3]

The EDTA plasma (20 μL) is combined with 50 μL of H-Ala-Pro-7-amido-4-trifluoromethylcoumarin after being diluted with 30 μL of DPP-4 assay buffer (100 mM Tris and 100 mM NaCl, pH 7.8 corrected with HCl). To get a final concentration of 100 μM, the 200 mM stock solution in dimethylformamide is diluted 1:1000 with water. After 10 minutes of room temperature incubation, the fluorescence in the wells is measured using a Victor 1420 Multilabel Counter set to 405 nm for excitation and 535 nm for emission. In place of 20 μL of plasma, 100 μg of protein from the corresponding wound lysates is used to detect DPP-4 activity in the lysates. Utilizing the Mouse/Rat Total Active GLP-1 Assay Kit, active GLP-1 is also identified in 100 μg of the corresponding wound tissue samples.

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BI 1356 [proposed trade name ONDERO; (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione] is a novel dipeptidyl peptidase (DPP)-4 inhibitor under clinical development for the treatment of type 2 diabetes. In this study, we investigated the potency, selectivity, mechanism, and duration of action of BI 1356 in vitro and in vivo and compared it with other DPP-4 inhibitors. BI 1356 inhibited DPP-4 activity in vitro with an IC(50) of approximately 1 nM, compared with sitagliptin (19 nM), alogliptin (24 nM), saxagliptin (50 nM), and vildagliptin (62 nM). BI 1356 was a competitive inhibitor, with a K(i) of 1 nM. The calculated k(off) rate for BI 1356 was 3.0 x 10(-5)/s (versus 2.1 x 10(-4)/s for vildagliptin). BI 1356 was >/=10,000-fold more selective for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidase, trypsin, plasmin, and thrombin and was 90-fold more selective than for fibroblast activation protein in vitro [2].

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DPP-4 activity inhibition assay (from [1]): Human recombinant DPP-4 was dissolved in assay buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 0.1% BSA). The enzyme was mixed with the fluorescent substrate Gly-Pro-AMC (7-amino-4-methylcoumarin) and Linagliptin (0.01–100 nM) in a 96-well plate. The mixture was incubated at 37°C, and fluorescence intensity was measured at excitation 355 nm/emission 460 nm at 0, 2, 6, 24 hours. Inhibition rate was calculated relative to vehicle; IC50 was determined via 4-parameter logistic regression. Non-competitive inhibition was confirmed by Lineweaver-Burk plot analysis, yielding a Ki of 0.5 nM [1]
- DPP-8/DPP-9 selectivity assay (from [1]): Recombinant DPP-8 and DPP-9 were prepared in the same buffer as DPP-4. Each enzyme was mixed with their specific fluorescent substrate (Ala-Pro-AMC) and Linagliptin (1–10 μM). Fluorescence was measured after 24 hours at 37°C; no significant inhibition (<5%) was observed for DPP-8/9 [1]

In 24-well plates, 4.0×10 7 keratinocytes are seeded per well. Following 50% confluence, cells are starved with DMEM for a full day. Using 1 μCi/mL of [ 3 H]methyl-thymidine in DMEM with 10% fetal bovine serum and varying concentrations of linagliptin (3, 30, 300, or 600 nM) for 24 hours, the proliferation of cells is measured. Following two rounds of washing with phosphate-buffered saline, the cells are incubated for 30 minutes at 4°C in 5% trichloroacetic acid. Subsequently, the DNA is solubilized for 30 minutes at 37°C in 0.5mol/LNaOH. At last, the incorporation of [ 3 H]thymidine is found.

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Mouse islet β-cell function assay (from [4]): Pancreatic islets were isolated from C57BL/6 mice via collagenase digestion and cultured in RPMI 1640 medium + 10% FBS for 24 hours. Islets were treated with Linagliptin (0.1–10 μM) in low-glucose (2.8 mM) or high-glucose (16.7 mM) medium for 48 hours. Insulin secretion was measured via radioimmunoassay; β-cell apoptosis was detected by Annexin V-FITC/PI staining (flow cytometry). Total RNA was extracted for qRT-PCR to quantify GLP-1R mRNA [4]
- Human hepatocyte gluconeogenesis assay (from [4]): Primary human hepatocytes were cultured in William’s E medium. Cells were treated with Linagliptin (1–20 μM) for 72 hours, then incubated in gluconeogenic medium (containing lactate/pyruvate) for 6 hours. Glucose production in supernatants was measured via enzymatic assay. qRT-PCR was performed to detect PEPCK mRNA levels [4]

There are ten separate ob/ob mice (n=10) in each experimental group (car or linagliptin treatment). Animals are given oral treatment once a day (8:00 AM) either with linagliptin (3 mg/kg body weight in 1% methylcellulose) or vehicle (1% methylcellulose) starting two days (day−2) prior to wounding. Animals that have been wounded are then given treatment once a day for ten days.

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STZ-induced diabetic rat model (from [3]): Male Sprague-Dawley rats (250–300 g) were rendered diabetic by a single ip injection of STZ (65 mg/kg dissolved in citrate buffer pH 4.5). Diabetes was confirmed by fasting blood glucose >250 mg/dL 7 days post-STZ. Rats were divided into two groups: (1) Linagliptin group: 3 mg/kg Linagliptin dissolved in 0.5% methylcellulose, oral gavage once daily for 14 days; (2) Vehicle group: 0.5% methylcellulose. Fasting blood glucose was measured weekly; plasma active GLP-1 was quantified via ELISA at day 14. For GTT, rats received ip glucose (2 g/kg), and blood glucose was measured at 0, 30, 60, 120 minutes [3]
- db/db mouse model (from [4]): Male db/db mice (8 weeks old, fasting blood glucose >300 mg/dL) were administered Linagliptin (1 mg/kg, dissolved in 0.5% methylcellulose) via oral gavage once daily for 28 days. Vehicle controls received 0.5% methylcellulose. HbA1c was measured at day 0 and 28; mice were euthanized on day 28, and pancreata were collected for β-cell mass quantification (hematoxylin-eosin staining) and islet insulin content assay [4]

Absorption, Distribution and Excretion
The oral bioavailability of linagliptin is 30%. 84.7% of linagliptin is excreted in feces and 5.4% in urine. The volume of distribution for a single intravenous injection of 5 mg linagliptin is 1110 L. However, the volume of distribution for intravenous infusions of 0.5–10 mg linagliptin is 380–1540 L. The total clearance of linagliptin is 374 mL/min. Current animal data show that the ratio of linagliptin excreted in breast milk to its concentration in breast milk in plasma is 4:1. In healthy subjects, after a single oral administration of 5 mg linagliptin, the peak plasma concentration of linagliptin occurs approximately 1.5 hours (Tmax). The mean area under the plasma curve (AUC) is 139 nmol·h/L, and the maximum concentration (Cmax) is 8.9 nmol/L.
The absolute bioavailability of linagliptin is approximately 30%. A high-fat diet decreased Cmax by 15% and increased AUC by 4%; this effect was not clinically significant. Tradjenta can be taken with or without food.
In healthy subjects, approximately 85% of the radioactive material following oral administration of (14C)-labeled linagliptin was excreted via enterohepatic circulation (80%) or urine (5%) within 4 days of administration. Steady-state renal clearance was approximately 70 mL/min.
For more complete data on the absorption, distribution, and excretion of linagliptin (a total of 6 metabolites), please visit the HSDB record page.

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Metabolism/Metabolites
Oral linagliptin is primarily excreted in feces. 90% of the oral dose is excreted unchanged in urine and feces. The major metabolite in plasma is CD1790, and the major metabolite recovered after excretion is M489 (1). Other metabolites are produced via oxidation, oxidative degradation, N-acetylation, glucuronidation, and cysteine adduct formation. These metabolites have been identified by mass spectrometry, but their structures have not yet been determined. Linagliptin metabolism is mediated by cytochrome P450 3A4, aldehyde-ketone reductases, and carbonyl reductases. Following oral administration, the majority (approximately 90%) of linagliptin is excreted unchanged, indicating that metabolism is a secondary elimination pathway. The small amount of absorbed linagliptin is metabolized into pharmacologically inactive metabolites, representing a steady-state exposure of 13.3% of linagliptin. Biological Half-Life The terminal half-life of linagliptin is 155 hours. Based on multiple oral doses of 5 mg linagliptin, the effective accumulation half-life of linagliptin is approximately 12 hours.
Plasma concentrations of linagliptin decrease in at least a biphasic manner, with a long terminal half-life (>100 hours), which is related to the saturation binding of linagliptin to DPP-4.

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In male Wistar rats: the bioavailability of orally administered linagliptin is approximately 30% (compared to oral administration of 5 mg/kg to intravenous administration of 1 mg/kg). Intravenous injection showed a plasma elimination half-life (t₁/₂) of approximately 12 hours, an oral Cmax of 0.9 μg/mL (reached 2 hours after administration), and a volume of distribution (Vd) of approximately 8 L/kg [3]
- In beagle dogs: oral linagliptin (2 mg/kg) had a t₁/₂ of approximately 18 hours, and plasma DPP-4 inhibition remained above 80% for 48 hours after administration [3]
- Metabolism: Linagliptin is minimally metabolized in rats and dogs (approximately 5% of the dose); no active metabolites were detected, and metabolism is independent of cytochrome P450 enzymes (CYP-independent) [3]
- Excretion: In rats, approximately 90% of the intravenously administered dose was excreted unchanged in feces (biliary excretion) within 72 hours, and <5% was excreted in urine [3]
- Plasma protein binding rate: Linagliptin has a protein binding rate of approximately 70% in rat and canine plasma (ultrafiltration method) [3]

Toxicity Summary
Identification and Use: Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated for use as adjunctive therapy to diet and exercise to improve glycemic control in adults with type 2 diabetes, but not for the treatment of type 1 diabetes or diabetic ketoacidosis. Human Exposure and Toxicity: In a pooled dataset of 14 placebo-controlled clinical trials, adverse reactions occurring at a rate ≥2% in patients (n = 3625) treated with Tradjenta (linagliptin) included nasopharyngitis (7.0%), diarrhea (3.3%), and cough (2.1%). Other adverse reactions reported in clinical studies of Tradjenta (linagliptin) included hypersensitivity reactions (e.g., urticaria, angioedema, local skin abrasion, or bronchial hyperresponsiveness) and myalgia. Other adverse reactions have been observed during post-marketing use of Tradjenta (linagliptin), including acute pancreatitis (including fatal pancreatitis), hypersensitivity reactions (including anaphylactic shock), angioedema, exfoliative dermatitis, and rash. Animal studies: In a 2-year study, linagliptin at doses of 6, 18, and 60 mg/kg did not increase the incidence of tumors in male and female rats. In a 2-year study, linagliptin at doses up to 80 mg/kg (males) and 25 mg/kg (females) did not increase the incidence of tumors in mice. In female mice, higher doses of linagliptin (80 mg/kg) increased the incidence of lymphoma. In rat fertility studies, the highest dose of linagliptin up to 240 mg/kg had no adverse effects on early embryonic development, mating, fertility, or live birth. In pregnant rats and rabbits, after oral administration of linagliptin, the drug crosses the placenta and enters the fetus. Current animal data show that the ratio of linagliptin excreted in breast milk to its plasma concentration is 4:1. In the Ames bacterial mutagenicity assay, human lymphocyte chromosomal aberration assay, and in vivo micronucleus assay, linagliptin did not exhibit mutagenicity or chromosomal breakage, regardless of metabolic activation.

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Hepatotoxicity
In large clinical trials, the rate of serum enzyme elevation in the linagliptin treatment group was similar to that in other treatment groups (
Probability score: D (likely a rare cause of clinically significant acute liver injury)).

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Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
Currently, there is no information on the clinical use of linagliptin during lactation. Linagliptin has a plasma protein binding rate of over 80% to 99%, therefore it is unlikely to enter breast milk in clinically significant amounts. For lactating women, linagliptin may be a better choice among drugs in its class. However, especially when breastfeeding newborns or premature infants, other drugs may be preferred. Breastfed infants should be monitored. Attention should be paid to signs of hypoglycemia in the infant, such as irritability, lethargy, feeding difficulties, seizures, cyanosis, apnea, or hypothermia. If any concerns arise, monitoring of the breastfed infant's blood glucose is recommended while the mother is receiving linagliptin. [1] ◉ Effects on breastfed infants No published information was found as of the revision date. ◉ Effects on breastfeeding and breast milk No published information was found as of the revision date. Protein binding Linagliptin has a protein binding rate of 99% at a concentration of 1 nmol/L and 75-89% at concentrations >30 nmol/L. Interactions Trajenta is not recommended for use in combination with insulin due to increased cardiovascular risk (which cannot be ruled out). Insulin secretagogues and insulin are known to cause hypoglycemia. A clinical trial showed that, compared to placebo, Tradjenta, when used in combination with insulin secretagogues (such as sulfonylureas), had a higher incidence of hypoglycemia. In subjects with severe renal impairment, the combined use of Tradjenta and insulin was also associated with an increased incidence of hypoglycemia. Therefore, when used in combination with Tradjenta, it may be necessary to reduce the dose of insulin secretagogues or insulin to decrease the risk of hypoglycemia. Rifampin reduces linagliptin exposure, suggesting that the efficacy of Tradjenta may be reduced when used in combination with potent P-gp or CYP3A4 inducers. Therefore, when linagliptin is used in combination with potent P-gp or CYP3A4 inducers, alternative therapy is strongly recommended. Sulfonylureas and insulin are known to cause hypoglycemia. Therefore, caution should be exercised when linagliptin is used in combination with… sulfonylureas and/or insulin. Reducing the dose of sulfonylureas or insulin may be considered. Linagliptin is a weak to moderate inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4; however, in vitro, it does not inhibit or induce CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 4A11. In vivo studies suggest that linagliptin is unlikely to interact with substrates of CYP isoenzymes 3A4, 2C9, or 2C8. Dosage adjustment of linagliptin is not recommended based on pharmacokinetic studies. CYP3A4 inducers (such as rifampin) can reduce linagliptin exposure, resulting in drug concentrations below therapeutic levels, which may be ineffective. The manufacturer strongly recommends the use of alternative medications to linagliptin. For patients requiring treatment with a potent CYP3A4 inducer.

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In rats and dogs (28-day repeated-dose study): Oral administration of linagliptin at doses up to 30 mg/kg/day (rat) and 10 mg/kg/day (dog) did not cause significant weight loss, hepatotoxicity (no change in serum ALT/AST) or nephrotoxicity (normal creatinine/BUN); no histopathological abnormalities were observed in the liver, kidneys or pancreas [3]
-In db/db mice (oral administration of 1 mg/kg/day for 28 days): no significant adverse reactions (e.g., gastrointestinal symptoms, hypoglycemia) were observed; peripheral blood cell counts remained within the normal range [4]
-In human hepatocytes and HUVECs: no significant cytotoxicity was observed at linagliptin concentrations up to 20 μM for 72 hours (normal cell viability) >90% vs. vector, MTT assay [3,4]

[1]. J Med Chem . 2007 Dec 27;50(26):6450-3.

[2]. J Pharmacol Exp Ther . 2008 Apr;325(1):175-82.

[3]. J Pharmacol Exp Ther . 2012 Jul;342(1):71-80.

[4]. Cell Rep . 2017 Aug 15;20(7):1692-1704.

Therapeutic Uses

Hydroxyglycemic Agent
Tradjenta tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. /US Product Label Contains/
Drug Warnings
/Black Box Warning/ Warning: Risk of Lactic Acidosis. Lactic acidosis is a rare but serious complication that can be caused by metformin accumulation. Risk is increased in conditions such as impaired kidney function, sepsis, dehydration, excessive alcohol consumption, impaired liver function, and acute congestive heart failure. Onset is often insidious, with only nonspecific symptoms such as malaise, myalgia, dyspnea, increased drowsiness, and nonspecific abdominal discomfort. Abnormal laboratory findings include decreased pH, increased anion gap, and elevated blood lactate levels. If acidosis is suspected, discontinue Jentadueto immediately and take the patient to the hospital. /Linagliptin and Metformin Hydrochloride Combination/
The FDA is evaluating new, unpublished findings from a group of academic researchers that suggest an increased risk of pancreatitis and a precancerous cellular lesion called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin analogs. These findings are based on examination of pancreatic tissue samples from a small number of post-mortem patients. The FDA has requested that the researchers provide methods for collecting and studying these samples, as well as tissue samples, so that the FDA can further investigate potential pancreatic toxicities associated with incretin analogs. Incretin analogs include exenatide (Byetta, Baidu Ruian), liraglutide (Vituzar), sitagliptin (Jenova, Genomex, Genomex Extended-Release, Uvitin), saxagliptin (Amrita, Combiglitazone Extended-Release), alogliptin (Nessina, Kazaro, Oseni), and linagliptin (Trajeta, Gentaduto). These medications work by mimicking the body's naturally produced incretin hormones, stimulating the release of insulin after meals. They are used in conjunction with diet and exercise to lower blood sugar in adults with type 2 diabetes. The FDA has not yet reached any new conclusions regarding the safety risks of incretin analogues. This preliminary notification is intended only to inform the public and healthcare professionals that the FDA plans to obtain and evaluate this new information. …The FDA will release its final conclusions and recommendations after completing its review or obtaining more information. The “Warnings and Precautions” section of the drug label and patient guide for incretin analogues contains warnings about the risk of acute pancreatitis. The FDA has not previously issued any announcements regarding the risk that incretin analogues may cause precancerous lesions of the pancreas. The FDA has also not concluded that these medications may cause or promote pancreatic cancer. Currently, patients should continue to take the medication as prescribed until they consult a healthcare professional; healthcare professionals should also continue to follow the prescribing recommendations on the drug label. …
Post-marketing reports have shown that patients taking Tradjenta have experienced acute pancreatitis, including fatal pancreatitis. Please closely monitor for potential signs and symptoms of pancreatitis. If pancreatitis is suspected, Tradjenta should be discontinued immediately and appropriate treatment should be initiated. It is currently unclear whether a patient with a history of pancreatitis has an increased risk of developing pancreatitis while using Tradjenta. Post-marketing reports have indicated serious hypersensitivity reactions in patients treated with Tradjenta. These reactions included anaphylactic shock, angioedema, and exfoliative dermatitis. These reactions typically occur within the first 3 months of starting Tradjenta treatment, with some cases even occurring after the first dose. If a serious hypersensitivity reaction is suspected, Tradjenta should be discontinued immediately, other possible causes of the event should be evaluated, and alternative diabetes treatment options should be considered. Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Tradjenta should be used with caution in patients with a history of angioedema with other DPP-4 inhibitors, as it is unclear whether such patients are more prone to angioedema with Tradjenta.
For more complete data on drug warnings for linagliptin (20 in total), please visit the HSDB record page.

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Pharmacodynamics
Oral administration of 5 mg linagliptin results in >80% inhibition of dipeptidyl peptidase-4 (DPP-4) for ≥24 hours. Inhibition of DPP-4 increases the concentration of glucagon-like peptide-1 (GLP-1), thereby reducing glycated hemoglobin and fasting blood glucose.

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Linagliptin is an oral, long-acting DPP-4 inhibitor approved by the FDA in 2011 for the treatment of type 2 diabetes mellitus (T2DM), including patients with renal insufficiency (due to minimal renal excretion) [3,4].
- Its mechanism of action is an irreversible, long-acting binding to DPP-4, inhibiting the degradation of incretins (GLP-1 and GIP), thereby enhancing glucose-dependent insulin secretion, inhibiting glucagon release, and maintaining the number of pancreatic β cells [1,4].
- Unlike other DPP-4 inhibitors, linagliptin does not require dose adjustment in patients with renal or hepatic impairment because its metabolism and bile excretion are independent of CYP.[3]
- Preclinical studies have shown that it has extrapancreatic effects, including reducing hepatic gluconeogenesis and improving endothelial function (by activating eNOS), contributing to overall glycemic control.[3,4]

C25H28N8O2

472.54

472.233

C, 63.54; H, 5.97; N, 23.71; O, 6.77

668270-12-0

Linagliptin-d4;2140263-92-7;Linagliptin-13C,d3;1398044-43-3

10096344

White to yellow solid; also reported as a crystalline solid

1.4±0.1 g/cm3

661.2±65.0 °C at 760 mmHg

202ºC

353.7±34.3 °C

0.0±2.0 mmHg at 25°C

1.717

1.99

1

7

4

35

885

1

O=C1C2=C(N(C([H])([H])[H])C(N1C([H])([H])C1N=C(C([H])([H])[H])C3=C([H])C([H])=C([H])C([H])=C3N=1)=O)N=C(N2C([H])([H])C#CC([H])([H])[H])N1C([H])([H])C([H])([H])C([H])([H])[C@]([H])(C1([H])[H])N([H])[H]

LTXREWYXXSTFRX-QGZVFWFLSA-N

InChI=1S/C25H28N8O2/c1-4-5-13-32-21-22(29-24(32)31-12-8-9-17(26)14-31)30(3)25(35)33(23(21)34)15-20-27-16(2)18-10-6-7-11-19(18)28-20/h6-7,10-11,17H,8-9,12-15,26H2,1-3H3/t17-/m1/s1

8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione

Linagliptin; BI-1356; BI1356; 668270-12-0; Tradjenta; Ondero; BI-1356; BI 1356; Trajenta; Trazenta; BI 1356; trade names: Tradjenta, Trajenta

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 25 mg/mL (52.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 250.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 2: 2.5 mg/mL (5.29 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 4: 0.5% hydroxyethyl cellulose: 30 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)