DPP-4 (IC50 = 18 nM)
Sitagliptin phosphate shows a strong inhibitory action on DPP-4 from extracts of Caco-2 cells, with an IC50 of 19 nM[1]. Via a mechanism involving cAMP/PKA/Rac1 activation, sitagliptin decreases the in vitro migration of isolated splenic CD4 T-cells[2]. A recent study shows that sitagliptin stimulates intestinal L cell GLP-1 secretion through a novel, direct action that is dependent on MEK-ERK1/2 and protein kinase A, but not on DPP-4. As a result, it lessens the impact of autoimmunity on graft survival[3].

Sitagliptin phosphate shows a strong inhibitory action on DPP-4 from extracts of Caco-2 cells, with an IC50 of 19 nM[1]. Via a mechanism involving cAMP/PKA/Rac1 activation, sitagliptin decreases the in vitro migration of isolated splenic CD4 T-cells[2]. A recent study shows that sitagliptin stimulates intestinal L cell GLP-1 secretion through a novel, direct action that is dependent on MEK-ERK1/2 and protein kinase A, but not on DPP-4. As a result, it lessens the impact of autoimmunity on graft survival[3].

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In vitro treatment of isolated splenic CD4⁺ T-cells with purified porcine kidney DPP-IV (100 mU/ml) resulted in approximately a 1.6-fold increase in T-cell migration. This effect was abolished by co-treatment with a DPP-IV inhibitor (100 μmol/l) [2].
Treatment of CD4⁺ T-cells with DPP-IV (100 mU/ml) for 30 minutes resulted in an approximately 2.7-fold increase in cAMP concentration compared to control, which was abolished by DPP-IV inhibitor. Incretins GIP or GLP-1 (100 nmol/l) had no significant effect on cAMP levels [2].
DPP-IV (100 mU/ml) treatment increased Rac1 GTP binding activity in CD4⁺ T-cells, whereas GIP or GLP-1 (100 nmol/l) had no effect [2].
DPP-IV (100 mU/ml) increased protein kinase A (PKA) activity in CD4⁺ T-cells. Sitagliptin (MK0431) decreased this DPP-IV-mediated PKA activation in a concentration-dependent manner but did not inhibit PKA activation by the cAMP analog 6-Bnz-cAMP [2].

For sitagliptin phosphate to inhibit plasma DPP-4 activity in vivo, the ED50 value in freely fed Han-Wistar rats is estimated to be 2.3 mg/kg seven hours postdose and 30 mg/kg twenty-four hours postdose[1]. Elevated DPP-4 levels in the plasma are seen in the streptozotocin-induced type 1 diabetes mouse model, but these levels can be significantly reduced in mice fed Sitagliptin phosphate. This is accomplished by possibly prolonging islet graft survival through a beneficial effect on the regulation of hyperglycemia[4]. Sitagliptin phosphate's plasma clearance and volume of distribution are higher in rats (40–48 mL/min/kg, 7-9 L/kg) than in dogs (9 mL/min/kg, 3 L/kg); additionally, rats' half-lives are shorter—two hours versus four hours in dogs[5].

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Treatment of non-obese diabetic (NOD) mice with Sitagliptin (MK0431) (mixed into diet at 4 g/kg) for about one month before and after islet transplantation (Pre MK0431 Tx group) significantly prolonged islet graft survival compared to non-treated controls (NCD Tx) or mice treated only after transplantation (Post MK0431 Tx). Graft survival was monitored by microPET imaging and metabolic parameters [2].
The Pre MK0431 Tx group maintained normal non-fasting and fasting blood glucose levels for up to 4 weeks post-transplantation, while the NCD and Post MK0431 Tx groups showed progressive hyperglycemia [2].
The Pre MK0431 Tx group showed stable glucose-stimulated insulin secretion and lower plasma glucagon levels post-transplantation, whereas insulin secretion was undetectable and glucagon levels increased in the control groups [2].
Sitagliptin (MK0431) pretreatment (~1 month) in NOD mice (starting at 8-10 weeks of age) reduced the incidence of diabetes (17.6% vs 35% in controls) and resulted in less severe insulitis (infiltration) and a significantly increased relative β-cell area in the pancreas compared to the control group [2].
Sitagliptin (MK0431) treatment decreased plasma DPP-IV activity and increased plasma levels of active (intact) GLP-1 in NOD mice [2].
Splenic CD4⁺ T-cell migration was significantly increased in diabetic NOD mice compared to non-diabetic controls. Sitagliptin (MK0431) treatment partially restored migration levels toward normal. The extent of CD4⁺ T-cell migration correlated with plasma DPP-IV activity and blood glucose levels [2].
Rac1 GTP binding activity was substantially higher in CD4⁺ T-cells from diabetic NOD mice and was decreased by Sitagliptin (MK0431) treatment [2].

Confluent Caco-2 cells are used to extract DPP-4. Following a 5-minute room temperature incubation period with lysis buffer (10 mM Tris-HCl, 150 mM NaCl, 0.04 U/mL aprotinin, 0.5% Nonidet P40, pH 8.0), the cells are centrifuged at 35,000 g for 30 minutes at 4 °C, and the supernatant is kept at -80°C afterwards. Twenty microliters of suitable compound dilutions are combined with fifty microliters of H-Ala-Pro-7-amido-4-trifluoromethylcoumarin (final concentration in the assay: 100 microliters) as the substrate for the DPP-4 enzyme, and thirty microliters of the Caco-2 cell extract (diluted 1000 times with 100 mM Tris-HCl, 100 mM NaCl, pH 7.8). Fluorescence is measured using a SpectraMax GeminiXS at excitation/emission wavelengths of 405/535 nm after plates are incubated for one hour at room temperature. After exposing Caco-2 cell extracts to high inhibitor concentrations (30 nM for BI 1356 and 3 μM for vildagliptin) for one hour, the dissociation kinetics of the inhibitors from the DPP-4 enzyme are ascertained. Once the preincubation mixture has been diluted 3000-fold with assay buffer, the enzymatic reaction is initiated by adding the substrate, H-Ala-Pro-7-amido-4-trifluoromethylcoumarini. The amount of an inhibitor that is still bound to the DPP-4 enzyme is indicated by the difference in DPP-4 activity at a given time in the presence or absence of the inhibitor. Using the SoftMax software of the SpectraMax, maximum reaction rates (fluorescence units/seconds × 1000) are calculated at 10-minute intervals and corrected for the rate of an uninhibited reaction [(vcontrol-vinhibitor)/vcontrol].

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Plasma DPP-IV activity was measured using a fluorometric assay. The specific protocol is not described in detail within the provided text [2].
A Rac1 GTP binding assay was performed using a fluorophore-based RhoGEF exchange assay kit on total cellular extracts isolated from CD4⁺ T-cells. Data were normalized to protein concentration [2].

Membrane inserts containing CD4T-cells are plated in serum-free RPMI 1640. Cell migration is measured using Corning Transwell chambers, either with or without DPP-4 inhibitor (100 μM) and purified porcine kidney DPP-4 (32.1 units/mg; final concentration of 100 mU/mL). Following an hour, cells that have moved into the lower compartment are counted and those on the upper surface are mechanically removed. The expression for the amount of migration is in relation to the control sample.

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Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted into the circulation by the intestinal L cell. The dipeptidylpeptidase-IV (DPP-IV) inhibitor, sitagliptin, prevents GLP-1 degradation and is used in the clinic to treat patients with type 2 diabetes mellitus, leading to improved glycated hemoglobin levels. When the effect of sitagliptin on GLP-1 levels was examined in neonatal streptozotocin rats, a model of type 2 diabetes mellitus, a 4.9 ± 0.9-fold increase in basal and 3.6 ± 0.4-fold increase in oral glucose-stimulated plasma levels of active GLP-1 was observed (P < 0.001), in association with a 1.5 ± 0.1-fold increase in the total number of intestinal L cells (P < 0.01). The direct effects of sitagliptin on GLP-1 secretion and L cell signaling were therefore examined in murine GLUTag (mGLUTag) and human hNCI-H716 intestinal L cells in vitro. Sitagliptin (0.1-2 μM) increased total GLP-1 secretion by mGLUTag and hNCI-H716 cells (P < 0.01-0.001). However, MK0626 (1-50 μM), a structurally unrelated inhibitor of DPP-IV, did not affect GLP-1 secretion in either model. Treatment of mGLUTag cells with the GLP-1 receptor agonist, exendin-4, did not modulate GLP-1 release, indicating the absence of feedback effects of GLP-1 on the L cell. Sitagliptin increased cAMP levels (P < 0.01) and ERK1/2 phosphorylation (P < 0.05) in both mGLUTag and hNCI-H716 cells but did not alter either intracellular calcium or phospho-Akt levels. Pretreatment of mGLUTag cells with protein kinase A (H89 and protein kinase inhibitor) or MAPK kinase-ERK1/2 (PD98059 and U0126) inhibitors prevented sitagliptin-induced GLP-1 secretion (P < 0.05-0.01). These studies demonstrate, for the first time, that sitagliptin exerts direct, DPP-IV-independent effects on intestinal L cells, activating cAMP and ERK1/2 signaling and stimulating total GLP-1 secretion[3].

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CD4⁺ T-cell migration assay: CD4⁺ T-cells were plated on membrane inserts (8-μm pore size) in serum-free RPMI 1640 medium using Transwell chambers. Cell migration was assessed in the presence or absence of purified porcine kidney DPP-IV (100 mU/ml final concentration) with or without a DPP-IV inhibitor (100 μmol/l). After 1 hour, cells on the upper surface were removed, and cells that had migrated into the lower compartment were counted. Migration extent was expressed relative to the control sample [2].
cAMP measurement: CD4⁺ T-cells were incubated for 30 minutes with test substances (e.g., DPP-IV, GIP, GLP-1) in the presence of 0.5 mmol/l IBMX (a phosphodiesterase inhibitor). cAMP concentration in the cell extracts was determined using a commercial cyclic AMP assay kit [2].
Protein Kinase A (PKA) activity assay: Activity was measured using a commercial PKA kinase activity assay kit according to the manufacturer's protocol. Enzyme activity was normalized to protein concentration [2].
Western blot analysis: Total cellular extracts were separated by SDS-PAGE, transferred to nitrocellulose membranes, and probed with antibodies against various phosphorylated and total signaling proteins (e.g., p38 MAPK, p42/44 MAPK, SAPK/JNK, PKB, β-actin). Immunoreactive bands were visualized by enhanced chemiluminescence [2].

Mice: C57BL/6J mice that have been fasted overnight are challenged with an oral glucose load (2 g/kg) 45 minutes after the compound is administered. Tail bleed predose and successive time points following the glucose load are used to draw blood samples for glucose measurement. DPP-4 inhibitors or a vehicle are given 16 hours prior to the glucose challenge in order to assess how long the effect lasts on glucose tolerance.

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\\n\\nEffects of MK0431 on islet graft survival in diabetic NOD mice were determined with metabolic studies and micropositron emission tomography imaging, and its underlying molecular mechanisms were assessed.\\n
\\nResults: Treatment of NOD mice with MK0431 before and after islet transplantation resulted in prolongation of islet graft survival, whereas treatment after transplantation alone resulted in small beneficial effects compared with nontreated controls. Subsequent studies demonstrated that MK0431 pretreatment resulted in decreased insulitis in diabetic NOD mice and reduced in vitro migration of isolated splenic CD4+ T-cells. Furthermore, in vitro treatment of splenic CD4+ T-cells with DPP-IV resulted in increased migration and activation of protein kinase A (PKA) and Rac1.\\n
\\nConclusions: Treatment with MK0431 therefore reduced the effect of autoimmunity on graft survival partially by decreasing the homing of CD4+ T-cells into pancreatic beta-cells through a pathway involving cAMP/PKA/Rac1 activation.[2]

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\\n\\n\\nEffects of the DPP-IV inhibitor MK0431 (sitagliptin) on glycemic control and functional islet mass in a streptozotocin (STZ)-induced type 1 diabetes mouse model were determined with metabolic studies and microPET imaging.\\n
\\nResults: The type 1 diabetes mouse model exhibited elevated plasma DPP-IV levels that were substantially inhibited in mice on an MK0431 diet. Residual beta-cell mass was extremely low in STZ-induced diabetic mice, and although active GLP-1 levels were increased by the MK0431 diet, there were no significant effects on glycemic control. After islet transplantation, mice fed normal diet rapidly lost their ability to regulate blood glucose, reflecting the suboptimal islet transplant. By contrast, the MK0431 group fully regulated blood glucose throughout the study, and PET imaging demonstrated a profound protective effect of MK0431 on islet graft size.\\n
\\nConclusions: Treatment with a DPP-IV inhibitor can prolong islet graft retention in an animal model of type 1 diabetes.[4]

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\\n \\nThe pharmacokinetics, metabolism, and excretion of sitagliptin [MK-0431; (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine], a potent dipeptidyl peptidase 4 inhibitor, were evaluated in male Sprague-Dawley rats and beagle dogs. The plasma clearance and volume of distribution of sitagliptin were higher in rats (40-48 ml/min/kg, 7-9 l/kg) than in dogs ( approximately 9 ml/min/kg, approximately 3 l/kg), and its half-life was shorter in rats, approximately 2 h compared with approximately 4 h in dogs. Sitagliptin was absorbed rapidly after oral administration of a solution of the phosphate salt. The absolute oral bioavailability was high, and the pharmacokinetics were fairly dose-proportional. After administration of [(14)C]sitagliptin, parent drug was the major radioactive component in rat and dog plasma, urine, bile, and feces. Sitagliptin was eliminated primarily by renal excretion of parent drug; biliary excretion was an important pathway in rats, whereas metabolism was minimal in both species in vitro and in vivo. Approximately 10 to 16% of the radiolabeled dose was recovered in the rat and dog excreta as phase I and II metabolites, which were formed by N-sulfation, N-carbamoyl glucuronidation, hydroxylation of the triazolopiperazine ring, and oxidative desaturation of the piperazine ring followed by cyclization via the primary amine. The renal clearance of unbound drug in rats, 32 to 39 ml/min/kg, far exceeded the glomerular filtration rate, indicative of active renal elimination of parent drug.[5]\\n\\n

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\nFemale NOD/LtJ mice (8-10 weeks old) were placed ad libitum on either a normal chow diet or a diet containing Sitagliptin (MK0431) (Purina Rodent Chow 5015 plus 4 g MK0431/kg). For the transplantation study, one group received the MK0431 diet for about one month before islet transplantation and continued thereafter (Pre MK0431 Tx). Another group received the MK0431 diet only after transplantation (Post MK0431 Tx). The control group received normal chow throughout (NCD Tx) [2].
\nIslets were isolated from non-diabetic male NOD mice by collagenase digestion. For imaging, islets were infected with a recombinant adenovirus expressing HSV1-sr39tk (250 MOI). Two hundred infected islets were transplanted under the right kidney capsule of diabetic female NOD mice [2].
\nMetabolic monitoring included measurements of non-fasting and fasting blood glucose, intraperitoneal glucose tolerance tests (IPGTTs; 2 g glucose/kg), and plasma hormone levels (insulin, glucagon, active GLP-1) at specified time points [2].
\nIslet graft survival was monitored non-invasively using microPET imaging. Mice were injected with the reporter probe [¹⁸F]FHBG and scanned at various time points post-transplantation [2].

Absorption, Distribution and Excretion
The oral bioavailability of sitagliptin is 87%, and its pharmacokinetics are not affected by administration on an empty stomach or with food. Sitagliptin reaches peak plasma concentration within 2 hours. Approximately 79% of sitagliptin is excreted unchanged in the urine. 87% of the dose is excreted in the urine, and 13% in the feces. 198 liters. 350 ml/min. Sitagliptin is secreted in the milk of lactating rats at a milk-to-plasma ratio of 4:1. It is unknown whether sitagliptin is secreted into human milk. In pregnant rats, placental translocation is approximately 45% at 2 hours and approximately 80% at 24 hours after administration. In pregnant rabbits, placental translocation is approximately 66% at 2 hours and approximately 30% at 24 hours after administration. Approximately 79% of sitagliptin is excreted unchanged in the urine, with a very small percentage metabolized.
Sitagliptin is primarily excreted by the kidneys, involving active tubular secretion. Sitagliptin is a substrate of human organic anion transporter-3 (hOAT-3), which may be involved in its renal excretion. The clinical significance of hOAT-3 in sitagliptin transport is unclear. Sitagliptin is also a substrate of P-glycoprotein, which may also be involved in its renal excretion. However, cyclosporine (a P-glycoprotein inhibitor) has not reduced the renal clearance of sitagliptin.
For more complete data on the absorption, distribution, and excretion of sitagliptin (out of 10), please visit the HSDB record page.
Metabolism/Metabolites

Sitagliptin is not primarily metabolized; 79% of the dose is excreted unchanged in the urine. Secondary metabolic pathways are primarily mediated by cytochrome P450 (CYP)3A4, with a smaller role for CYP2C8. After 18 hours, 81% of the dose remained unchanged; 2% was N-sulfated to the M1 metabolite; 6% was oxidized, desaturated, and cyclized to the M2 metabolite; <1% was glucuronized at an unknown site to the M3 metabolite; <1% was carbamylated and glucuronized to the M4 metabolite; 6% was oxidized, saturated, and cyclized to the M5 metabolite; and 2% was hydroxylated at an unknown site to the M6 metabolite. The M2 metabolite is the cis isomer of the M5 metabolite, while the M5 metabolite is the trans isomer. Metabolism and excretion were investigated after a single oral administration of 83 mg/193 μCi sitagliptin in humans. Urine, fecal, and plasma samples were collected periodically over a period of up to 7 days. The primary route of excretion of the radioactive material was the kidneys, with an average of 87% of the administered dose recovered in urine. The average amount excreted in feces was 13% of the administered dose. The parent drug is the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin is primarily excreted via the kidneys. The parent drug accounts for approximately 74% of the total radioactive AUC in plasma. Six trace metabolites were detected, each with a radioactivity level in plasma ranging from less than 1% to 7%. These metabolites include N-sulfate and N-carbamoyl glucuronide conjugates of the parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by the cyclization of piperazine after epoxidation and desaturation. These metabolites were also detected in urine, but at low levels. The metabolite profile in feces was similar to that in urine and plasma, except that glucuronide was not detected in feces. CYP3A4 is the major cytochrome P450 isoenzyme for the limited oxidative metabolism of sitagliptin, with CYP2C8 also contributing slightly. Following oral administration of 14C-labeled sitagliptin, approximately 16% of the radioactivity is excreted as sitagliptin metabolites. Six trace metabolites were detected, which are not expected to affect the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies have shown that the major enzyme involved in the limited metabolism of sitagliptin is CYP3A4, with CYP2C8 also contributing. The biological half-life is approximately 12.4 hours. Other studies have reported a half-life of approximately 11 hours. Two double-blind, randomized, placebo-controlled, alternating-group studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single oral dose of sitagliptin (1.5–600 mg) in healthy male volunteers. Sitagliptin is well absorbed (approximately 80% is excreted unchanged in the urine), with an apparent terminal half-life of 8 to 14 hours. ...
The apparent terminal half-life after oral administration of 100 mg sitagliptin is approximately 12.4 hours....

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This study administered sitagliptin (MK0431) orally via feed at a concentration of 4 g/kg. Treatment effectively inhibited the activity of DPP-IV in the plasma of NOD mice and increased the level of circulating active GLP-1[2].

Toxicity Summary
Identification and Uses: Sitagliptin is a viscous liquid. It is a dipeptidyl peptidase-4 inhibitor used to improve glycemic control in patients with type 2 diabetes. Human Exposure and Toxicity: Sitagliptin improves glycemic control and is generally well tolerated in patients with type 2 diabetes. Use of sitagliptin is associated with an increased risk of heart failure-related hospitalization in patients with type 2 diabetes who have a history of heart failure. A recent study indicated that sitagliptin may be useful for treating certain neurodegenerative diseases of the peripheral nervous system. Sitagliptin does not appear to cause adverse reactions such as weight gain and hypoglycemia as some other treatments. Animal Studies: In rodents, renal and hepatic toxicity was observed at systemic exposure to sitagliptin doses up to 58 times the human exposure level. In dogs, several treatment-related transient signs were observed at exposure doses approximately 23 times the clinical exposure dose, some of which suggested neurotoxicity, such as open-mouth breathing, salivation, white frothy vomiting, ataxia, tremor, decreased activity, and/or arched posture. Carcinogenicity studies in mice showed no increase in tumor incidence in any organ at doses up to 500 mg/kg; however, in rats, at 500 mg/kg, the mixed incidence of hepatic adenoma/carcinoma increased in both male and female rats, and the incidence of hepatocellular carcinoma also increased in female rats. Reproductive toxicity in rats and rabbits was only observed at doses above 250 mg/kg. Abnormalities in the incisors of rats were observed at exposure doses 67 times the clinical exposure dose. Sitagliptin did not exhibit mutagenicity or chromosomal breakage in the Ames bacterial mutagenicity test, Chinese hamster ovary (CHO) chromosome aberration test, CHO cell in vitro cytogenetics test, rat hepatocyte DNA in vitro alkaline elution test, and in vivo micronucleus test, regardless of metabolic activation.
Hepatotoxicity
Liver injury caused by sitagliptin is rare.
Probability score: D (Possibly a rare cause of clinically significant liver injury).
Pregnancy and lactation effects
◉ Overview of use during lactation
There is currently no information regarding the clinical use of sitagliptin during lactation. Sitagliptin has a shorter half-life than most other dipeptidyl peptidase IV inhibitors, therefore it may be a better option among these drugs for breastfeeding women. It is recommended to monitor the blood glucose levels of breastfed infants while the mother is taking sitagliptin. However, especially in breastfed newborns or preterm infants, alternative medications may be necessary.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding rate
38%.

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Drug interactions
Cyclosporine and sitagliptin may increase sitagliptin absorption and plasma concentrations. However, this interaction is not clinically significant.
Sitagliptin and metformin may have an additive effect on active glucagon-like peptide-1 (GLP-1) concentrations. Pharmacokinetic interactions are unlikely. The relevance of these effects to glycemic control in patients with type 2 diabetes is unclear.
After 10 days of combined use of sitagliptin 100 mg with digoxin, the area under the curve (AUC) of digoxin increased slightly (11%), and the mean peak concentration (Cmax) increased slightly (18%). Patients taking digoxin should be monitored appropriately. Dosage adjustment of digoxin or genovit is not recommended.
The incidence of hypoglycemia is higher when sitagliptin is used in combination with sulfonylureas or insulin than in patients taking placebo in combination with sulfonylureas or insulin. In a 52-week long-term non-inferiority clinical study, the incidence of hypoglycemia was lower with sitagliptin/metformin combination therapy than with glipizide/metformin combination therapy. However, in a 24-week clinical study, the incidence of hypoglycemia was higher in patients receiving sitagliptin and glimepiride (with or without metformin) than in patients receiving glimepiride and metformin alone. Patients receiving sitagliptin may need to reduce the dose of insulin secretagogues (such as sulfonylureas) or insulin to lower the risk of hypoglycemia.

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Non-human toxicity values
Oral LD50 in mice: 4000 mg/kg
Oral LD50 in rats: >3000 mg/kg

[1]. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylm ethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of acti.

[2]. Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation. Diabetes, 2009. 58(3): p. 641-51.

[3]. Novel biological action of the dipeptidylpeptidase-IV inhibitor, sitagliptin, as a GLP-1 secretagogue. Endocrinology, 2012. 153(2): p. 564-73.

[4]. Inhibition of dipeptidyl peptidase IV with sitagliptin (MK0431) prolongs islet graft survival in streptozotocin-induced diabetic mice. Diabetes, 2008. 57(5): p. 1331-9.

[5]. Disposition of the dipeptidyl peptidase 4 inhibitor sitagliptin in rats and dogs. Drug Metab Dispos, 2007. 35(4): p. 525-32.

Therapeutic Uses
Januvia is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. /US product label includes/ Januvia should not be used to treat type 1 diabetes or diabetic ketoacidosis, as it is ineffective in these conditions. Type 2 diabetes is a common chronic disease that causes significant morbidity and mortality worldwide. The primary goal of treatment is to control blood glucose by maintaining glycated hemoglobin levels at approximately 6-7%, while preventing hypoglycemia. Diabetes results from increased hepatic glucose production, decreased β-cell insulin secretion, and peripheral tissue insulin resistance. Currently available antidiabetic drugs lower blood glucose levels through different mechanisms. However, tolerability and safety issues exist for each drug, limiting their use and dosage adjustments. Sitagliptin is the first dipeptidyl peptidase-4 inhibitor antidiabetic drug. It increases the level of incretin in circulation, thereby stimulating insulin secretion and inhibiting glucose production. Sitagliptin has been approved by the U.S. Food and Drug Administration (FDA) for use in conjunction with diet and exercise to improve glycemic control in adults with type 2 diabetes. Sitagliptin can be used alone or in combination with metformin or thiazolidinediones (pioglitazone or rosiglitazone) when glycemic control is inadequate. The usual adult dose is 100 mg once daily. For patients with moderate to severe renal impairment, a dose of 25–50 mg once daily is recommended. In randomized, placebo-controlled trials lasting up to 6 months, sitagliptin reduced glycated hemoglobin levels by 0.5–0.8%. In a 52-week clinical trial, sitagliptin was non-inferior to glipizide as an adjunct to metformin monotherapy in patients with inadequate glycemic control. Sitagliptin is well tolerated; the most common adverse reactions are gastrointestinal upset (incidence up to 16%), including abdominal pain, nausea, and diarrhea; the incidence of hypoglycemia and weight gain is similar to that in the placebo group. In general, sitagliptin can be used as monotherapy or as adjunctive therapy to metformin or thiazolidinediones in patients with poorly controlled type 2 diabetes. Sitagliptin is also an alternative therapy for patients with contraindications or intolerance to other hypoglycemic agents. For more complete data on the therapeutic uses of sitagliptin (6 types in total), please visit the HSDB record page.
Drug Warning
/Black Box Warning/ Warning: Lactic acidosis. Lactic acidosis is a rare but serious complication that can be caused by metformin accumulation. Risk is increased in conditions such as sepsis, dehydration, excessive alcohol consumption, liver impairment, kidney impairment, and acute congestive heart failure. The onset of lactic acidosis 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, Janumet should be discontinued immediately and the patient taken to a hospital. /Sitagliptin and Metformin Hydrochloride Combination/
The U.S. Food and Drug Administration (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 receiving treatment 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 the potential pancreatic toxicity associated with incretin analogs. Incretin analogues include exenatide (Byetta, Baidu Ruian), liraglutide (Vituzar), sitagliptin (Jenova, Genomex, Genomex Extended Release, Uvitine), saxagliptin (Amligiz, Combigliza Extended Release), alogliptin (Nesina, Kazzano, Osenib), and linagliptin (Trajeta, Gentaduto). These drugs 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, and 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 labels and patient guides for incretin analogues contains warnings about the risk of acute pancreatitis. The FDA has not previously issued any announcement regarding the risk that incretin analogues may cause precancerous lesions of the pancreas. The FDA has also not concluded that these drugs may cause or promote pancreatic cancer. Currently, patients should continue to take the medication as prescribed by their doctor until they consult a healthcare professional; healthcare professionals should also continue to follow the prescribing advice on the drug label. …
Post-marketing surveillance data shows that patients taking sitagliptin or sitagliptin/metformin have experienced acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. The most common symptoms of pancreatitis are abdominal pain, nausea, and vomiting. Of the 88 reported cases, 66% required hospitalization, including two cases of hemorrhagic or necrotizing pancreatitis requiring long-term hospitalization and intensive care unit (ICU) treatment. Pancreatitis occurred in 21% of cases within 30 days of starting sitagliptin or sitagliptin/metformin treatment; after discontinuation of the drug, pancreatitis symptoms resolved in 53% of patients. 51% of cases had at least one other risk factor (e.g., obesity, high cholesterol, and/or high triglyceride levels). Renal function should be assessed regularly before and after starting sitagliptin. Post-marketing experience indicates that some patients experience worsening renal function, including acute renal failure that sometimes requires dialysis. Some of these patients had pre-existing renal insufficiency, and some were taking an inappropriate dose of sitagliptin. Renal insufficiency usually resolves to baseline with supportive care and discontinuation of the underlying cause. If other causes of acute worsening renal function are suspected, restarting sitagliptin should be considered cautiously. The manufacturer states that no nephrotoxicity has been observed at clinically relevant doses of sitagliptin in clinical trials or preclinical studies. For more complete data on drug warnings for sitagliptin (17 in total), please visit the HSDB records page.

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Pharmacodynamics
Sitagliptin inhibits DPP-4, resulting in increased levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), decreased glucagon levels, and enhanced insulin response to glucose.

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Sitagliptin is a DPP-IV inhibitor approved for the treatment of type 2 diabetes. It works by inhibiting the degradation of the incretin hormones GIP and GLP-1, thereby enhancing their insulinotropic and β-cell protective effects [2].
This study suggests that sitagliptin may exert an immunomodulatory effect in a type 1 diabetes/transplant setting by reducing CD4⁺ T cell migration and insulitis through DPP-IV, cAMP, PKA, and Rac1 activation pathways, independent of its effect of increasing incretin levels [2].

C16H15F6N5O

407.32

407.118

C, 47.18; H, 3.71; F, 27.99; N, 17.19; O, 3.93

486460-32-6

Sitagliptin phosphate;654671-78-0;Sitagliptin phosphate monohydrate;654671-77-9;(S)-Sitagliptin phosphate;823817-58-9;(Rac)-Sitagliptin;823817-56-7;Sitagliptin-d4 hydrochloride

4369359

White to off-white solid powder

1.6±0.1 g/cm3

529.9±60.0 °C at 760 mmHg

274.3±32.9 °C

0.0±1.4 mmHg at 25°C

1.590

1.3

1

10

4

28

566

1

FC(C1=NN=C2C([H])([H])N(C(C([H])([H])[C@@]([H])(C([H])([H])C3=C([H])C(=C(C([H])=C3F)F)F)N([H])[H])=O)C([H])([H])C([H])([H])N21)(F)F

MFFMDFFZMYYVKS-SECBINFHSA-N

InChI=1S/C16H15F6N5O/c17-10-6-12(19)11(18)4-8(10)3-9(23)5-14(28)26-1-2-27-13(7-26)24-25-15(27)16(20,21)22/h4,6,9H,1-3,5,7,23H2/t9-/m1/s1

(3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one

EC 690-730-1; HSDB 7516; HSDB7516; HSDB-7516; Januvia; LEZ 763; LEZ-763; LEZ763; Tesavel; Xelevia; (R)-3-AMINO-1-(3-(TRIFLUOROMETHYL)-5,6-DIHYDRO-[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL)-4-(2,4,5-TRIFLUOROPHENYL)BUTAN-1-ONE; sitagliptina; MK-0431; MK0431; MK 0431; MK-431; MK431; MK 431; Sitagliptin Phosphate; Sitagliptin Phosphate Monohydrate; trade name: Januvia Xelevia Janumet

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: ≥ 2.5 mg/mL (6.14 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 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 2: ≥ 2.5 mg/mL (6.14 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 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 (6.14 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; Need heat to 60°C.
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 corn oil and mix evenly.

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