glucagon-like peptide-1 receptor ( IC50 = 3.22 nM )

Exendin-4 dramatically and dose-dependently raises NO production, phosphorylation of endothelial NO synthase (eNOS), and GTP cyclohydrolase 1 (GTPCH1) in human umbilical vein endothelial cells[2]. MCF-7 breast cancer cells exhibit cytotoxic effects from exendin-4, with an IC50 of 5 μM after 48 hours[3].

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Exendin-4 is a GLP-1 analog used for the treatment of type 2 diabetes mellitus in its synthetic form. As women with diabetes have higher breast cancer incidence and mortality, we examined the effect of the incretin drug exendin-4 on breast cancer cells. The aim of the study is to investigate anticancer mechanism of exendin-4 in MCF-7 breast cancer cells. Cytotoxic effects of exendin-4 were determined by XTT assay. IC50 dose in MCF-7 cells were detected as 5 μM at 48th hour. Gene messenger RNA (mRNA) expressions were evaluated by real-time PCR. According to results, caspase-9, Akt, and MMP2 expression was reduced in dose group cells, compared with the control group cells. p53, caspase-3, caspase-8, caspase-10, BID, DR4, DR5, FADD, TRADD, PARP, PTEN, PUMA, NOXA, APAF, TIMP1, and TIMP2 expression was increased in dose group cells, compared with the control group cells. Effects of exendin-4 on cell invasion, colony formation, and cell migration were detected by Matrigel chamber, colony formation assay, and wound-healing assay, respectively. To conclude, it is thought that exendin-4 demonstrates anticarcinogenesis activity by effecting apoptosis, invasion, migration, and colony formation in MCF-7 cells. Exendin-4 may be a therapeutic agent for treatment of breast cancer as single or in combination with other agents. More detailed researches are required to define the pathways of GLP-1 effect on breast cancer cells because of the molecular biology of breast cancer that involves a complex network of interconnected signaling pathways that have role in cell growth, survival, and cell invasion[3].

Exendin-4 treatment, at both low and high doses, improves serum ALT and lowers serum glucose levels in ob/ob mice as well as computes HOMA scores in comparison to control. In the last four weeks of the study, the net weight gain of the ob/ob mice treated with extendin-4 is significantly reduced[4]. The Exendin-4-treated animals weigh a great deal less than the control rats and exhibit increased pyknotic nuclei and pancreatic acinar inflammation. Rats treated with extendin-4 have lower HOMA values and lower levels of leptin[5]. The rat thoracic aorta relaxes in response to exenatide in a dose-dependent manner. This relaxation is mediated primarily by H₂S but also by NO and CO, and it is evoked through the GLP-1 receptor[6].

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Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology, and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. Ob/ob mice, or their lean littermates, were treated with Exendin-4 [10 microg/kg or 20 microg/kg] for 60 days. Serum was collected for measurement of insulin, adiponectin, fasting glucose, lipids, and aminotransferase concentrations. Liver tissue was procured for histological examination, real-time RT-PCR analysis and assay for oxidative stress. Rat hepatocytes were isolated and treated with GLP-1. Ob/ob mice sustained a reduction in the net weight gained during Exendin-4 treatment. Serum glucose and hepatic steatosis was significantly reduced in Exendin-4 treated ob/ob mice. Exendin-4 improved insulin sensitivity in ob/ob mice, as calculated by the homeostasis model assessment. The measurement of thiobarbituric reactive substances as a marker of oxidative stress was significantly reduced in ob/ob-treated mice with Exendin-4. Finally, GLP-1-treated hepatocytes resulted in a significant increase in cAMP production as well as reduction in mRNA expression of stearoyl-CoA desaturase 1 and genes associated with fatty acid synthesis; the converse was true for genes associated with fatty acid oxidation. In conclusion, Exendin-4 appears to effectively reverse hepatic steatosis in ob/ob mice by improving insulin sensitivity. Our data suggest that GLP-1 proteins in liver have a novel direct effect on hepatocyte fat metabolism.[4]

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Aims/hypothesis: Exendin-4 is a 39 amino acid agonist of the glucagon-like peptide receptor and has been approved for treatment of type 2 diabetes. Many reports describe an increased incidence of acute pancreatitis in humans treated with exendin-4 (exenatide). Previous studies have evaluated the effect of exendin-4 on beta cells and beta cell function. We evaluated the histological and biochemical effects of exendin-4 on the pancreas in rats. Methods: We studied 20 Sprague-Dawley male rats, ten of which were treated with exendin-4 and ten of which were used as controls. The study period was 75 days. Serum and pancreatic tissue were removed for biochemical and histological study. Blood glucose, amylase, lipase, insulin and adipocytokines were compared between the two groups. Results: Animals treated with exendin-4 had more pancreatic acinar inflammation, more pyknotic nuclei and weighed significantly less than control rats. They also had higher serum lipase than control animals. Exendin-4 treatment was associated with lower insulin and leptin levels as well as lower HOMA values than in the untreated control group. Conclusions/interpretation: Although the use of exendin-4 in rats is associated with decreased weight gain, lower insulin resistance and lower leptin levels than in control animals, extended use of exendin-4 in rats leads to pancreatic acinar inflammation and pyknosis. This raises important concerns about the likelihood of inducing acute pancreatitis in humans receiving incretin mimetic therapy.[5]

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Background: It has been reported that GLP-1 agonist exenatide (exendin-4) decreases blood pressure. The dose-dependent vasodilator effect of exendin-4 has previously been demonstrated, although the precise mechanism is not thoroughly described. Here we have aimed to provide in vitro evidence for the hypothesis that exenatide may decrease central (aortic) blood pressure involving three gasotransmitters, namely nitric oxide (NO) carbon monoxide (CO), and hydrogen sulphide (H2S). Methods: We determined the vasoactive effect of exenatide on isolated thoracic aortic rings of adult rats. Two millimetre-long vessel segments were placed in a wire myograph and preincubated with inhibitors of the enzymes producing the three gasotransmitters, with inhibitors of reactive oxygen species formation, prostaglandin synthesis, inhibitors of protein kinases, potassium channels or with an inhibitor of the Na+/Ca2+-exchanger. Results: Exenatide caused dose-dependent relaxation of rat thoracic aorta, which was evoked via the GLP-1 receptor and was mediated mainly by H2S but also by NO and CO. Prostaglandins and superoxide free radical also play a part in the relaxation. Inhibition of soluble guanylyl cyclase significantly diminished vasorelaxation. We found that ATP-sensitive-, voltage-gated- and calcium-activated large-conductance potassium channels are also involved in the vasodilation, but that seemingly the inhibition of the KCNQ-type voltage-gated potassium channels resulted in the most remarkable decrease in the rate of vasorelaxation. Inhibition of the Na+/Ca2+-exchanger abolished most of the vasodilation. Conclusions: Exenatide induces vasodilation in rat thoracic aorta with the contribution of all three gasotransmitters. We provide in vitro evidence for the potential ability of exenatide to lower central (aortic) blood pressure, which could have relevant clinical importance[6].

Competitive binding of peptides to GLP-1 receptor in intact cells [1]
Binding studies were performed as described by Montrose-Rafizadeh et al. Briefly, CHO/GLP-1R cells were grown to confluency on 12-well plates and washed with serum-free ham F-12 medium for 2 h before the experiment. After two washes in 0.5 ml binding buffer, cells were incubated overnight at 4 °C with 0.5 ml buffer containing 2% bovine serum albumin, 50 μm DPP-IV inhibitor, 400 kallikrein inactivator units (KIU) aprotinin, 10 mM glucose, 1–1000 nM GLP-1 or other peptides and 30,000 cpm [125I]GLP-1. At the end of the incubation, the supernatant was discarded and the cells were washed three times with ice-cold phosphate-buffered saline (PBS) and incubated at room temperature with 0.5 ml of 0.5 M NaOH and 0.1% sodium dodecylsulfate for 10 min. Radioactivity in cell lysates was measured in an ICN Apec-Series γ-counter. Specific binding was determined as total binding minus the radioactivity associated with cells incubated in the presence of a large excess of unlabeled GLP-1 (1 μM).

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Exendin-4, a 39-amino acid (AA) peptide, is a long-acting agonist at the glucagon-like peptide-1 (GLP-1) receptor. Consequently, it may be preferable to GLP-1 as a long-term treatment for type 2 diabetes mellitus. Exendin-4 (Ex-4), unlike GLP-1, is not degraded by dipeptidyl peptidase IV (DPP IV), is less susceptible to degradation by neutral endopeptidase, and possesses a nine-AA C-terminal sequence absent from GLP-1. Here we examine the importance of these nine AAs for biological activity of Ex-4, a sequence of truncated Ex-4 analogs, and native GLP-1 and GLP-1 analogs to which all or parts of the C-terminal sequence have been added. We found that removing these AAs from Ex-4 to produce Ex (1-30) reduced the affinity for the GLP-1 receptor (GLP-1R) relative to Ex-4 (IC50: Ex-4, 3.22+/-0.9 nM; Ex (1-30), 32+/-5.8 nM) but made it comparable to that of GLP-1 (IC50: 44.9+/-3.2 nM). The addition of this nine-AA sequence to GLP-1 improved the affinity of both GLP-1 and the DPP IV resistant analog GLP-1 8-glycine for the GLP-1 receptor (IC50: GLP-1 Gly8 [GG], 220+/-23 nM; GLP-1 Gly8 Ex (31-39), 74+/-11 nM). Observations of the cAMP response in an insulinoma cell line show a similar trend for biological activity [1].

Cytotoxicity assay [3]
Cytotoxicity assays and determination of IC50 dose of Exenatide (Exendin-4) in MCF-7 cells were performed by using trypan blue dye exclusion test and XTT assay as indicated in the manufacturers’ instruction.

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Wound-healing assay [3]
The control and dose group cells were plated at 106 cells per well of 60 × 15 mm xstyle cell culture dishes and grown overnight at 37 °C with 5 % CO2. The 80 % confluent control group and dose group cells were treated with 5 μM Exenatide (Exendin-4) after a straight line scratch was made on a confluent monolayer of cells using a sterile 200-μl plastic pipette tip. To remove debris and smooth the edge of the scratch, the cells were washed with 2 ml serum-free DMEM. Images of the MCF-7 cell proliferation were taken at 0 16, 24, and 48 h after the scratch. The scratch assay was performed in triplicate.

Rats: 20 Sprague-Dawley male rats, ten of which are treated with exendin-4 (10 μg/kg) and ten of which are used as controls. There are 75 days in the study period. Pancreatic tissue and serum are extracted for histological and biochemical analysis. The two groups' levels of blood glucose, lipase, amylase, and adipocytokines are compared[5].
Mice: For the first 14 days, 10 μg/kg is administered to the exendin-4 treatment groups every 24 hours. This therapy is the initiating stage. Every 24 hours, the corresponding control mice (lean and ob/ob) are given saline. Exendin-4-treated mice are split into two groups at random after 14 days: the first group is given a high dose of exendin-4 (20 μg/kg) every 12 hours, while the second group is given a low dose of exendin-4 (10 μg/kg) every 12 hours. Every twelve hours, saline is still given to the control mice. Every day for the duration of the 60-day treatment, the mice are weighed[4].

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Use of ob/ob Mouse Model and Treatment With Exenatide (Exendin-4) [4]
Obese male (ob/ob) 6-week-old mice and their lean littermates were used. For both ob/ob mice and their lean littermates the we followed the same treatment strategy. All animals were treated for 60 days. The Exenatide (Exendin-4) treatment groups were treated with 10 μg/kg every 24 hours for the first 14 days. This treatment was the induction phase. Respective control mice (lean and ob/ob) received saline every 24 hours. After 14 days Exendin-4–treated mice were randomly divided into two groups: one group received high dose Exendin-4 (20 μg/kg) every 12 hours, while the second group continued with low dose Exendin-4 (10 μg/kg) every 12 hours.

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Exenatide (Exendin-4) administration and tissue removal [5]
Highly purified drug (Exenatide (Exendin-4)) was stored at −70°C and dosages prepared as needed. In line with previous publications on exendin-4 in rats and in order to better elucidate the effect of exendin-4 on the pancreas, it was decided to use a dose of 10 μg/kg [7]. This dosage was administered subcutaneously to the treated group each day immediately before the 12 h dark cycle when rats are known to feed. Animal weights were recorded weekly and doses adjusted according to weight. The ten exendin-treated rats and ten control animals were killed after 75 days of treatment. Serum was obtained from each animal and necropsy tissue collection specimens were fixed in 10% formalin.

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Vasoreactivity experiments [6]
After all vessel segments had reached a stable contraction plateau, increasing doses of Exenatide (Exendin-4) were administered to the organ baths, and relaxant responses were assessed. The dose of exenatide that was applied to relax the aorta correlated with the dose of epinephrine we used to preconstrict the vessels. Plasma epinephrine level is approximately 30 pM at rest, while in our experiments we used 100 nM, which is a 3000 times higher concentration. The plasma exenatide level was found to be 70 pM, while in our experiments we used a 4500 times higher concentration.
In order to identify the extracellular and intracellular mediators of the vasodilator effect of Exenatide (Exendin-4) we performed a series of experiments. Prior to contracting the vessels with epinephrine we preincubated the vessels (n = 5 of each experiment) with different materials. To determine whether the vasodilation due to exenatide evoked via the GLP-1R, we preincubated vessels with GLP-1R antagonist exendin(9–39) (32 μM, 30 min). Because the affinity of exendin(9–39) to bind GLP-1R is smaller than that of exenatide, we applied a ten times higher concentration of the receptor antagonist than the highest dose of exenatide.

Absorption, Distribution and Excretion
Exenatide reaches peak plasma concentration within 2.1 hours. Due to its subcutaneous administration, its bioavailability is 1. Exenatide is primarily filtered by the glomeruli, followed by proteolytic hydrolysis, and ultimately excreted in the urine. 28.3 L. 9.1 L/hour. Following a single injection of Bydureon, exenatide is released from the microspheres over approximately 10 weeks. The initial phase involves the release of surface-bound exenatide, followed by gradual release from the microspheres, resulting in two peaks in plasma exenatide concentration around week 2 and week 6-7, representing microsphere hydration and erosion, respectively. After starting a 2 mg Bydureon administration every 7 days (weekly), plasma exenatide concentrations gradually increase over 6-7 weeks. After 6 to 7 weeks, with dosing intervals of 7 days (weekly), the mean exenatide concentration remained at approximately 300 pg/mL, indicating steady state. Non-clinical studies indicate that exenatide is primarily cleared by glomerular filtration, followed by proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/hr, and the mean terminal half-life is 2.4 hr. These pharmacokinetic characteristics of exenatide are dose-independent. In most individuals, exenatide concentrations are detectable approximately 10 hours after administration. The mean apparent volume of distribution of exenatide after a single subcutaneous injection of byetida is 28.3 L. In patients with type 2 diabetes, the median peak plasma concentration was reached within 2.1 hours after subcutaneous injection of exenatide. Following subcutaneous injection of 10 μg Byetta, the mean peak concentration (Cmax) of exenatide was 211 pg/mL, and the mean area under the time-concentration curve (AUC0-inf) was 1036 pg·hr/mL. Exenatide exposure (AUC) increased proportionally within the therapeutic dose range of 5 μg to 10 μg. Within the same dose range, the increase in Cmax was less than the increase in AUC. Similar drug exposures can be achieved by subcutaneous injection of Byetta in the abdomen, thigh, or upper arm. For more complete data on the absorption, distribution, and excretion of exenatide (6 items in total), please visit the HSDB record page. Metabolites/Metabolites After glomerular filtration, exenatide is degraded into smaller peptides and amino acids by dipeptidyl peptidase-4, metalloproteinases, endopeptidase 24-11, aminoproteases, and serine proteases. Currently, metalloproteinases are considered to be the main enzymes involved in the degradation of exenatide. Exenatide is metabolized by enzymes in the kidneys into small peptides less than 3 amino acids in length.

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Biological half-life
2.4 hours
The terminal half-life is 18 minutes in mice and 114 minutes in rats.
The average terminal half-life in humans is 2.4 hours.

Toxicity Summary
Identification and Uses: Exenatide is a white to off-white powder formulated as a subcutaneous injection. It is available in twice-daily and once-weekly extended-release formulations. Exenatide is a synthetic, long-acting human glucagon-like peptide-1 (GLP-1) receptor agonist (an incretin analog). It is used in combination with diet and exercise to improve glycemic control in adults with type 2 diabetes. Human Exposure and Toxicity: One clinical study reported an overdose of exenatide. Adverse reactions included severe nausea, severe vomiting, and a rapid decline in blood glucose levels. Post-marketing reports also include acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis requiring hospitalization, and severe hypersensitivity reactions (e.g., anaphylactic shock and angioedema). There have been reports of worsening renal function (e.g., elevated serum creatinine levels, impaired/insufficient renal function, chronic renal failure, and sometimes even acute renal failure requiring hemodialysis or kidney transplantation) following exenatide use. At clinically relevant doses, exenatide extended-release formulations also induced thyroid C-cell tumors in rats. It is currently unclear whether this drug induces thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as neither clinical nor non-clinical studies have established its relevance in humans. Therefore, exenatide extended-release formulations are contraindicated in patients with a personal or family history of MTC, or in patients with type 2 multiple endocrine neoplasia syndrome. Animal studies: In male mice, administration of exenatide at doses up to 760 μg/kg/day did not reveal any adverse effects on fertility. However, exenatide did cause developmental toxicity in rats, mice, and rabbits. Subcutaneous injection of 0.3, 1, or 3 mg/kg of exenatide extended-release formulation into pregnant rats on days 6, 9, 12, and 15 of gestation resulted in inhibited fetal growth in all dose groups, with skeletal ossification defects observed in the 1 and 3 mg/kg dose groups, accompanied by maternal effects (reduced food intake and decreased weight gain). During days 6 to 15 of gestation (organogenesis), pregnant mice were subcutaneously injected with exenatide at doses of 6, 68, 460, or 760 μg/kg/day. Cleft palate (partially with a cleft) and abnormal rib and skull development were observed in the 6 μg/kg/day dose group. During days 6 to 18 of gestation (organogenesis), pregnant rabbits were subcutaneously injected with exenatide at doses of 0.2, 2, 22, 156, or 260 μg/kg/day. Abnormal fetal ossification was observed in the 2 μg/kg/day dose group. Furthermore, exenatide carcinogenicity studies were conducted in rats. Benign thyroid C-cell adenomas were observed in female rats subcutaneously injected with exenatide at doses of 18, 70, or 250 μg/kg/day. In another carcinogenicity study of an extended-release exenatide formulation, male and female rats were subcutaneously injected with doses of 0.3, 1.0, and 3.0 mg/kg every other week. The results showed a significant increase in the incidence of thyroid C-cell tumors in both male and female rats. Compared with the control group (13% in males and 7% in females), the incidence of C-cell adenomas was statistically significantly increased in all dose groups (27%–31% in females) and in the 1.0 mg/kg and 3.0 mg/kg dose groups (46% and 47% in males, respectively). The incidence of C-cell carcinoma in females in the high-dose group was significantly higher than that in the control group (6%), while the incidence of C-cell carcinoma in males in the low-dose, medium-dose, and high-dose groups was 3%, 7%, and 4%, respectively (not statistically significant compared with the control group), but numerically higher than that in the control group (0% in both males and females). An increase in benign fibromas was observed in the subcutaneous tissue at the injection site in males receiving the 3 mg/kg dose. No treatment-related injection site fibrosarcomas were observed in any dose group. Exenatide did not exhibit mutagenicity or chromosome breakage in the Ames bacterial mutagenicity test or the Chinese hamster ovary cell chromosome aberration test, regardless of metabolic activation. The in vivo mouse micronucleus test was negative.

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Hepatotoxicity
Liver injury caused by exenatide, even if it occurs, is extremely rare. In large clinical trials, the incidence of elevated serum enzymes in the exenatide treatment group was not higher than that in the placebo or control groups, and no clinically significant cases of liver injury were reported. Since its market launch, no cases of exenatide-induced hepatotoxicity have been reported, and liver injury is not listed as an adverse event in the product information leaflet. Exenatide has been associated with rare cases of acute pancreatitis, but even this complication usually does not cause an increase in serum bilirubin and transaminase levels.

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Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
There is currently no information on the clinical use of exenatide during lactation. Because exenatide is a large peptide molecule with a molecular weight of 4187 Daltons, its content in breast milk is likely to be very low, and it is unlikely to be absorbed due to possible partial degradation in the infant's gastrointestinal tract. Its short half-life makes it a better choice among similar drugs for lactating women. If a mother needs to use exenatide, breastfeeding does not need to be discontinued. However, breastfeeding women should use exenatide with caution, especially when breastfeeding newborns or premature infants, until more data are available.
◉ 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
The protein binding of exenatide has not been determined.

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Drug interactions
Post-marketing experience has reported increases in the International Normalized Ratio (INR) when exenatide is used in combination with warfarin, sometimes accompanied by bleeding. In a drug interaction study, when warfarin sodium (a single 25 mg dose) was administered 35 minutes after exenatide (5 μg subcutaneously twice daily for 2 days; followed by 10 μg subcutaneously twice daily for 7 days), no clinically significant changes were observed in the AUC, peak plasma concentration, or treatment response (expressed as INR) of warfarin (S- or R-enantiomer); however, the time to peak warfarin concentration was delayed by approximately 2 hours. For patients receiving warfarin, prothrombin time should be monitored more frequently after initiation or modification of exenatide treatment. Once prothrombin time stabilizes, it can be monitored at the usual recommended intervals for patients receiving warfarin treatment. In healthy women, subcutaneous injection of exenatide (10 μg, twice daily) followed by daily administration of a fixed-dose combined oral contraceptive (30 μg ethinylestradiol and 150 μg levonorgestrel) 30 minutes later reduced peak plasma concentrations of ethinylestradiol and levonorgestrel by 45% and 27%, respectively, and delayed the time to peak plasma concentrations by 3 hours and 3.5 hours, respectively. Repeating daily administration of the fixed-dose combined oral contraceptive 1 hour before exenatide injection reduced the mean peak plasma concentration of ethinylestradiol by 15%; however, the mean peak plasma concentration of levonorgestrel did not change significantly. In both dosing regimens, exenatide did not alter the mean trough concentration of levonorgestrel after repeated daily administration of the fixed-dose combined oral contraceptive; however, when the fixed-dose combined oral contraceptive was administered 30 minutes after exenatide injection, the mean trough concentration of ethinylestradiol increased by 20%. In this study, the effect of exenatide on the pharmacokinetics of oral contraceptives may be influenced by the effects of food on oral contraceptives. Therefore, oral contraceptives should be taken at least 1 hour before taking exenatide. Subcutaneous injection of exenatide (10 μg, twice daily) 30 minutes before taking lovastatin (40 mg orally) reduces the AUC and peak plasma concentration of lovastatin by approximately 40% and 28%, respectively, and delays the time to peak plasma concentration by 4 hours. In clinical trials, exenatide did not cause persistent changes in lipid profiles compared to baseline in patients already receiving HMG-CoA reductase inhibitors (statins). In patients with mild to moderate hypertension receiving a stable dose of lisinopril (5–20 mg daily), subcutaneous injection of exenatide (10 μg twice daily) did not alter the steady-state AUC or peak plasma concentration of lisinopril, nor did it change the 24-hour mean systolic and diastolic blood pressure. However, the steady-state time to peak plasma concentration of lisinopril was delayed by 2 hours. For more complete (10) drug interaction data on exenatide, please visit the HSDB record page.

[1]. The importance of the nine-amino acid C-terminal sequence of exendin-4 for binding to the GLP-1 receptor and for biological activity. Regul Pept. 2003 Jul 15;114(2-3):153-8.

[2]. Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner. Am J Physiol Endocrinol Metab. 2016 Jun 1;310(11):E947-57.

[3]. Antidiabetic exendin-4 activates apoptotic pathway and inhibits growth of breast cancer cells. Tumour Biol. 2016 Feb;37(2):2647-53.

[4]. Exendin-4, a glucagon-like protein-1 (GLP-1) receptor agonist, reverses hepatic steatosis in ob/obmice. Hepatology. 2006 Jan;43(1):173-81.

[5]. Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia. 2010 Jan;53(1):153-9.

[6]. Exenatide induces aortic vasodilation increasing hydrogen sulphide, carbon monoxide and nitric oxide production. Cardiovasc Diabetol. 2014 Apr 2;13:69.

Therapeutic Uses

Hydroxyglycemic Agents
Byetta is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated for use as adjunctive therapy to improve glycemic control in adults with type 2 diabetes. /US Product Label/
Bydureon is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated for use as adjunctive therapy to improve glycemic control in adults with type 2 diabetes. Bydureon is a sustained-release formulation of exenatide. Do not use concurrently with Byetta. /US Product Label/
Byetta is not required before starting treatment with Bydureon. If you decide to start Bydureon in a suitable patient who is already taking Byetta, Byetta should be discontinued. Patients switching from Byetta to Bydureon may experience a transient (approximately 2 weeks) increase in blood glucose levels.
For more complete data on the therapeutic uses of exenatide (8 items in total), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Warning: Risk of thyroid C-cell tumors. At clinically relevant exposure levels, exenatide extended-release tablets have caused thyroid C-cell tumors in rats. It is currently unknown whether badurr can cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as its relevance to humans has not been established in either clinical or non-clinical studies. Badurr is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia type 2 (MENS2).
Postmarketing surveillance data have shown that exenatide can cause acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis requiring hospitalization. Persistent, severe abdominal pain, possibly accompanied by vomiting, is a typical symptom of acute pancreatitis. Most patients who develop pancreatitis have at least one other risk factor for acute pancreatitis (e.g., gallstones, severe hypertriglyceridemia, alcohol consumption) and require hospitalization. Some patients experience serious complications, including dehydration and renal failure, suspected intestinal obstruction, cellulitis, and ascites. A transient association exists between acute or exacerbating pancreatitis in some patients and an increase in the exenatide dose from 5 mcg twice daily to 10 mcg twice daily (maximum recommended dose). Some patients experience symptoms of acute pancreatitis (e.g., nausea, vomiting, abdominal pain) after reactivation of the drug; one patient experienced relief of abdominal pain after permanent discontinuation of the drug. Most patients experience improvement after discontinuation of exenatide. The U.S. Food and Drug Administration (FDA) is evaluating unpublished research results suggesting an increased risk of pancreatitis and precancerous cellular changes (pancreatic duct metaplasia) in patients with type 2 diabetes treated with incretin analogues (exenatide, liraglutide, sitagliptin, saxagliptin, alogliptin, or linagliptin). These findings are based on examination of pancreatic tissue specimens from a small number of patients who died from unexplained causes while receiving incretin analogues. The FDA has not drawn any new conclusions regarding the safety risks of incretin analogues. The FDA will notify healthcare professionals of its review findings and recommendations as soon as the review is complete or as further information becomes available. The FDA notes that clinicians should continue to follow the recommendations in the incretin analogue prescribing information. The manufacturer states that patients should be closely monitored for signs and symptoms of acute pancreatitis (e.g., unexplained, persistent, severe abdominal pain that may radiate to the back; nausea; vomiting; elevated serum amylase or lipase levels) after initiating exenatide and as the dose is increased. If pancreatitis is suspected, exenatide and other medications that may cause pancreatitis should be discontinued immediately, and confirmatory tests (e.g., serum amylase or lipase levels, imaging studies) should be performed, and appropriate treatment should be initiated. If pancreatitis is diagnosed, exenatide should not be restarted. Exenatide has not been studied in patients with a history of pancreatitis. For such patients, other antidiabetic therapies should be considered. Rare reports of renal function deterioration following exenatide treatment (e.g., elevated serum creatinine levels, renal impairment/insufficiency, exacerbation of chronic renal failure, acute renal failure, sometimes requiring hemodialysis or kidney transplantation) have emerged. Some of these events occur in patients experiencing nausea, vomiting, and/or diarrhea (with or without dehydration); these adverse reactions may lead to changes in renal function in these patients. Some of these events also occur in patients receiving exenatide in combination with other medications known to affect renal function or hydration (e.g., angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, diuretics). No direct nephrotoxicity of exenatide has been identified in preclinical or clinical studies. Renal damage is usually reversed with supportive care and discontinuation of potentially causative medications, including exenatide. Changes in renal function may be a consequence of diabetes and are unrelated to any risks associated with exenatide treatment. Clinicians should closely monitor patients receiving exenatide for signs and symptoms of renal impairment and consider discontinuing the drug if renal impairment is suspected and cannot be explained by other causes.
For more drug warnings (full version) (15 items) on exenatide, please visit the HSDB record page.

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Pharmacodynamics
After taking exenatide, the body's natural response to glucose is regulated. Upon glucose stimulation, insulin release increases and glucagon release decreases; however, in the case of hypoglycemia, glucagon release is normal. Exenatide also slows gastric emptying, thereby slowing and prolonging the time it takes for glucose to be released into the systemic circulation. These effects work together to prevent hyperglycemia and hypoglycemia.

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Glucagon-like peptide-1 (GLP-1) may have direct beneficial effects on the cardiovascular system. This study aimed to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and its potential mechanisms. The study included newly diagnosed patients with type 2 diabetes, who were randomly assigned to two groups, receiving either lifestyle intervention or lifestyle intervention combined with exenatide. After 12 weeks of treatment, coronary flow velocity reserve (CFVR, an important indicator of coronary endothelial function) was significantly improved, and serum soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) levels in the exenatide treatment group were significantly lower than baseline and in the control group. Notably, CFVR was negatively correlated with glycated hemoglobin (HbA1c) and positively correlated with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exenatide-4 (an exenatide derivative) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclase 1 (GTPCH1) levels in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exenatide (9-39) or GLP-1R siRNA, adenylate cyclase inhibitor SQ-22536, AMPK inhibitor Compound C, and PI3K inhibitor LY-294002 can all eliminate the effects of exenatide-4. In addition, exenatide-4 reverses homocysteine-induced endothelial dysfunction by reducing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Similarly, exenatide (9-39) attenuates the protective effect of exenatide-4 against homocysteine-induced endothelial dysfunction. In summary, exenatide can significantly improve coronary endothelial function in newly diagnosed type 2 diabetes patients. Its mechanism of action may be through the activation of the AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism. [2]

C186H286N50O62S

4246.62388277054

4244.05

914454-01-6

Exendin-4; 141758-74-9

H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2; L-histidyl-glycyl-L-alpha-glutamyl-glycyl-L-threonyl-L-phenylalanyl-L-threonyl-L-seryl-L-alpha-aspartyl-L-leucyl-L-seryl-L-lysyl-L-glutaminyl-L-methionyl-L-alpha-glutamyl-L-alpha-glutamyl-L-alpha-glutamyl-L-alanyl-L-valyl-L-arginyl-L-leucyl-L-phenylalanyl-L-isoleucyl-L-alpha-glutamyl-L-tryptophyl-L-leucyl-L-lysyl-L-asparagyl-glycyl-glycyl-L-prolyl-L-seryl-L-seryl-glycyl-L-alanyl-L-prolyl-L-prolyl-L-prolyl-L-serinamide

HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; H-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-[NH2]

Solid powder

NC(=O)[C@@H](NC([C@@H]1CCCN1C([C@@H]1CCCN1C([C@@H]1CCCN1C(=O)[C@@H](NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC([C@@H]1CCCN1C(=O)CNC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@]([H])(NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@]([H])(NC(=O)[C@@H](NC(=O)[C@@]([H])(NC(=O)CNC(=O)[C@@H](NC(=O)CNC(=O)[C@@H](N[H])CC1=CN=CN1)CCC(O)=O)[C@@H](C)O)CC1=CC=CC=C1)[C@@H](C)O)CO)CC(O)=O)CC(C)C)CO)CCCCN)CCC(N)=O)CCSC)CCC(O)=O)CCC(O)=O)CCC(O)=O)C)C(C)C)CCCNC(N)=N)CC(C)C)CC1=CC=CC=C1)[C@H](CC)C)CCC(O)=O)CC1C2C=CC=CC=2NC=1)CC(C)C)CCCCN)CC(=O)N)=O)CO)CO)C)=O)=O)=O)CO.OC(=O)C

PIJVPWRREHDVDN-IFKXHDEJSA-N

InChI=1S/C76H159N22O6/c1-8-61(7)74(88-31-29-85-45-64(86-9-2)40-59(3)4)53-94-63(21-22-76(103)104)44-84-28-30-87-65(41-60(5)6)49-89-62(16-10-11-23-77)48-90-66(42-75(79)102)46-82-26-24-80-32-38-95-34-12-17-70(95)51-93-69(58-101)50-91-68(57-100)47-83-27-25-81-33-39-96-35-14-19-72(96)54-98-37-15-20-73(98)55-97-36-13-18-71(97)52-92-67(43-78)56-99/h2,28-29,33,59-74,80-94,99-101H,8-27,30-32,34-58,77-78H2,1,3-7H3,(H2,79,102)(H,103,104)/t61-,62-,63-,64-,65-,66-,67+,68+,69+,70-,71-,72-,73-,74+/m0/s1

(4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-4-amino-1-[[2-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[(2S)-2-[(2S)-2-[(2S)-2-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-2-oxoethyl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]acetyl]amino]-5-oxopentanoic acid

Exendin-4 acetate; Exenatide acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO: ≥ 66.66 mg/mL (~15.7 mM)
H2O: ~25 mg/mL (~5.9 mM)

Note: Please refer to the "Guidelines for Dissolving Peptides" section in the 4th page of the "Instructions for use" file (upper-right section of this webpage) for how to dissolve peptides.

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Solubility in Formulation 1: 100 mg/mL (23.55 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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