Pharmacokinetic actions of exendin‐4 in the rat: Comparison with glucagon‐like peptide‐1

Parkes, David G.; Jodka, Carolyn M.; Smith, Porsha L.; Nayak, Sonali; Rinehart, Liz; Gingerich, Ron; Chen, Kim; Young, Andrew

doi:10.1002/ddr.1195

Cited by 152 publications

(139 citation statements)

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“…Data are means±SEM. * p<0.05 indicates net extraction of peptide previously reported [6], the extraction pattern for GLP-1 is complex, involving hepatic, peripheral and renal extraction, whereas, earlier assumptions that the kidneys are the only clearance site for exendin-4 [14,27] were confirmed. Thus, hepatic clearance of GLP-1 can be fully accounted for by DPPIV-mediated degradation because only Nterminal degradation is observed and DPPIV is abundant on hepatocytes [28], whereas the peripheral elimination of GLP-1 is a combination of C-terminal and N-terminal degradation, which may involve DPPIV in combination with other ectopeptidases, such as NEP, which are insufficient to affect the metabolism of exendin-4.…”

Section: Discussionmentioning

confidence: 82%

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

2006

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Aims/hypothesis: The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is rapidly degraded in vivo as a result of the combination of extensive enzymatic degradation and renal extraction. The GLP-1 receptor agonist, exendin-4, has a longer duration of action, and has recently been approved as a new agent for the treatment of type 2 diabetes mellitus. Exendin-4 is less prone to enzymatic degradation, but it is still unclear what other factors contribute to the increased metabolic stability. Materials and methods:The overall metabolism of GLP-1 and exendin-4 was directly compared in anaesthetised pigs (n=9). Results: Metabolism of GLP-1 (C-terminal RIA; t 1/2 2.0±0.2 min, metabolic clearance rate [MCR] 23.2±2.8 ml min −1 kg −1 ; N-terminal RIA; t 1/2 1.5±0.2 min, MCR 88.1±10.6 ml min −1 kg −1 ) was significantly faster than the metabolism of exendin-4 (t 1/2 22.0±2

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Section: Discussionmentioning

confidence: 82%

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

2006

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“…25,27 Consistent with a plasma half-life of 150 min in rats (i.p. ), 5 the effect of exenatide, at the ED 50 dose, was sustained for 5 h post-injection. Although dose dependent, this effect has shown to be durable in normal mice for 24 h. 31 Sustained exenatide exposure produced a persistent reduction in body weight in both mice and rats, with a maximal weight loss at 4 weeks of 16 and 11%, respectively.…”

Section: Discussionmentioning

confidence: 90%

“…4 Nonetheless, it shares many of the glucoregulatory actions observed with GLP-1 and is termed as 'incretin mimetic'. Unlike GLP-1, exenatide exhibits extended kinetics 5 due to resistance to proteolytic degradation by dipeptidyl peptidase IV (DPPIV), and has up to 3000-fold higher in vivo potency for glucose-lowering in some animal models. 6 Agents that activate the GLP-1 receptor possess high therapeutic potential for the treatment of diabetes; [7][8][9] exenatide is a currently marketed antidiabetic agent that is shown to improve glycemic control in patients with type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Mack¹,

Moore²,

Jodka³

et al. 2006

Int J Obes

129

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Background: Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents. Objective: To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity. Methods and results: High-fat-fed C57BL/6 mice and Sprague-Dawley rats were treated with exenatide (3, 10 and 30 mg/kg/ day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague-Dawley rats following a single intraperitoneal injection of exenatide (0.1-10 mg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 mg/kg/day (Po0.05). Decreased body weight gain was associated with a significant decrease in fat mass (Po0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (Po0.05). Exenatide at 10 mg/kg significantly reduced food intake (Po0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity. Conclusion: Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

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“…Vessel cannulation in animals has been the cornerstone for performing PK experiments and is the standard practice in drug discovery as it has been shown to provide accurate and reliable results [12][13][14][15][16][17]. PK experiments involve administering the drug compound and taking blood samples in order to assess the biological effect.…”

Section: Ra-cusum Analysis For Jugular Vein Cannulationmentioning

confidence: 99%

“…The cannulation of these vessels was used in an animal model developed in-house in order to evaluate the pharmacokinetic properties (PK) of peptides developed as part of a drug discovery anti-obesity program. The use of animals for such PK experiments is standard practice and provides accurate and reliable results [12][13][14][15][16][17]. Optimal and timely vessel cannulation is important for this protocol; time is a critical component when performing PK experiments as there are limitations to time animals can remain under anaesthesia.…”

Section: Introductionmentioning

confidence: 99%

Learning curve of vessel cannulation in rats using cumulative sum analysis

Christakis

Georgiou

Minnion

et al. 2015

Journal of Surgical Research

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Extensive experience in rodent surgery and training junior surgeons Cover LetterDear Ms/Mr, We would be grateful if you would consider our manuscript entitled "Learning curve of cannulation of jugular and femoral vein in rats using Cumulative Summation Analysis" for publication in The Journal of Surgical Research. Our study investigates the learning curve required for competency and proficiency at blood vessel cannulation in rodents.Vessel cannulation in rats, such as of the femoral and jugular vein, is a technically challenging procedure even for an experienced surgeon. In this study we analyse the results of 200 cannulations of the femoral and jugular vein in rats performed within one year by a single surgeon. The use of Cumulative Summation analysis allows calculating the required experience to most effectively cannulate the jugular and femoral vein, which is approximately 50 and 100 cases, respectively.These results highlight the difficulty involved in performing such micro-surgical operations in rodents. The knowledge of the average time taken to cannulate these vessels allows experiments to be optimally planned, avoiding unexpected time over-runs. Furthermore, our results bring into the spotlight the need for training and direct supervision for the inexperienced researchers, as there is an ongoing need to reduce animal use in research through minimising adverse events.To the authors' knowledge this is the first study to report the learning curve for mastering the technique of catheterisation of the femoral and jugular vein in rats. We feel it will be of interest to readers of The Journal of Surgical Research, and particularly those using rodent microsurgery. Subject category: ResearchAuthors' contributions I.C., J.C., R.S. carried out the design and coordinated the study, participated in all of the experiments and prepared the manuscript. J.M., P.G., V.C., F.P., K.M., S.B.provided assistance in the design of the study, coordinated and carried out most of the experiments and participated in manuscript preparation. T.T., F.P., K.M. and S.B.approved the final version of the manuscript. All authors have read and approved the content of the manuscript.-3 - AbstractBackground:

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Pharmacokinetic actions of exendin‐4 in the rat: Comparison with glucagon‐like peptide‐1

Cited by 152 publications

References 22 publications

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

Learning curve of vessel cannulation in rats using cumulative sum analysis

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