Comparison of half-disappearance times, distribution volumes and metabolic clearance rates of exogenous glucagon-like peptide 1 and glucagon in rats

Oshima, Ichiyo; Hirota, Masakazu; Ohboshi, Chizuko; Shima, Kenji

doi:10.1016/0167-0115(88)90093-6

Cited by 28 publications

(23 citation statements)

References 18 publications

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“…The plasma level of GLP-1 is regulated by its rate of production, due to synthesis and secretion by the L-cell of the gastrointestinal tract (1,3,10), and by the rate of disappearance from the blood stream, resulting from its enzymatic degradation (1.5 -2 min) (10) and the renal clearance (12 min) (10,11). The chief regulatory mechanism employed for the control of the concentration of active GLP-1 is represented by its rate of degradation.…”

Section: Discussionmentioning

confidence: 99%

The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects

Hui

Farilla

Merkel

et al. 2002

European Journal of Endocrinology

116

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The incretin hormone glucagon-like peptide-1 (GLP-1) is capable of ameliorating glucose-dependent insulin secretion in subjects with diabetes. However, its very short half-life (1.5 -5 min) in plasma represents a major limitation for its use in the clinical setting. The present study was designed to characterize the duration of the effect of GLP-1 in the Zucker diabetic fatty (ZDF) rat. ZDF rats were subjected to a 48 h infusion of human GLP-1 (30 pmol/kg per min), followed by an i.p. glucose tolerance test (IPGTT) (1 g/kg body weight), 2 h after removing the infusion pump. At 15 min from the beginning of the test, GLP-1-treated animals had lower plasma glucose levels (442^38 mg/dl) than salineinfused controls ð583^63 mg=dl; P , 0:01Þ: This was reflected in the higher insulin levels attained in the GLP-1-treated animals ð1999^163 vs 1250^51 pmol=l; GLP-1 vs saline respectively, P , 0:01Þ: Repetition of the IPGTT on day 3, 9 and 16 from the removal of the infusion pump revealed a surprising lasting 'memory' of the exposure to GLP-1. Indeed, the best insulin secretory response was observed approximately 1 week after discontinuation of the GLP-1 infusion, and lasted up to 3 weeks from the early exposure to GLP-1. Detection of fasting plasma levels of GLP-1 during the 3 weeks of the experiment showed a very rapid decline, consistent with the data reported by others. Our findings provide evidence for a long-lasting beneficial effect of GLP-1 that persists for weeks even when the circulating levels of GLP-1 are back to normal.

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Section: Discussionmentioning

confidence: 99%

The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects

Hui

Farilla

Merkel

et al. 2002

European Journal of Endocrinology

116

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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%

“…In this study we evaluated the learning curve for cannulating the femoral and the external jugular vein, two of the most commonly used i.v. accesses (other including the saphenous vein and the carotid artery) [12,13,17,25].…”

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%

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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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“…Over the last two decades, the use of PK modelling techniques to aid investigating the drug actions has become standard practice [8,9]. Rodents, and in particular rats, are extensively used as experimental models for PK studies helping to optimise and select drugs prior to human trials [8,[10][11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Measuring the Pharmacokinetic Properties of Drugs with a Novel Surgical Rat Model

Christakis

Scott

Minnion

et al. 2016

Journal of Investigative Surgery

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BackgroundThe pharmacokinetic (PK) parameters in animal models can help optimise novel candidate drugs prior to testing them in man. However, due to the complexity of PK experiments, their use is limited in academia. We present a novel surgical rat model for investigation of the PK parameters and its use in an anti-obesity drug development program. Materials and MethodsThe model uses anesthetised male Wistar rats, a jugular and a femoral catheter and an insulin pump for peptide infusion. The following PK parameters were measured; metabolic clearance rate (MCR), half-life, and volume of distribution (Vd). Glucagonlike peptide 1 (GLP-1), glucagon (GCG) and exendin-4 (Ex-4) were used to validate the model. The PK parameters of anti-obesity drug candidates X1, X2 and X3 were then measured. ResultsGLP-1 had a significantly higher MCR (83.9±14.1 ml/min/kg) compared to GCG (40.7±14.3 ml/min/kg) and Ex-4 (10.1±2.5 ml/min/kg) (p<0.01 and p<0.001 respectively). Ex-4 had a statistically significant longer half-life (35.1±7.4 min) compared to both GCG (3.2±1.7 min) and GLP-1 (1.2±0.4 min) (p<0.01 for both GCG and GLP-1). Ex-4 had a statistically significant higher Vd (429.7±164.9 ml/kg) compared to both GCG (146.8±49.6 ml/kg) and GLP-1 (149.7±53.5 ml/kg) (p<0.01for both GCG and GLP-1). Peptide X3 had a statistically significant longer half-life (21.3±3.5 min) compared to both X1 (3.9±0.4 min) and X2 (16.1±2.8 min) (p<0.001 for both X1 and X2). Page | 4 ConclusionsWe present an affordable and easily accessible platform for the measurement of the PK parameters of peptides. This novel surgical rat model produces consistent and reproducible results while minimising animal use.

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Comparison of half-disappearance times, distribution volumes and metabolic clearance rates of exogenous glucagon-like peptide 1 and glucagon in rats

Cited by 28 publications

References 18 publications

The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects

The short half-life of glucagon-like peptide-1 in plasma does not reflect its long-lasting beneficial effects

Learning curve of vessel cannulation in rats using cumulative sum analysis

Measuring the Pharmacokinetic Properties of Drugs with a Novel Surgical Rat Model

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