Pharmacokinetic/Pharmacodynamic Modeling of GLP-1 in Healthy Rats

Cao, Yanguang; Gao, Wei; Jusko, William J.

doi:10.1007/s11095-011-0652-x

Cited by 20 publications

(12 citation statements)

References 35 publications

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“…Previous studies used a dual indirect response model involving feedback regulation and homeostasis to describe the glucose-insulin system. 33,34) In contrast, in order to elucidate the mechanism underlying olanzapine-induced hyperglycemia, we developed a simple pharmacokinetic-pharmacodynamic model assuming that the olanzapine-induced secretion of epinephrine increases the serum concentration of glucose (Fig. 1).…”

Section: Discussionmentioning

confidence: 99%

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine

Nagata

Nakajima

Ishiwata

et al. 2016

Biological & Pharmaceutical Bulletin

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Acute administration of olanzapine rapidly elevates blood glucose levels. However, the mechanism underlying the rapid development of hyperglycemia with the administration of olanzapine remains unclear. The aim of the present study was to clarify the mechanism underlying olanzapine-induced acute hyperglycemia. Male Wistar rats received an intravenous infusion of saline (control) or olanzapine 2.5, 5, or 10 mg/kg. Blood samples were obtained periodically after olanzapine infusion to determine serum concentrations of glucose, olanzapine, and several endogenous substances. In a separate experiment, rats received an intravenous injection of propranolol (2 mg/kg) 30 min before infusion of olanzapine (10 mg/kg). The intravenous infusion of olanzapine induced dose-dependent increases in the serum concentrations of glucose, epinephrine, and insulin. Pretreatment with propranolol suppressed olanzapine-induced elevations in the serum concentration of glucose, but did not affect the serum concentration of olanzapine or olanzapine-induced increase in the serum concentration of epinephrine. Although the serum concentration of corticosterone increased after administration of olanzapine, no significant differences were observed among the olanzapine dose groups. Furthermore, administration of olanzapine did not affect the serum concentration of glucagon or histamine. We developed a pharmacokinetic-pharmacodynamic model assuming that the olanzapine-induced secretion of epinephrine leads to elevated serum glucose concentrations. This model appeared to satisfactorily characterize olanzapine-induced hyperglycemia. In conclusion, a single intravenous dose of olanzapine dosedependently increased the serum concentration of glucose in rats, and epinephrine plays a role in olanzapineinduced acute hyperglycemia.

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Section: Discussionmentioning

confidence: 99%

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine

Nagata

Nakajima

Ishiwata

et al. 2016

Biological & Pharmaceutical Bulletin

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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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“…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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Pharmacokinetic/Pharmacodynamic Modeling of GLP-1 in Healthy Rats

Cited by 20 publications

References 35 publications

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine

Mechanism Underlying Induction of Hyperglycemia in Rats by Single Administration of Olanzapine

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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