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

ABSTRACT

Purpose/aim of the study: The pharmacokinetic (PK) parameters in animal models can help optimize novel candidate drugs prior to human trials. However, due to the complexity of pharmacokinetic experiments, their use is limited in academia. We present a novel surgical rat model for investigation of pharmacokinetic parameters and its use in an anti-obesity drug development program. Materials and methods: The model uses anesthetized male Wistar rats, a jugular, a femoral catheter, and an insulin pump for peptide infusion. The following pharmacokinetic parameters were measured: metabolic clearance rate (MCR), half-life, and volume of distribution (Vd). Glucagon-like peptide 1 (GLP-1), glucagon (GCG), and exendin-4 (Ex-4) were used to validate the model. The pharmacokinetic parameters of anti-obesity drug candidates X1, X2, and X3 were measured. Results: GLP-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 < .01 and p < .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 < .01 for both GCG and GLP-1). Ex-4 had a statistically significant higher volume of distribution (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 < .01 for 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 < .001 for both X1 and X2). Conclusions: We present an affordable and easily accessible platform for the measurement of PK parameters of peptides. This novel surgical rat model produces consistent and reproducible results while minimizing animal use.

Keywords::

• half-life
• pharmacokinetics
• metabolic clearance rate
• jugular vein
• femoral vein
• drug

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Funding

We, the authors, do not have any financial conflicts of interest to disclose. The Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, BBSRC, NIHR, an Integrative Mammalian Biology (IMB) Capacity Building Award, an FP7-HEALTH-2009-241592 EuroCHIP grant, and is supported by the NIHR Biomedical Research Centre Funding Scheme. The views expressed are those of the author(s) and not necessarily those of the NHS, NIHR, or department of health.

AUTHORS CONTRIBUTIONS

Ioannis Christakis, James Minnion, Rebecca Scott, and Joyceline Cuenco carried out the design and coordinated the study, participated in all of the experiments, and prepared the manuscript. Stephen Bloom, Fausto Palazzo, and Tricia Tan provided assistance in the design of the study, coordinated most of the experiments, and participated in manuscript preparation. All authors have read and approved the content of the manuscript.