title: Pharmacokinetic/pharmacodynamic modeling of GLP-1 in healthy rats.
abstract: OBJECTIVE
  To provide a mechanism-based model to quantitatively describe GLP-1 pharmacokinetics (PK) and pharmacodynamics (PD) in rats.
  
  
  METHODS
  Intravenous (IV), infusion (IF), subcutaneous (SC), and intraperitoneal (IP) doses of GLP-1 were administered after glucose challenge in healthy Sprague-Dawley rats. Blood was analyzed for GLP-1, glucose, and insulin. The PK-PD modeling was performed with ADAPT 5. The concentration-response curve was generated and analyzed in comparison with other incretin-related therapeutics.
  
  
  RESULTS
  The PK of GLP-1 was described using a two-compartment model with a zero-order input accounting for endogenous GLP-1 synthesis. For SC and IP dosing, sequential zero-order and first-order absorption models reasonably described the rapid absorption process and flip-flop kinetics. In dynamics, GLP-1 showed insulinotropic effects (3-fold increase) after IV glucose challenge in a dose-dependent manner. The concentration-response curve was bell-shaped, which was captured using a biphasic two-binding site Adair model. Receptor binding of GLP-1 exhibited high capacity and low affinity kinetics for both binding sites (K(D) = 9.94 × 10(3) pM, K(2) = 1.56 × 10(-4) pM(-1)).
  
  
  CONCLUSIONS
  The PK of GLP-1 was linear and bi-exponential and its PD showed glucose-dependent insulinotropic effects. All profiles were captured by the present mechanistic model and the dynamic analysis yields several implications for incretin-related therapies.
authors.affiliation: Department of Pharmaceutical Sciences School of Pharmacy & Pharmaceutical Sciences, State University of New York at Buffalo, 565 Hochstetter Hall, Buffalo, New York 14260, USA.
authors.forename: Yanguang
authors.initials: Y
authors.lastname: Cao
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004333:Drug Administration Routes; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D010599:Pharmacokinetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D007328:Insulin; D052216:Glucagon-Like Peptide 1; D005947:Glucose