title: Pharmacokinetic and pharmacodynamic modeling of exendin-4 in type 2 diabetic Goto-Kakizaki rats.
abstract: The pharmacokinetics (PK) and pharmacodynamics (PD) of exendin-4 were studied in type 2 diabetic Goto-Kakizaki rats after single doses at 0.5, 1, 5, or 10 μg/kg by intravenous administration and 5 μg/kg by subcutaneous administration. Plasma exendin-4, glucose, and insulin concentrations were determined. A target-mediated drug disposition model was used to characterize the PK of exendin-4. Glucose turnover was described by an indirect response model, with insulin stimulating glucose disposition. Insulin turnover was characterized by an indirect response model with a precursor compartment. After intravenous doses, exendin-4 rapidly disappeared from the circulation, whereas it exhibited rapid absorption (T(max) = 15-20 min) and incomplete bioavailability (F = 0.51) after the subcutaneous dose. Exendin-4 increased insulin release at 2 to 5 min with capacity S(max) = 6.91 and sensitivity SC₅₀ = 1.29 nM, followed by a rebound at 10 to 15 min and a slow return to the baseline. Glucose initially declined because of enhanced insulin secretion, and then gradually increased because of the activation of the neural system by exendin-4. The hyperglycemic action was modeled with increased hepatic glucose production with a linear factor S(RC) = 0.112 1/nM. The mechanistic PK/PD model satisfactorily described the disposition and effects of exendin-4 on glucose and insulin homeostasis in type 2 diabetic rats.
authors.affiliation: Department of Pharmaceutical Sciences, State University of New York, Buffalo, NY, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008297:Male; D008958:Models, Molecular; D010455:Peptides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D014688:Venoms / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide