The pharmacokinetics (PK) and pharmacodynamics (PD) of exendin-4 were studied in type 2 diabetic Goto-Kakizaki (GK) rats after single doses at 0.5, 1, 5 or 10 μg/kg by intravenous (iv) and 5 μg/kg by subcutaneous (sc) administration. Plasma exendin-4, glucose, and insulin concentrations were determined. A target-mediated drug disposition (TMDD) 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 iv doses, exendin-4 rapidly disappeared from the circulation, while it exhibited rapid absorption (Tmax = 15-20 min) and incomplete bioavailability (F = 0.51) after the sc dose. Exendin-4 increased insulin release at 2 to 5 min with capacity Smax = 6.91 and sensitivity SC50 = 1.29 nmol/L, followed by a rebound at 10 to 15 min and a slow return to the baseline. Glucose initially declined due to enhanced insulin secretion, and then gradually increased due to the activation of the neural system by exendin-4. The hyperglycemic action was modeled with increased hepatic glucose production with a linear factor SRC = 0.112 L/nmol. The mechanistic PK/PD model satisfactorily described the disposition and effects of exendin-4 on glucose and insulin homeostasis in type 2 diabetic rats.
- Received September 30, 2010.
- Revision received December 9, 2010.
- Accepted December 13, 2010.
- The American Society for Pharmacology and Experimental Therapeutics