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 (Tmax = 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 Smax = 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 SRC = 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.
Footnotes
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants GM24211, GM57980].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.175752.
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ABBREVIATIONS:
- GLP-1
- glucagon-like peptide-1
- GLP-1R
- GLP-1 receptor
- GK
- Goto-Kakizaki
- TMDD
- target-mediated drug disposition
- PK
- pharmacokinetics
- PD
- pharmacodynamics
- SD
- Sprague Dawley
- RC
- drug-receptor complex
- MM
- Michaelis-Menten.
- Received September 30, 2010.
- Accepted December 13, 2010.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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