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Clinical Pharmacology
CLINICAL PHARMACOLOGY
Mechanism of Action Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPAR). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Text Continues Below
Activation of PPAR nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPAR -responsive genes also participate in the regulation of fatty acid metabolism. Insulin resistance is a common feature characterizing the pathogenesis of type 2 diabetes. The antidiabetic activity of rosiglitazone has been demonstrated in animal models of type 2 diabetes in which hyperglycemia and/ or impaired glucose tolerance is a consequence of insulin resistance in target tissues. Rosiglitazone reduces blood glucose concentrations and reduces hyperinsulinemia in the ob/ ob obese mouse, db/ db diabetic mouse, and fa/ fa fatty Zucker rat. In animal models, rosiglitazone's antidiabetic activity was shown to be mediated by increased sensitivity to insulin's action in the liver, muscle, and adipose tissues. The expression of the insulin-regulated glucose transporter GLUT-4 was increased in adipose tissue. Rosiglitazone did not induce hypoglycemia in animal models of type 2 diabetes and/ or impaired glucose tolerance. Pharmacokinetics and Drug Metabolism: Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range (see Table 1). The elimination half-life is 3 to 4 hours and is independent of dose.
Table 1. Mean (SD) Pharmacokinetic Parameters for Rosiglitazone Following Single Oral Doses (N = 32) Page: 1 | 2 | 3 | 4 | 5 | Next >>
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