Rosiglitazone

Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. Like other thiazolidinediones, the mechanism of action of rosiglitazone is by activation of the intracellular receptor class of the peroxisome proliferator-activated receptors (PPARs), specifically PPARγ. Rosiglitazone is a selective ligand of PPARγ, and has no PPARα-binding action. Apart from its effect on insulin resistance, it appears to have an anti-inflammatory effect: nuclear factor kappa-B (NFκB) levels fall and inhibitor (IκB) levels increase in patients on rosiglitazone. Recent research has suggested that rosiglitazone may also be of benefit to a subset of patients with Alzheimer's disease not expressing the ApoE4 allele. This is the subject of a clinical trial currently underway.

Rosiglitazone is a thiazolidinedione indicated as an adjunct to diet and exercise to maintain glycemic control in type 2 diabetes.

Rosiglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

• Type 2 Diabetes Mellitus

When rosiglitazone is used as monotherapy, it is associated with increases in total cholesterol, LDL, and HDL. It is also associated with decreases in free fatty acids. Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time.

Rosiglitazone acts as a highly selective and potent agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin.

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in C_max and a delay in T_max (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.

• 17.6 L [oral volume of distribution Vss/F]
• 13.5 L [population mean, pediatric patients]
  

99.8% bound to plasma proteins, primarily albumin.

Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively.

3-4 hours (single oral dose, independent of dose)

• Oral clearance (CL) = 3.03 ± 0.87 L/hr [1 mg Fasting]
• Oral CL = 2.89 ± 0.71 L/hr [2 mg Fasting]
• Oral CL = 2.85 ± 0.69 L/hr [8 mg Fasting]
• Oral CL = 2.97 ± 0.81 L/hr [8 mg Fed]
• 3.15 L/hr [Population mean, Pediatric patients]

Side effects include fluid retention, congestive heart failure (CHF), liver disease

• Take with or without food.