| Indication |
For the treatment of Type II diabetes mellitus |
| Pharmacodynamics |
Rosiglitazone, a member of the drug group known as the
thiazolidinediones or "insulin sensitizers", is not chemically or
functionally related to the alpha-glucosidase inhibitors, the
biguanides, or the sulfonylureas. Rosiglitazone targets insulin
resistance and, hence, is used alone or with metformine or sulfonylurea
to improve glycemic control in patients with type 2 diabetes mellitus. |
| Mechanism of action |
Rosiglitazone acts as an 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. |
| Absorption |
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 Cmax and a delay in Tmax
(1.75 hours). These changes are not likely to be clinically
significant; therefore, rosiglitazone may be administered with or
without food. |
| Volume of distribution |
|
| Protein binding |
99.8% bound to plasma proteins, primarily albumin. |
| Metabolism |
Hepatic. Rosiglitazone is extensively metabolized in the liver
to inactive metabolites via N-demethylation, hydroxylation, and
conjugation with sulfate and glucuronic acid. In vitro data have shown
that Cytochrome (CYP) P450 isoenzyme 2C8 (CYP2C8) and to a minor extent
CYP2C9 are involved in the hepatic metabolism of rosiglitazone. |
| Route of elimination |
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. |
| Half life |
3-4 hours |
| Clearance |
- Oral 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]
|
| Toxicity |
Side effects include fluid retention, congestive heart failure (CHF), liver disease |
