| Item |
Information |
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Drug Groups
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approved; investigational |
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Description
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Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is marketed by the pharmaceutical company GlaxoSmithKline as a stand-alone drug (Avandia) and in combination with metformin (Avandamet) or with glimepiride (Avandaryl).
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. |
| Indication |
For the treatment of Type II diabetes mellitus |
| Pharmacology |
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. |
| Toxicity |
Side effects include fluid retention, congestive heart failure (CHF), liver disease |
| Affected Organisms |
| • |
Humans and other mammals |
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| Biotransformation |
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. |
| 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. |
| Half Life |
3-4 hours |
| Protein Binding |
99.8% bound to plasma proteins, primarily albumin. |
| 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. |
| Distribution |
* 6 L |
| 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] |
| References |
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Mohanty P, Aljada A, Ghanim H, Hofmeyer D, Tripathy D, Syed T, Al-Haddad W, Dhindsa S, Dandona P: Evidence for a potent antiinflammatory effect of rosiglitazone. J Clin Endocrinol Metab. 2004 Jun;89(6):2728-35.
[Pubmed]
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Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G: Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006 Dec 7;355(23):2427-43. Epub 2006 Dec 4.
[Pubmed]
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