Rosiglitazone
From Proteopedia
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Better Known as: Avandia
- Marketed By: GlaxoSmithKline (No Longer Marketed)
- Major Indication: Hypoglycemia & Type 2 Diabetes
- Drug Class: PPAR-γ Agonist - Thiazolidinedione (Glitazones)
- Date of FDA Approval (Patent Expiration): 1999 (2012)
- 2009 (2006) Sales: $400 Million ($2.5 Billion)[1]
- Why You Should Care: Once the best selling Diabetes treatment in the world. Lawsuits and legal action being pursued against GlaxoSmithKline for manipulation of clinical data upon which Avandia was approved with regards to its side effect profile.
- The following is a list of Pharmacokinetic Parameters. See: Pharmaceutical Drugs for more information
Mechanism of Action
Rosiglitazone is a selective agonist for (PPAR). Unliganded PPAR forms a complex with various co-repressors which possess histone deacetylation activity, maintaining tight chromatin structure and preventing gene transcription. This complex is released upon ligand binding (typical ligands are lipids), allowing various co-activators and co-activator-associated proteins to be recruited. Rosiglitazone functions by by binding to the active site of PPARγ, causing the release of co-repressors and activation of the receptor. Activation of PPAR results in transcription of insulin responsive genes involved in the control of glucose production, transport and utilization. This explains why the glitazones are referred to as "insulin sensitizers." Rosiglitazone occupies roughly 40% of the LBD. It assumes a U-shaped conformation with the TZD head group that stabilize the agonist. Rosiglitazone forms hydrogen bond interactions with H323 and H449 and its TZD group, the sulfur atom of the TZD occupies a hydrophobic pocket formed by Phe363, Glu286, Phe282, Leu330, Ile326 and Leu469, and the central benzene ring occupies a pocket formed by Cys285 and Met364 [2]
Pharmacokinetics
| Glitazone Pharmacokinetics Comparison at Equivalent Dosages [3][4][5][6] | |||||
|---|---|---|---|---|---|
| Parameter | Pioglitazone (Actos) | Rosiglitazone (Avandia) | |||
| Tmax (hr) | 1.8 | 1 | |||
| Cmax (ng/ml) | 617 | 361 | |||
| Bioavailability (%) | 83 | 99 | |||
| Protein Binding (%) | 99 | 99 | |||
| T1/2 (hr) | 3-8 | 3-4 | |||
| AUC (ng/ml/hr) | 6244 | 2024 | |||
| IC50 (nM) | 360 | 10 | |||
| Equivalent Dosage (mg) | 30 | 4 | |||
| Metabolism | Hepatic (CYP2C8) | Hepatic (CYP2C8) | |||
Effectiveness and Side Effects
Effectiveness
Side Effects
Interesting Facts
The Jist
References
- ↑ http://drugpatentwatch.com/ultimate/preview/tradename/index.php?query=AVANDIA
- ↑ Nolte RT, Wisely GB, Westin S, Cobb JE, Lambert MH, Kurokawa R, Rosenfeld MG, Willson TM, Glass CK, Milburn MV. Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-gamma. Nature. 1998 Sep 10;395(6698):137-43. PMID:9744270 doi:10.1038/25931
- ↑ Kalliokoski A, Neuvonen M, Neuvonen PJ, Niemi M. No significant effect of SLCO1B1 polymorphism on the pharmacokinetics of rosiglitazone and pioglitazone. Br J Clin Pharmacol. 2008 Jan;65(1):78-86. Epub 2007 Jul 17. PMID:17635496 doi:10.1111/j.1365-2125.2007.02986.x
- ↑ Saad S, Agapiou DJ, Chen XM, Stevens V, Pollock CA. The role of Sgk-1 in the upregulation of transport proteins by PPAR-{gamma} agonists in human proximal tubule cells. Nephrol Dial Transplant. 2009 Apr;24(4):1130-41. Epub 2008 Nov 8. PMID:18997160 doi:10.1093/ndt/gfn614
- ↑ Young PW, Buckle DR, Cantello BC, Chapman H, Clapham JC, Coyle PJ, Haigh D, Hindley RM, Holder JC, Kallender H, Latter AJ, Lawrie KW, Mossakowska D, Murphy GJ, Roxbee Cox L, Smith SA. Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J Pharmacol Exp Ther. 1998 Feb;284(2):751-9. PMID:9454824
- ↑ Derosa G. Pioglitazone plus glimepiride: a promising alternative in metabolic control. Int J Clin Pract Suppl. 2007 Jun;(153):28-36. PMID:17594391 doi:10.1111/j.1742-1241.2007.01362.x
