Pioglitazone
From Proteopedia
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* Importance: It is the best selling drug to treat Diabetes and is the 10th best selling drug in the United States. | * Importance: It is the best selling drug to treat Diabetes and is the 10th best selling drug in the United States. | ||
* The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information | * The following is a list of Pharmacokinetic Parameters. See: [[Pharmaceutical Drugs]] for more information | ||
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| + | ===Mechanism of Action=== | ||
| + | Pioglitazone is a selective agonist for Peroxisome Proliferator-Activated Receptor Gamma ([[PPAR]]). When PPAR is not bound by ligand, it 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. Pioglitazone 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 [[Molecular Playground/Insulin|insulin]] responsive genes involved in the control of glucose production, transport and utilization. This explains why the glitazones are referred to as "insulin sensitizers." <ref>PMID:9744270</ref> | ||
===Pharmacokinetics=== | ===Pharmacokinetics=== | ||
Revision as of 06:48, 2 December 2010
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Better Known as: Actos
- Marketed By: Takeda Pharmaceuticals
- Major Indication: Hypoglycemia & Type 2 Diabetes
- Drug Class: PPAR-γ Agonist - Thiazolidinedione (Glitazones)
- Date of FDA Approval (Patent Expiration): 1999 (2011)
- 2009 Sales: $2.4 Billion [1]
- Importance: It is the best selling drug to treat Diabetes and is the 10th best selling drug in the United States.
- The following is a list of Pharmacokinetic Parameters. See: Pharmaceutical Drugs for more information
Mechanism of Action
Pioglitazone is a selective agonist for Peroxisome Proliferator-Activated Receptor Gamma (PPAR). When PPAR is not bound by ligand, it 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. Pioglitazone 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." [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) | |||
References
- ↑ http://drugpatentwatch.com/ultimate/preview/tradename/index.php?query=ACTOS
- ↑ 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
