PIOGLITAZONE

Details

Stereochemistry	RACEMIC
Molecular Formula	C19H20N2O3S
Molecular Weight	356.439
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CCC1=CC=C(CCOC2=CC=C(CC3SC(=O)NC3=O)C=C2)N=C1

InChI

InChIKey=HYAFETHFCAUJAY-UHFFFAOYSA-N

InChI=1S/C19H20N2O3S/c1-2-13-3-6-15(20-12-13)9-10-24-16-7-4-14(5-8-16)11-17-18(22)21-19(23)25-17/h3-8,12,17H,2,9-11H2,1H3,(H,21,22,23)

HIDE SMILES / InChI

Molecular Formula	C19H20N2O3S
Molecular Weight	356.439
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021073s048lbl.pdf
Curator's Comment: description was created based on several sources, including http://reference.medscape.com/drug/actos-pioglitazone-342726 | https://www.drugbank.ca/drugs/DB01132 | https://www.drugs.com/cdi/pioglitazone.html | https://www.ncbi.nlm.nih.gov/pubmed/25760794

Pioglitazone (brand name Actos) is a prescription drug of the thiazolidinedione class with hypoglycemic action used in the treatment of type 2 diabetes. Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-γ) and to a lesser extent PPAR-α. It modulates the transcription of the genes involved in the control of glucose and lipid metabolism in the muscle, adipose tissue, and the liver. As a result, pioglitazone reduces insulin resistance in the liver and peripheral tissues, decreases gluconeogenesis in the liver, and reduces the quantity of glucose and glycated hemoglobin in the bloodstream. Pioglitazone is used to lower blood glucose levels in the treatment of diabetes mellitus type 2 (T2DM) either alone or in combination with a sulfonylurea, metformin, or insulin. Pioglitazone cannot be used in patients with a known hypersensitivity to pioglitazone, other thiazolidinediones or any of components of its pharmaceutical forms. It is ineffective and possibly harmful to diabetes mellitus type 1 and diabetic ketoacidosis. Pioglitazone can cause fluid retention and peripheral edema. As a result, it may precipitate congestive heart failure (which worsens with fluid overload in those at risk). It may cause anemia. Mild weight gain is common due to increase in subcutaneous adipose tissue. In studies, patients on pioglitazone had an increased proportion of upper respiratory tract infection, sinusitis, headache, myalgia and tooth problems.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Peroxisome proliferator-activated receptor gamma 111 Target ID: CHEMBL235 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26595749	Partial Agonist 290		200.0 nM [EC50]
Peroxisome proliferator-activated receptor alpha 62 Target ID: CHEMBL239 Sources: https://www.ncbi.nlm.nih.gov/pubmed/11831892	Partial Agonist 290		6680.0 nM [EC50]

Conditions

Condition	Modality	Highest Phase	Product
Type 2 diabetes mellitus 259 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021073s048lbl.pdf	Primary	Approved 8429	ACTOS Approved Use Pioglitazone tablets are a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. (1.1, 14) Important Limitation of Use: •Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1.2) 1.1 Monotherapy and Combination Therapy Pioglitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14) Launch Date 1999
X-linked adrenoleukodystrophy 8 Sources: http://reference.medscape.com/drug/actos-pioglitazone-342726	Primary	Approved 8429	ACTOS Approved Use Pioglitazone tablets are a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. (1.1, 14) Important Limitation of Use: •Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1.2) 1.1 Monotherapy and Combination Therapy Pioglitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14) Launch Date 1999
Friedreich ataxia 12 Sources: https://clinicaltrials.gov/ct2/show/NCT00811681	Primary	Phase III 656	ACTOS Approved Use Pioglitazone tablets are a thiazolidinedione and an agonist for peroxisome proliferator-activated receptor (PPAR) gamma indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. (1.1, 14) Important Limitation of Use: •Not for treatment of type 1 diabetes or diabetic ketoacidosis. (1.2) 1.1 Monotherapy and Combination Therapy Pioglitazone tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies (14) Launch Date 1999

C_max

Value	Dose	Co-administered	Analyte	Population
890 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16172178	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PIOGLITAZONE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: FEMALE / MALE food status: FED

AUC

Value	Dose	Co-administered	Analyte	Population
8662 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16172178	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PIOGLITAZONE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: FEMALE / MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
12.6 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/16172178	45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		PIOGLITAZONE plasma	Homo sapiens population: UNHEALTHY age: ADOLESCENT sex: FEMALE / MALE food status: FED

Doses

Dose	Population	Adverse events
0.75 mg/kg 1 times / day multiple, oral MTD Dose: 0.75 mg/kg, 1 times / day Route: oral Route: multiple Dose: 0.75 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/30498564 Page: p.7, 9	unhealthy, 5-12 n = 18 Health Status: unhealthy Condition: Autistic disorder\|Asperger syndrome Age Group: 5-12 Sex: M+F Population Size: 18 Sources: https://pubmed.ncbi.nlm.nih.gov/30498564 Page: p.7, 9	Sources: https://pubmed.ncbi.nlm.nih.gov/30498564 Page: p.7, 9
30 mg 1 times / day multiple, oral Recommended Dose: 30 mg, 1 times / day Route: oral Route: multiple Dose: 30 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27322798 Page: p.983, 984	unhealthy, 58.1 n = 60 Health Status: unhealthy Condition: Nonalcoholic Steatohepatitis and Prediabetes\|Type 2 Diabetes Mellitus Age Group: 58.1 Sex: M+F Population Size: 60 Sources: https://pubmed.ncbi.nlm.nih.gov/27322798 Page: p.983, 984	Disc. AE: Edema, ALT increased... AEs leading to discontinuation/dose reduction: Edema (mild, 1.67%) ALT increased (grade 2-4, 1.67%) Sources: https://pubmed.ncbi.nlm.nih.gov/27322798 Page: p.983, 984
180 mg 1 times / day multiple, oral Overdose Dose: 180 mg, 1 times / day Route: oral Route: multiple Dose: 180 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.21	unhealthy Health Status: unhealthy Condition: Type 2 diabetes mellitus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.21	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.21
45 mg 1 times / day multiple, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: multiple Dose: 45 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Type 2 diabetes mellitus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1	Disc. AE: Congestive heart failure, Edema... AEs leading to discontinuation/dose reduction: Congestive heart failure Edema Hepatic failure (grade 5) Fractures Bladder cancer Hypoglycemia Macular edema Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1

AEs

AE	Significance	Dose	Population
ALT increased	grade 2-4, 1.67% Disc. AE	30 mg 1 times / day multiple, oral Recommended Dose: 30 mg, 1 times / day Route: oral Route: multiple Dose: 30 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27322798 Page: p.983, 984	unhealthy, 58.1 n = 60 Health Status: unhealthy Condition: Nonalcoholic Steatohepatitis and Prediabetes\|Type 2 Diabetes Mellitus Age Group: 58.1 Sex: M+F Population Size: 60 Sources: https://pubmed.ncbi.nlm.nih.gov/27322798 Page: p.983, 984
Edema	mild, 1.67% Disc. AE	30 mg 1 times / day multiple, oral Recommended Dose: 30 mg, 1 times / day Route: oral Route: multiple Dose: 30 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/27322798 Page: p.983, 984	unhealthy, 58.1 n = 60 Health Status: unhealthy Condition: Nonalcoholic Steatohepatitis and Prediabetes\|Type 2 Diabetes Mellitus Age Group: 58.1 Sex: M+F Population Size: 60 Sources: https://pubmed.ncbi.nlm.nih.gov/27322798 Page: p.983, 984
Bladder cancer	Disc. AE	45 mg 1 times / day multiple, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: multiple Dose: 45 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Type 2 diabetes mellitus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1
Congestive heart failure	Disc. AE	45 mg 1 times / day multiple, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: multiple Dose: 45 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Type 2 diabetes mellitus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1
Edema	Disc. AE	45 mg 1 times / day multiple, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: multiple Dose: 45 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Type 2 diabetes mellitus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1
Fractures	Disc. AE	45 mg 1 times / day multiple, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: multiple Dose: 45 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Type 2 diabetes mellitus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1
Hypoglycemia	Disc. AE	45 mg 1 times / day multiple, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: multiple Dose: 45 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Type 2 diabetes mellitus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1
Macular edema	Disc. AE	45 mg 1 times / day multiple, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: multiple Dose: 45 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Type 2 diabetes mellitus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1
Hepatic failure	grade 5 Disc. AE	45 mg 1 times / day multiple, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: multiple Dose: 45 mg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Type 2 diabetes mellitus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021073s043s044lbl.pdf Page: p.1

PubMed

Title	Date	PubMed
Bisphenol a diglycidyl ether (BADGE) suppresses tumor necrosis factor-alpha production as a PPARgamma agonist in the murine macrophage-like cell line, RAW 264.7.	2002	11991651
Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size.	2002 Jul	12087064
Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase.	2003 Oct 29	14586007
Simultaneous determination of pioglitazone and its two active metabolites in human plasma by LC-MS/MS.	2003 Sep 15	12946536
Pioglitazone prevents acute liver injury induced by ethanol and lipopolysaccharide through the suppression of tumor necrosis factor-alpha.	2004 Aug	15318101
Comparison of the effects of pioglitazone and rosiglitazone on macrophage foam cell formation.	2004 Oct 22	15381068
Regulated expression of endothelial lipase by porcine brain capillary endothelial cells constituting the blood-brain barrier.	2005 Jul	15953354
Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice.	2005 Jun	15817521
Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone.	2005 May	15900286
Angiotensin II induces peroxisome proliferator-activated receptor gamma in PC12W cells via angiotensin type 2 receptor activation.	2005 Sep	15992368
Regulation of adiponectin receptor 1 in human hepatocytes by agonists of nuclear receptors.	2005 Sep 2	16023994
[Resveratrol inhibits expression of EMMPRIN from macrophages].	2006 Jul	17007354
Peroxisome proliferator-activated receptor-gamma and retinoic acid X receptor alpha represses the TGFbeta1 gene via PTEN-mediated p70 ribosomal S6 kinase-1 inhibition: role for Zf9 dephosphorylation.	2006 Jul	16611854
Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-gamma agonist: molecular mechanism of the antiproteinuric effect of pioglitazone.	2006 Jun	16687628
The direct antioxidative and anti-inflammatory effects of peroxisome proliferator-activated receptors ligands are associated with the inhibition of angiotensin converting enzyme expression in streptozotocin-induced diabetic rat aorta.	2006 Nov 7	16979161
Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction.	2006 Oct	16837568
Modulation of airway remodeling and airway inflammation by peroxisome proliferator-activated receptor gamma in a murine model of toluene diisocyanate-induced asthma.	2006 Oct 15	17015710
Activating effect of benzbromarone, a uricosuric drug, on peroxisome proliferator-activated receptors.	2007	18274627
Resveratrol inhibits macrophage expression of EMMPRIN by activating PPARgamma.	2007 Feb	17055343
Effect of pioglitazone treatment on behavioral symptoms in autistic children.	2007 Jan 5	17207275
[Effects of peroxisome proliferators activated receptors on caveolin-1 expression in foam cells].	2007 Jul	17961437
Inhibitory effect of PPAR on the expression of EMMPRIN in macrophages and foam cells.	2007 May 2	16860414
NR4A orphan nuclear receptors modulate insulin action and the glucose transport system: potential role in insulin resistance.	2007 Oct 26	17785466
MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone.	2007 Sep 4	17766440
Inhibition of advanced glycation end products: an implicit goal in clinical medicine for the treatment of diabetic nephropathy?	2008 Apr	18448808
Treating Hispanic patients for type 2 diabetes mellitus: special considerations.	2008 May	18519840
JNK- and IkappaB-dependent pathways regulate MCP-1 but not adiponectin release from artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate in vitro.	2008 May	18303122
Bezafibrate prevents hepatic stellate cell activation and fibrogenesis in a murine steatohepatitis model, and suppresses fibrogenic response induced by transforming growth factor-beta1 in a cultured stellate cell line.	2008 Oct	18513333
Aldosterone induces interleukin-18 through endothelin-1, angiotensin II, Rho/Rho-kinase, and PPARs in cardiomyocytes.	2008 Sep	18660453
Chronic, in vivo, PPARalpha activation prevents lipid overload in rat liver induced by high fat feeding.	2009	19403437
On the mechanism for PPAR agonists to enhance ABCA1 gene expression.	2009 Aug	19201410
Chronic administration of voglibose, an alpha-glucosidase inhibitor, increases active glucagon-like peptide-1 levels by increasing its secretion and decreasing dipeptidyl peptidase-4 activity in ob/ob mice.	2009 May	19208898
Rational design of a pirinixic acid derivative that acts as subtype-selective PPARgamma modulator.	2010 Apr 15	20307981
Pioglitazone ameliorates behavioral, biochemical and cellular alterations in quinolinic acid induced neurotoxicity: possible role of peroxisome proliferator activated receptor-Upsilon (PPARUpsilon) in Huntington's disease.	2010 Aug	20450929
Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats.	2010 Jul 9	20507283
Troglitazone, a ligand of peroxisome proliferator-activated receptor-{gamma}, stabilizes NUCB2 (Nesfatin) mRNA by activating the ERK1/2 pathway: isolation and characterization of the human NUCB2 gene.	2010 Jun	20427483
Different effects of pioglitazone and rosiglitazone on lipid metabolism in mouse cultured liver explants.	2010 May	20503262
The role of adiponectin in the pathogenesis and treatment of non-alcoholic fatty liver disease.	2010 May	20415685
Suppression of NF-kappaB and GSK-3beta is involved in colon cancer cell growth inhibition by the PPAR agonist troglitazone.	2010 Oct 6	20540935
Differential modulatory effects of rosiglitazone and pioglitazone on white adipose tissue in db/db mice.	2010 Sep 25	20723549

Patents

Sample Use Guides

In Vivo Use Guide

Initiate ACTOS (Pioglitazone) at 15 mg or 30 mg once daily. Limit initial dose to 15 mg once daily in patients with NYHA Class I or II heart failure. If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily.

Route of Administration: Oral

In Vitro Use Guide

For the cell counting assay, Human aortic smooth muscle cells (HASMCs) were seeded at 3× 10^3 cells on to a 96-well dish; 24 hours after the plating, the cells were serum-starved to render them quiescent by replacing the medium with DMEM containing 0.2% FBS. The quiescent SMCs were then preincubated with globular adiponectin (1μg/mL or 3μg/mL) or pioglitazone (1μM or 10μM) for 30min. PDGF-BB (10ng/mL) was added to stimulate the cells for 24hours. These cells were incubated with 10 μl of CCK (cell counting kit)-8 (DOJINDO) or WST-1 (Roche) solution for 2hours before conducting the measurements. We measured the absorbance at 450nm using a microplate reader. 10 μl of BrdU (Roche) solution was added these cells simultaneously with PDGF-BB. BrdU incorporation was measured by chemiluminescent assay

Substance Class	Chemical Created by `admin` on `Sat Dec 16 16:18:57 GMT 2023` Edited by `admin` on `Sat Dec 16 16:18:57 GMT 2023`
Record UNII	X4OV71U42S
Record Status	`Validated (UNII)`
Record Version

Download

Name

Type

Language

PIOGLITAZONE

Official Name

English

5-(4-(2-(5-ETHYLPYRIDIN-2-YL)ETHOXY)BENZYL)THIAZOLIDINE-2,4-DIONE

Systematic Name

English

PIOGLITAZONE [MI]

Common Name

English

pioglitazone [INN]

Common Name

English

ZACTOS

Brand Name

English

5-((4-(2-(5-ETHYL-2-PYRIDINYL)ETHOXY)PHENYL)METHYL)-2,4-THIAZOLIDINEDIONE

Systematic Name

English

AD-4833

Code

English

PIOGLITAZONE [EMA EPAR]

Common Name

English

PIOGLITAZONE [VANDF]

Common Name

English

(RS)-5-(4-(2-(5-ETHYLPYRIDIN-2-YL)ETHOXY)BENZYL)THIAZOLIDINE-2,4-DIONE

Systematic Name

English

2,4-THIAZOLIDINEDIONE, 5-((4-(2-(5-ETHYL-2-PYRIDINYL)ETHOXY)PHENYL)METHYL)-, (±)-

Systematic Name

English

PIOGLITAZONE [HSDB]

Common Name

English

2,4-THIAZOLIDINEDIONE, 5-((4-(2-(5-ETHYL-2-PYRIDINYL)ETHOXY)PHENYL)METHYL)-

Systematic Name

English

PIOGLITAZONE [IARC]

Common Name

English

GLUSTIN

Brand Name

English

Pioglitazone [WHO-DD]

Common Name

English

U-72107

Code

English

(±)-5-(P-(2-(5-ETHYL-2-PYRIDYL)ETHOXY)BENZYL)-2,4-THIAZOLIDINEDIONE

Common Name

English

5-(4-(2-(5-ETHYL-2-PYRIDYL)ETHOXY)BENZYL)THIAZOLIDINE-2,4-DIONE

Systematic Name

English

Classification Tree Code System Code

NDF-RT

N0000170118