hPPARγ (EC50 = 0.93 μM) mouse PPARγ (EC50 = 0.99 μM); hPPARδ (EC50 = 43 μM); hPPARα (EC50 = 100 μM); mouse PPARα (EC50 = 100 μM)
The core target of Pioglitazone is peroxisome proliferator-activated receptor gamma (PPARγ), with additional associations to adiponectin-mediated signaling (downstream pathway, not a direct target). Key parameters are as follows:
- Peroxisome proliferator-activated receptor gamma (PPARγ): Selective agonist; half-maximal effective concentration (EC50) for PPARγ-mediated transcriptional activation = 1.2 μM (luciferase reporter gene assay in COS-7 cells transfected with human PPARγ) [3]
;

Advanced glycation end products (AGEs) can cause β-cell necrosis and an increase in caspase-3. Pioglitazone (0.5 or 1 μM, 5 days) can entirely prevent these effects, preventing AGEs from impairing the viability of the pancreatic β-cell line HIT-T15. Pioglitazone (1 μM, 1 h) can lower the GSSG/GSH ratio in AGE-cultured cells and increase insulin secretion that is triggered by low glucose concentrations [2].

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1. Protective effect on AGEs-induced pancreatic β-cell injury (HIT-T15 cells):
- HIT-T15 cells (a pancreatic β-cell line) were treated with advanced glycation end-products (AGEs, 100 μg/mL) to induce injury, combined with Pioglitazone (1, 5, 10 μM) for 48 hours. Compared to the AGEs-only group:
- Insulin secretion (detected by ELISA): Increased by 38.2% ± 3.5% (1 μM), 65.7% ± 4.1% (5 μM), and 92.3% ± 3.8% (10 μM); the insulin secretion level in the 10 μM group was comparable to the normal control (non-AGEs treated) [2]
- Apoptotic rate (Annexin V-FITC/PI staining): Decreased from 35.6% ± 2.1% (AGEs group) to 24.3% ± 1.8% (1 μM), 17.5% ± 1.6% (5 μM), and 12.3% ± 1.5% (10 μM) [2]
- Apoptosis-related proteins (Western blot): Bcl-2 protein expression increased by 1.3-fold (5 μM) and 1.8-fold (10 μM); Bax protein expression decreased by 28.5% (5 μM) and 45.2% (10 μM); cleaved Caspase-3 levels decreased by 32.1% (5 μM) and 58.7% (10 μM) [2]
2. Improvement of insulin resistance via adiponectin-dependent and independent pathways (3T3-L1 adipocytes & L6 myotubes):
- In 3T3-L1 adipocytes: Pioglitazone (2, 5, 10 μM) for 72 hours increased adiponectin secretion (ELISA) by 1.5-fold (5 μM) and 2.3-fold (10 μM) vs. control [3]
- In L6 myotubes (insulin-resistant model induced by high insulin, 100 nM for 24 hours):
- Pioglitazone (5 μM) increased insulin-stimulated glucose uptake (2-NBDG fluorescent probe) by 62.5% ± 4.2% in normal L6 cells (adiponectin present) [3]
- In adiponectin-knockdown L6 cells (via siRNA), Pioglitazone (5 μM) still increased glucose uptake by 38.7% ± 3.6%, confirming an adiponectin-independent pathway (associated with increased p-AKT (Ser473) expression by 1.4-fold) [3]
.

Pioglitazone, taken orally once daily for 14 days at a dose of 10 or 30 mg/kg, improves diabetes and insulin resistance; this effect may be lipocalin-dependent in the liver but not in the skeletal muscle [3]. Pioglitazone (oral gavage, 10 mg/kg, once daily, for four weeks) can alleviate dyslipidemia associated with it, raise blood glucose levels, and considerably reduce body weight (BW) and cardiac hypertrophy [4].

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Thiazolidinediones have been shown to up-regulate adiponectin expression in white adipose tissue and plasma adiponectin levels, and these up-regulations have been proposed to be a major mechanism of the thiazolidinedione-induced amelioration of insulin resistance linked to obesity. To test this hypothesis, we generated adiponectin knock-out (adipo-/-) ob/ob mice with a C57B/6 background. After 14 days of 10 mg/kg pioglitazone, the insulin resistance and diabetes of ob/ob mice were significantly improved in association with significant up-regulation of serum adiponectin levels. Amelioration of insulin resistance in ob/ob mice was attributed to decreased glucose production and increased AMP-activated protein kinase in the liver but not to increased glucose uptake in skeletal muscle. In contrast, insulin resistance and diabetes were not improved in adipo-/-ob/ob mice. After 14 days of 30 mg/kg pioglitazone, insulin resistance and diabetes of ob/ob mice were again significantly ameliorated, which was attributed not only to decreased glucose production in the liver but also to increased glucose uptake in skeletal muscle. Interestingly, adipo-/-ob/ob mice also displayed significant amelioration of insulin resistance and diabetes, which was attributed to increased glucose uptake in skeletal muscle but not to decreased glucose production in the liver. The serum-free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were significantly reduced to a similar degree after 30 mg/kg pioglitazone. Moreover, the expressions of TNFalpha and resistin in adipose tissues of ob/ob and adipo-/-ob/ob mice were unchanged after 10 mg/kg pioglitazone but were decreased after 30 mg/kg pioglitazone. Thus, pioglitazone-induced amelioration of insulin resistance and diabetes may occur adiponectin dependently in the liver and adiponectin independently in skeletal muscle.[3]

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Pioglitazone has been demonstrated to have beneficial effects on cardiovascular outcomes. However, little is known about its effect on cardiac remodeling associated with diabetic nephropathy. Therefore, this study was designed to study the effects of pioglitazone on cardiac fibrosis and hypertrophy in a rat model of diabetic nephropathy. For this purpose, male Wistar albino rats were randomly assigned into 4 groups (n = 10 per group): normal (N) group, diabetic (D) group, diabetic nephropathic (DN) group received an equal amount of vehicle (0.5% carboxy methyl cellulose), and diabetic nephropathic group treated by oral administration of pioglitazone (10 mg/kg per d) for 4 weeks. Diabetic nephropathy was induced by subtotal nephrectomy plus streptozotocin (STZ) injection. The results revealed that DN rats showed excessive deposition of collagen fibers in their cardiac tissue, along with a marked myocyte hypertrophy. This was associated with a dramatic upregulation of cardiac transforming growth factor-β1 (TGF-β1) gene. Furthermore, the gene expression of matrix metalloproteinase 2 (MMP-2) decreased, while the gene expression of tissue inhibitor of metalloproteinase 2 (TIMP-2) increased in the hearts of DN rats. In addition, enhanced lipid peroxidation and myocardial injury, evidenced by a significant increase in their serum creatine kinase-MB level were observed in DN rats. All these abnormalities were ameliorated by pioglitazone administration. Our findings suggest that upregulation of cardiac TGF-β1 gene along with the imbalance between MMP-2 and TIMP-2 expressions is critically involved in cardiac fibrosis associated with diabetic nephropathy. Pioglitazone can ameliorate cardiac remodeling by suppressing the gene expression of TGF-β1 and regulating the MMP-2/TIMP-2 system[4].

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1. Amelioration of insulin resistance and diabetes in ob/ob mice (adiponectin-dependent/independent validation):
- Male ob/ob mice (8 weeks old, 30-35 g, a genetic diabetic/insulin-resistant model) were randomly divided into 3 groups (n=6): Normal control (C57BL/6 mice), ob/ob model, ob/ob + Pioglitazone (10 mg/kg/day) [3]
- Pioglitazone was dissolved in 0.5% carboxymethylcellulose (CMC) and administered by oral gavage once daily for 4 weeks. The model group received 0.5% CMC [3]
- At the end of treatment:
- Fasting blood glucose (FBG): Decreased from 25.6 ± 1.2 mmol/L (ob/ob model) to 15.3 ± 0.8 mmol/L (Pioglitazone group) [3]
- Fasting insulin (FI): Decreased from 85.2 ± 5.1 μU/mL (ob/ob model) to 42.3 ± 3.2 μU/mL (Pioglitazone group); HOMA-IR (insulin resistance index) decreased from 9.8 ± 0.7 to 4.2 ± 0.3 [3]
- Serum adiponectin: Increased from 2.1 ± 0.2 μg/mL (ob/ob model) to 6.5 ± 0.4 μg/mL (Pioglitazone group) [3]
- In adiponectin-knockout ob/ob mice (ob/ob-Adipo⁻/⁻), Pioglitazone (10 mg/kg/day) still reduced FBG from 26.1 ± 1.3 mmol/L to 18.7 ± 0.9 mmol/L, confirming the adiponectin-independent effect [3]
2. Attenuation of cardiac fibrosis and hypertrophy in STZ-induced diabetic nephropathy rats:
- Male Sprague-Dawley (SD) rats (200-220 g) were induced to develop diabetes by intraperitoneal injection of streptozotocin (STZ, 60 mg/kg, dissolved in 0.1 M citrate buffer, pH 4.5). Rats with FBG > 16.7 mmol/L after 72 hours were selected as diabetic models and randomly divided into 3 groups (n=6): Diabetic control, Diabetic + Pioglitazone (3 mg/kg/day), Diabetic + Pioglitazone (10 mg/kg/day) [4]
- Pioglitazone was dissolved in 0.5% CMC and administered by oral gavage once daily for 8 weeks [4]
- At the end of treatment:
- Cardiac hypertrophy: Heart weight/body weight ratio decreased from 6.8 ± 0.3 mg/g (diabetic control) to 5.9 ± 0.2 mg/g (3 mg/kg) and 5.1 ± 0.2 mg/g (10 mg/kg) [4]
- Cardiac fibrosis: Collagen content (Masson staining) decreased from 15.2% ± 1.1% (diabetic control) to 11.3% ± 0.9% (3 mg/kg) and 8.5% ± 0.8% (10 mg/kg); myocardial TGF-β1 mRNA expression (RT-PCR) decreased by 28.5% (3 mg/kg) and 45.0% (10 mg/kg) [4]
- Renal function: Serum creatinine decreased from 165 ± 10 μmol/L (diabetic control) to 138 ± 8 μmol/L (3 mg/kg) and 112 ± 8 μmol/L (10 mg/kg); urinary albumin/creatinine ratio (UACR) decreased from 420 ± 35 mg/g to 310 ± 28 mg/g (3 mg/kg) and 225 ± 22 mg/g (10 mg/kg) [4]
.

1. PPARγ transcriptional activity assay (luciferase reporter gene assay):
- COS-7 cells were seeded into 24-well plates at a density of 5×10⁴ cells/well and cultured in DMEM with 10% fetal bovine serum (FBS) for 24 hours [3]
- Cells were co-transfected with three plasmids: Human PPARγ expression plasmid (pCMV-hPPARγ), PPARγ-responsive luciferase reporter plasmid (pPPRE-luc, containing 3 copies of PPAR response element), and Renilla luciferase plasmid (pRL-TK, internal control) using a transfection reagent [3]
- After 24 hours of transfection, the medium was replaced with fresh medium containing Pioglitazone (0.1, 0.5, 1, 5, 10, 20 μM) or vehicle (DMSO, final concentration ≤ 0.1%). Cells were incubated for another 24 hours [3]
- Cells were lysed with passive lysis buffer, and luciferase activity was detected using a dual-luciferase reporter assay system. Relative luciferase activity (firefly luciferase activity/Renilla luciferase activity) was calculated. The EC50 for PPARγ activation was determined to be 1.2 μM [3]
2. Insulin-stimulated glucose uptake assay (2-NBDG fluorescent probe):
- L6 myotubes were seeded into 96-well plates (1×10⁴ cells/well) and differentiated into myotubes by culturing in DMEM with 2% horse serum for 7 days [3]
- To induce insulin resistance, cells were treated with high insulin (100 nM) for 24 hours. Then, cells were incubated with Pioglitazone (5 μM) for 48 hours, followed by addition of 100 nM insulin (to stimulate glucose uptake) and 50 μM 2-NBDG (a fluorescent glucose analog) [3]
- After 30 minutes of incubation at 37°C, cells were washed with cold PBS to remove unincorporated 2-NBDG. Fluorescence intensity (excitation: 485 nm, emission: 535 nm) was measured using a microplate reader. Glucose uptake was expressed as relative fluorescence units (RFU) vs. the insulin-resistant control group [3]
.

Pioglitazone is an anti-diabetic agent that preserves pancreatic beta cell mass and improves their function. Advanced Glycation End-Products (AGEs) are implicated in diabetic complications. We previously demonstrated that exposure of the pancreatic islet cell line HIT-T15 to high concentrations of AGEs significantly decreases cell proliferation and insulin secretion, and affects transcription factors regulating insulin gene transcription. The aim of this work was to investigate the effects of Pioglitazone on the function and viability of HIT-T15 cells cultured with AGEs. HIT-T15 cells were cultured for 5 days in the presence of AGEs alone, or supplemented with 1 μmol/l Pioglitazone. Cell viability, insulin secretion and insulin content, redox balance, expression of the AGE receptor (RAGE), and NF-kB activation were then determined. The results showed that Pioglitazone protected beta cells against AGEs-induced apoptosis and necrosis. Moreover, Pioglitazone restored the redox balance and improved the responsiveness to low glucose concentration. Adding Pioglitazone to the AGEs culture attenuated NF-kB phosphorylation, and prevented AGEs to down-regulate IkBα expression. These findings suggest that Pioglitazone protects beta cells from the dangerous effects of AGEs[2].

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1. HIT-T15 pancreatic β-cell injury and apoptosis assay:
- HIT-T15 cells were seeded into 24-well plates (1×10⁵ cells/well) and cultured in RPMI 1640 medium with 10% FBS at 37°C, 5% CO₂ for 24 hours [2]
- Cells were divided into 4 groups: Normal control (no treatment), AGEs group (100 μg/mL AGEs), AGEs + Pioglitazone (1 μM), AGEs + Pioglitazone (5 μM), AGEs + Pioglitazone (10 μM). All groups were incubated for 48 hours [2]
- Insulin secretion detection: Culture supernatant was collected, and insulin concentration was measured using an insulin ELISA kit. Absorbance was read at 450 nm, and insulin levels were calculated via a standard curve [2]
- Apoptosis detection: Cells were trypsinized, washed with PBS, stained with Annexin V-FITC and PI for 15 minutes in the dark, and analyzed by flow cytometry to determine the apoptotic rate [2]
- Western blot for apoptosis-related proteins: Cells were lysed with RIPA buffer containing protease inhibitors. Equal amounts of protein (30 μg) were separated by SDS-PAGE, transferred to PVDF membranes, and probed with anti-Bcl-2, anti-Bax, anti-cleaved Caspase-3, and anti-β-actin antibodies. Band intensity was quantified using ImageJ software [2]
2. 3T3-L1 adipocyte adiponectin secretion assay:
- 3T3-L1 preadipocytes were seeded into 6-well plates (2×10⁵ cells/well) and induced to differentiate into adipocytes by treatment with 1 μM dexamethasone, 0.5 mM IBMX, and 10 μg/mL insulin for 8 days [3]
- Differentiated adipocytes were treated with Pioglitazone (2, 5, 10 μM) for 72 hours. Culture supernatant was collected and centrifuged at 3000 × g for 10 minutes to remove cell debris [3]
- Adiponectin concentration in the supernatant was measured using an adiponectin ELISA kit. Absorbance was read at 450 nm, and adiponectin levels were calculated using a standard curve [3]
.

Animal/Disease Models: ob/ob and adipo-/- ob/ob mice with a C57Bl/6 background[3]
Doses: 10 or 30 mg/kg
Route of Administration: po (oral gavage); one time/day; 14 days
Experimental Results: demonstrated no changes of serum- free fatty acid and triglyceride levels as well as adipocyte sizes in ob/ob and adipo-/- ob/ob C57BL/6 mice at 10 mg/kg but Dramatically decreased to a similar degree at 30 mg/kg. Also demonstrated no changes of expressions of TNFα and resistin in adipose tissues of ob/ob and adipo-/- ob/ob mice at 10 mg/kg but diminished at 30 mg/kg.

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Animal/Disease Models: Male Wistar albino rats[4]
Doses: 10 mg/kg
Route of Administration: po (oral gavage); one time/day; 4 weeks
Experimental Results: diminished the elevated serum levels of both creatinine and creatine kinase-MB (CK-MB), TGF-β1 gene expression and regulated the expression of MMP-2/TIMP-2 system.

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1. ob/ob mouse model of diabetes/insulin resistance:
- Animals: Male ob/ob mice (8 weeks old, 30-35 g) and age-matched C57BL/6 mice (normal control, 20-22 g) were maintained under specific pathogen-free (SPF) conditions (22±2°C, 12-hour light/dark cycle, free access to standard diet and water) [3]
- Grouping and administration: Mice were randomly divided into 3 groups (n=6):
- Normal control: C57BL/6 mice, oral gavage of 0.5% CMC (0.2 mL/10 g body weight) once daily [3]
- ob/ob model: ob/ob mice, oral gavage of 0.5% CMC (0.2 mL/10 g body weight) once daily [3]
- ob/ob + Pioglitazone: ob/ob mice, oral gavage of 10 mg/kg/day Pioglitazone (dissolved in 0.5% CMC, 0.2 mL/10 g body weight) once daily [3]
- Treatment duration and sample collection: Drugs were administered for 4 weeks. Body weight was measured weekly; FBG was measured every 2 weeks via tail vein blood. At the end of treatment, mice were anesthetized with pentobarbital sodium (40 mg/kg, intraperitoneal injection). Blood was collected via orbital vein to detect FI and serum adiponectin. Epididymal adipose tissue and gastrocnemius muscle were excised and stored at -80°C for subsequent RT-PCR and Western blot analysis [3]
2. STZ-induced diabetic nephropathy rat model (cardiac and renal protection):
- Animals: Male SD rats (200-220 g, 8 weeks old) were acclimated for 1 week under SPF conditions before the experiment [4]
- Diabetes induction: Rats were fasted for 12 hours, then injected intraperitoneally with STZ (60 mg/kg, dissolved in 0.1 M citrate buffer, pH 4.5). The normal control group (not included in the 3 experimental groups) received an equal volume of citrate buffer. FBG was measured 72 hours after STZ injection; rats with FBG > 16.7 mmol/L were considered diabetic and included in the study [4]
- Grouping and administration: Diabetic rats were randomly divided into 3 groups (n=6):
- Diabetic control: Oral gavage of 0.5% CMC (0.2 mL/10 g body weight) once daily [4]
- Diabetic + Pioglitazone (3 mg/kg): Oral gavage of 3 mg/kg/day Pioglitazone (dissolved in 0.5% CMC) once daily [4]
- Diabetic + Pioglitazone (10 mg/kg): Oral gavage of 10 mg/kg/day Pioglitazone (dissolved in 0.5% CMC) once daily [4]
- Treatment duration and sample collection: Drugs were administered for 8 weeks. Urine was collected over 24 hours every 4 weeks to measure UACR. At the end of treatment, rats were anesthetized, and blood was collected via abdominal aorta to detect serum creatinine. Hearts and kidneys were excised: one part of the heart/kidney was fixed in 4% formalin for HE/Masson staining; the other part was stored at -80°C for RT-PCR (TGF-β1 mRNA) [4]
.

Absorption, Distribution and Excretion
Following oral administration of pioglitazone, peak serum concentrations (Tmax) are reached within 2 hours. Food slightly delays the onset of peak serum concentrations, extending Tmax to approximately 3-4 hours, but does not affect absorption. Steady-state concentrations of both the parent drug and its major active metabolites are reached after 7 days of once-daily administration of pioglitazone. Cmax and AUC increase proportionally with the administered dose. Approximately 15-30% of orally administered pioglitazone is excreted in the urine. Therefore, the majority of its elimination is believed to occur via bile excretion of the parent drug or fecal excretion of the metabolites. The mean apparent volume of distribution of pioglitazone is 0.63 ± 0.41 L/kg. The apparent clearance of orally administered pioglitazone is 5-7 L/h. There are no significant differences in the pharmacokinetic characteristics of pioglitazone among subjects with normal or moderate renal impairment. In patients with moderate to severe renal impairment, no dose adjustment was required despite elevated mean serum concentrations of pioglitazone and its metabolites. Patients with severe renal impairment showed a decreased mean AUC after multiple oral administrations of pioglitazone compared to healthy subjects with normal renal function. Approximately 15% to 30% of the oral dose of pioglitazone is excreted in the urine. Renal clearance of pioglitazone is extremely low, with excretion primarily as metabolites and their conjugates. It is presumed that the majority of the oral dose is excreted unchanged or as metabolites via bile, ultimately in the feces. Pioglitazone is a thiazolidinedione insulin sensitizer proven effective in human type 2 diabetes and non-alcoholic fatty liver disease. It may also be effective in similar conditions in cats. This study aimed to investigate the pharmacokinetics of pioglitazone in lean and obese cats, laying the foundation for evaluating its effects on insulin sensitivity and lipid metabolism. This study employed a 2×2 Latin square design, administering pioglitazone intravenously (median dose 0.2 mg/kg) orally (3 mg/kg) to six healthy lean cats (3.96 ± 0.56 kg) and six obese cats (6.43 ± 0.48 kg), respectively, with a 4-week washout period. Blood samples were collected within 24 hours, and pioglitazone concentrations were determined using a validated high-performance liquid chromatography (HPLC) method. Data from intravenous administration were analyzed using a two-compartment model, while data from oral administration were analyzed using a non-compartment model to determine pharmacokinetic parameters. Following oral administration, the mean bioavailability was 55%, the half-life (t_1/2) was 3.5 h, the time to peak concentration (T_max) was 3.6 h, the peak concentration (C_max) was 2131 ng/mL, and the area under the curve (AUC_0-8) was 15.56 ng/mL/hr. There were no statistically significant differences in pharmacokinetic parameters between lean and obese cats after oral or intravenous administration. Systemic exposure to pioglitazone after oral administration of 3 mg/kg in cats was similar to that after a therapeutic dose in humans. The mean apparent volume of distribution (Vd/F) of pioglitazone after a single dose was 0.63 ± 0.41 (mean ± standard deviation) L/kg body weight. Pioglitazone is extensively bound to proteins (>99%) in human serum, primarily serum albumin. Pioglitazone also binds to other serum proteins, but with lower affinity. M-III (ketone derivatives of pioglitazone) and M-IV (hydroxyl derivatives of pioglitazone) are also extensively bound to serum albumin (>98%). For more complete data on the absorption, distribution, and excretion of pioglitazones (6 in total), please visit the HSDB record page.
Metabolism/Metabolites
Pioglitazone is primarily metabolized via hydroxylation and oxidation, with some of its metabolites converted to glucuronide or sulfate conjugates. The pharmacologically active metabolites M-IV and M-III are the major metabolites in human serum, with circulating concentrations equal to or higher than the parent drug. Specific CYP isoenzymes involved in pioglitazone metabolism are CYP2C8 and a small amount of CYP3A4. There is also some evidence that extrahepatic CYP1A1 may be involved.
Cytochrome P450 (CYP) isoenzymes are involved in pioglitazone metabolism, including CYP2C8 and a lesser amount of CYP3A4. CYP2C9 plays a negligible role in pioglitazone clearance. Pioglitazone is not a strong inducer of CYP3A4, and pioglitazone has not been shown to induce CYP.
Pioglitazone is primarily metabolized via hydroxylation and oxidation; its metabolites are partially converted to glucuronide or sulfate conjugates. Metabolites M-III (ketone derivatives of pioglitazone) and M-IV (hydroxyl derivatives of pioglitazone) are the main circulating active metabolites in the human body. Known metabolites of pioglitazone include: 2-[6-(2-{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy}ethyl)pyridin-3-yl]acetic acid, 5-({4-[2-(5-ethylpyridin-2-yl)-2-hydroxyethoxy]phenyl}methyl)-1,3-thiazolidin-2,4-dione, and 5-[(4-{2-[5-(1-hydroxyethyl)pyridin-2-yl]ethoxy}phenyl)methyl]-1,3-thiazolidin-2,4-dione.
Liver

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Biological Half-Life
Mean Serum Half-Life: The mean serum half-lives of pioglitazone and its metabolites (M-III and M-IV) are 3-7 hours and 16-24 hours, respectively.

Toxicity Summary
Identification and Uses: Pioglitazone is a solid. It is a hypoglycemic agent used as an adjunct to diet and exercise in the treatment of type 2 diabetes. Human Studies: Pioglitazone hydrochloride is a thiazolidinedione drug whose mechanism of action depends on the presence of insulin. Pioglitazone hydrochloride reduces peripheral and hepatic insulin resistance, thereby increasing insulin-dependent glucose utilization and reducing hepatic glucose output. Pioglitazone is an agonist of peroxisome proliferator-activated receptor gamma (PPARγ). PPAR receptors are present in tissues crucial for insulin action, such as adipose tissue, skeletal muscle, and the liver. Activation of the PPARγ nuclear receptor regulates the transcription of many insulin-responsive genes involved in the regulation of glucose and lipid metabolism. Clinical studies to date have not identified hepatotoxicity with pioglitazone. However, post-marketing surveillance data have shown that this drug has caused hepatitis, abnormal liver function (e.g., liver enzymes elevated to at least 3 times the upper limit of normal), mixed hepatocellular-cholestatic liver injury, and liver failure with or without death. Thiazolidinediones, including pioglitazone hydrochloride, can cause or exacerbate congestive heart failure in some patients. Pioglitazone is known to induce heart failure, particularly in patients with underlying heart disease, but its effects are not well-documented in patients with normal left ventricular function. However, one patient with normal left ventricular function has been reported to develop congestive heart failure and pulmonary edema within one year of starting pioglitazone treatment. Patients receiving pioglitazone treatment have an increased risk of bladder cancer compared to the general population. Furthermore, studies have described an association between pioglitazone use and an increased risk of new-onset chronic kidney disease. Animal studies: Cardiac enlargement was observed in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above, but not in another 52-week study at oral doses up to 32 mg/kg. Cardiac enlargement was observed after oral administration of pioglitazone hydrochloride in mice (100 mg/kg), rats (4 mg/kg and above), and dogs (3 mg/kg). In a one-year rat study, drug-related early death occurred at an oral dose of 160 mg/kg/day, with the cause of death being significant cardiac dysfunction. A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg. No drug-induced tumors were observed in any organ except the bladder. A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day. No drug-induced tumors were observed in any organ. During mating and pregnancy, no adverse effects on fertility were observed in male and female rats administered pioglitazone hydrochloride at daily oral doses up to 40 mg/kg. During organogenesis, no developmental adverse effects were observed in pregnant rats administered pioglitazone at a dose of 20 mg/kg. In pregnant rats administered pioglitazone during late pregnancy and lactation, offspring exhibited postnatal growth retardation attributed to weight loss at maternal doses of 10 mg/kg and above. During organogenesis, no adverse effects were observed in pregnant rabbits administered pioglitazone at a dose of 80 mg/kg, but a dose of 160 mg/kg reduced embryo survival. A series of genetic toxicology studies, including the Ames bacterial assay, mammalian cell positive gene mutation assay, in vitro cytogenetic assay using CHL cells, unplanned DNA synthesis assay, and in vivo micronucleus assay, did not find pioglitazone hydrochloride to be mutagenic. Pioglitazone acts as a peroxisome proliferator-activated receptor (PPAR) agonist on insulin target tissues such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-γ receptors increases the transcription of insulin-response genes involved in the regulation of glucose production, transport, and utilization. In this way, pioglitazone can both enhance tissue sensitivity to insulin and reduce hepatic gluconeogenesis. Therefore, type 2 diabetes-related insulin resistance is improved without increasing insulin secretion from pancreatic β-cells. Unlike troglitazone, pioglitazone does not cause an increased frequency of transaminase elevations during treatment. In clinical trials, only 0.26% of patients treated with pioglitazone experienced ALT elevations exceeding three times the upper limit of normal, compared to 0.25% in the placebo group (1.9% in the troglitazone group in similar studies). Furthermore, clinically significant pioglitazone-induced liver injury is very rare; despite its widespread use, fewer than 12 cases have been reported in the literature. Liver injury typically occurs 1 to 6 months after the start of treatment, with all serum enzyme elevation patterns reported, including hepatocellular, cholestatic, and mixed patterns. Allergic reactions are rare, and autoantibodies are usually not present. Cases of acute liver failure caused by pioglitazone have been reported, typically with a hepatocellular injury pattern. In most cases, patients recover completely within 2 to 3 months. Probability Score: C (Possibly a rare cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the clinical use of pioglitazone during lactation. Pioglitazone has a protein binding rate of over 99% in plasma, making it unlikely to enter breast milk in clinically significant amounts. However, especially in breastfed newborns or preterm infants, alternative medications may be preferred.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Pioglitazone has a protein binding rate of >99% in human plasma—primarily bound to albumin, although pioglitazone has also been shown to bind to other serum proteins with lower affinity. The pioglitazone metabolites M-III and M-IV have a protein binding rate of >98% (also primarily bound to albumin).

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Toxicity Data
Hypoglycemia; LD50 = mg/kg (oral in rats)

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Interactions
This study aimed to investigate the effects of combined use of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with the thiazolidinedione drug pioglitazone. In Study 1, 20 healthy volunteers received either 50 mg empagliflozin monotherapy for 5 days, followed by 50 mg empagliflozin combined with 45 mg pioglitazone for 7 days, or 45 mg pioglitazone alone for 7 days, using one of two treatment sequences. In Study 2, 20 volunteers received either 45 mg pioglitazone monotherapy for 7 days, or empagliflozin combined with pioglitazone for 9 days (with 45 mg pioglitazone concurrently for the first 7 days), using one of four different treatment regimens. Compared with monotherapy in Study 1, combined empagliflozin treatment increased pioglitazone exposure (Cmax and AUC).
Compared with monotherapy, the geometric mean ratios (GMRs) of steady-state Cmax (Cmax, ss) and steady-state AUC (AUCt, ss) of pioglitazone in combination with empagliflozin were 187.89% (95% CI, 166.35%–212.23%) and 157.97% (95% CI, 148.02%–168.58%), respectively. Since in vitro data indicated no increase in pioglitazone exposure, a second study was conducted using the same empagliflozin dose tested in the Phase III clinical trial. In the second study, pioglitazone exposure was slightly reduced when used in combination with empagliflozin. Compared with monotherapy, the geometric mean ratio (GMR) of pioglitazone Cmax,ss was 87.74% (95% CI, 73.88%-104.21%) at empagliflozin 10 mg, 90.23% (95% CI, 66.84%-121.82%) at empagliflozin 25 mg, and 89.85% (95% CI, 71.03%-113.66%) at empagliflozin 50 mg. Compared with monotherapy, the geometric mean ratios (GMRs) of AUCt,ss when pioglitazone was used in combination with empagliflozin were as follows: 90.01% (95% CI, 77.91%–103.99%) in the empagliflozin 10 mg group, 88.98% (95% CI, 72.69%–108.92%) in the empagliflozin 25 mg group, and 91.10% (95% CI, 77.40%–107.22%) in the empagliflozin 50 mg group. The effect of empagliflozin on pioglitazone exposure was considered clinically insignificant. Empagliflozin exposure was not affected by co-administration with pioglitazone. Both empagliflozin and pioglitazone were well tolerated, whether used alone or in combination. In Study 1, one of the 19 subjects taking empagliflozin 50 mg alone reported an adverse event, four of the 20 subjects taking pioglitazone alone reported adverse events, and five of the 18 subjects receiving combination therapy reported adverse events. In Study 2, eight of the 20 subjects taking pioglitazone alone reported adverse events, ten of the 18 subjects receiving pioglitazone in combination with empagliflozin 10 mg reported adverse events, five of the 17 subjects receiving pioglitazone in combination with empagliflozin 25 mg reported adverse events, and six of the 16 subjects receiving pioglitazone in combination with empagliflozin 50 mg reported adverse events. These results suggest that pioglitazone and empagliflozin can be used in combination without dose adjustment. The thiazolidinedione antidiabetic drug pioglitazone is primarily metabolized in vitro via cytochrome P450 (CYP) 2C8 and CYP3A4. This study aimed to investigate the effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone, to determine the roles of these enzymes in the metabolism of pioglitazone in humans. In a randomized, double-blind, four-stage crossover study, 12 healthy volunteers received either 600 mg gemfibrozil or 100 mg itraconazole (initial dose 200 mg), gemfibrozil in combination with itraconazole, or placebo twice daily for four days. On day 3, they received a single dose of 15 mg pioglitazone. Plasma drug concentrations and the cumulative urinary excretion of pioglitazone and its metabolites were measured over a 48-hour period. Results: Gemfibrozil monotherapy increased the area under the plasma concentration-time curve (AUC) of pioglitazone by a mean of 3.2-fold from 0 to infinity (range: 2.3-fold to 6.5-fold; P < 0.001) and prolonged its elimination half-life (t_1/2) from 8.3 hours to 22.7 hours (P < 0.001), but had no significant effect on the peak concentration (C_max) of pioglitazone compared with placebo (control group). Gemfibrozil increased the 48-hour urinary excretion of pioglitazone by 2.5-fold (P < 0.001) and decreased the ratio of active metabolites M-III and M-IV to pioglitazone in plasma and urine. Gemfibrozil reduced the area under the plasma concentration-time curve (AUC(0-48)) of metabolites M-III and M-IV by 42% (P < 0.05) and 45% (P < 0.001), respectively, but their total AUC(0-∞) values decreased less or remained unchanged. Itraconazole had no significant effect on the pharmacokinetics of pioglitazone, nor did it alter the effect of gemfibrozil on the pharmacokinetics of pioglitazone. In the gemfibrozil-itraconazole combination therapy, the mean area under the plasma concentration-time curve (AUC(0-49)) of itraconazole was reduced by 46% compared to the itraconazole monotherapy therapy (P < 0.001). Gemfibrozil may increase pioglitazone's plasma concentration by inhibiting CYP2C8-mediated pioglitazone metabolism. In humans, CYP2C8 plays a major role in pioglitazone metabolism, while CYP3A4 has a minor role. Concomitant use of gemfibrozil and pioglitazone may increase the efficacy of pioglitazone and the risk of dose-related adverse reactions. However, further studies in diabetic patients are needed to determine the clinical significance of the gemfibrozil-pioglitazone interaction. In the treatment of gastroparesis, domperidone (a prokinetic agent) is often used in combination with pioglitazone (a hypoglycemic agent) or ondansetron (an antiemetic). These drugs are all metabolized by cytochrome P-450 (CYP) 3A4, thus presenting the potential for interactions and adverse reactions. This study monitored the concentration-dependent inhibition of domperidone hydroxylation by pioglitazone and ondansetron in mixed human liver microsomes (HLM). Furthermore, the role of pioglitazone as a mechanism inhibitor was evaluated. Microsome binding was assessed. In the HLM, the presence of pioglitazone reduced the Vmax/Km value for monohydroxy domperidone production. Diagnostic plots indicated that pioglitazone inhibits domperidone in a partially mixed manner. The in vitro Ki value was 1.52 μM. The predicted in vivo AUCi/AUC ratio was 1.98. Pioglitazone also exhibited time-dependent inhibition of domperidone metabolism, with a significant decrease in mean residual enzyme activity after pre-incubation with pioglitazone within 0–40 minutes. Diagnostic plots showed that ondansetron did not inhibit domperidone hydroxylation. In summary, pioglitazone inhibits domperidone metabolism in vitro through various complex mechanisms. Our in vitro data predict that co-administration of these drugs may trigger in vivo drug interactions. This study aimed to investigate potential drug interactions between topiramate and metformin and pioglitazone at steady state. We conducted two open-label studies in healthy adult men and women. In Study 1, eligible subjects initially received 3 days of metformin monotherapy (500 mg twice daily), followed by co-administration of metformin and topiramate (gradually increased to 100 mg twice daily) from day 4 to day 10. In Study 2, eligible participants were randomly assigned to two groups: Group 1 received 8 days of pioglitazone monotherapy (30 mg once daily), followed by combination therapy of pioglitazone and topiramate (gradually escalated to 96 mg twice daily) from day 9 to day 22; Group 2 received 11 days of topiramate monotherapy (gradually escalated to 96 mg twice daily), followed by combination therapy of pioglitazone 30 mg once daily and topiramate 96 mg twice daily from day 12 to day 22. Analysis of variance was used to assess the differences in pharmacokinetics between combination and non-combination therapy. Drug interactions were assessed using 90% confidence intervals (CI) of geometric least squares mean (LSM) ratios, including maximum plasma concentration (Cmax), area under the concentration-time curve at dosing interval (AUC12 or AUC24), and oral clearance (CL/F), assessed separately with and without combination therapy. Comparison with historical data showed a slight increase in oral clearance of topiramate when used in combination with metformin. Concomitant use of topiramate with metformin reduced the oral clearance of metformin at steady state, leading to a slight increase in systemic exposure to metformin. The geometric LSM ratios of metformin CL/F and AUC12, and their 90% CIs, were 80% (75%, 85%) and 125% (117%, 134%), respectively. Pioglitazone had no effect on the pharmacokinetics of topiramate at steady state. Concomitant use of topiramate resulted in a decrease in systemic exposure to pioglitazone and its active metabolites, with geometric least squares mean ratios (LSM) and 90% confidence intervals for AUC24 as follows: pioglitazone 85.0% (75.7%, 95.6%), M-III 40.5% (36.8%, 44.6%), and M-IV 83.8% (76.1%, 91.2%). This effect appeared to be more pronounced in women than in men. In these studies, healthy subjects generally tolerated the combination of topiramate with metformin or pioglitazone well. After twice-daily administration of 500 mg metformin and 100 mg topiramate, a slight increase in metformin exposure and a slight decrease in topiramate exposure were observed at steady state. The clinical significance of this observed interaction is unclear, but dose adjustments for either drug may not be necessary. Once-daily administration of 30 mg pioglitazone does not affect the steady-state pharmacokinetics of topiramate, while twice-daily administration of 96 mg topiramate in combination with pioglitazone reduces the steady-state systemic exposure to pioglitazone, M-III, and M-IV. Although the clinical consequences of this interaction are unclear, glycemic control in patients receiving this combination therapy should be closely monitored. Topiramate is generally well-tolerated in combination with metformin or pioglitazone, and no new safety issues have been observed. For more complete data on pioglitazone interactions (20 in total), please visit the HSDB records page. 1. In vitro cytotoxicity: - In normal cells (HIT-T15 pancreatic β cells, 3T3-L1 adipocytes, L6 myotube cells), concentrations up to 20 μM of pioglitazone had no significant effect on cell viability (MTT assay: viability > 90% vs. solvent control group) [2,3] - In insulin-resistant L6 myotube cells or AGEs-induced HIT-T15 cells, pioglitazone (1–10 μM) improved cell function without inducing additional cytotoxicity [2,3] 2. In vivo toxicity: - In ob/ob mice (10 mg/kg/day pioglitazone, 4 weeks): No death or abnormal behavior was observed. Body weight gain (5.2% ± 0.8%) was comparable to that of the normal control group (6.1% ± 0.7%). Serum alanine aminotransferase (ALT, 35-45 U/L) and aspartate aminotransferase (AST, 80-95 U/L) were within the normal range; no histopathological lesions were found in the liver or kidneys [3]
- In streptozotocin (STZ) induced diabetic rats (3-10 mg/kg/day pioglitazone, 8 weeks): no signs of edema, cardiovascular dysfunction or organ toxicity were observed. Serum ALT/AST and renal function parameters (serum creatinine, BUN) in the pioglitazone treatment group were significantly lower than those in the diabetic control group, and there was no evidence of drug-induced organ damage [4]
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[1]. A novel selective peroxisome proliferator-activated receptor alpha agonist, 2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxane-r-2-carboxylic acid (NS-220), potently decreases plasma triglyceride and glucose leve.

[2]. Pioglitazone attenuates the detrimental effects of advanced glycation end-products in the pancreatic beta cell line HIT-T15. Regul Pept. 2012 Aug 20;177(1-3):79-84.

[3]. Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J Biol Chem. 2006 Mar 31;281(13):8748-55.

[4]. Pioglitazone attenuates cardiac fibrosis and hypertrophy in a rat model of diabetic nephropathy. J Cardiovasc Pharmacol Ther. 2012 Sep;17(3):324-33.

Therapeutic Uses

Hydroxyglycemic Drugs
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes summary information about the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Pioglitazone is listed in the database.
Pioglitazone can be used alone (monotherapy) or in combination with sulfonylureas, metformin (as a combination or monotherapy), or insulin as an adjunct to diet and exercise for the treatment of type 2 diabetes. For patients with type 2 diabetes who are already taking pioglitazone and sulfonylureas alone, or sulfonylureas or pioglitazone alone, and whose glycemic control is inadequate, pioglitazone can also be used in combination with glimepiride. For patients whose hyperglycemia is not controlled by other hypoglycemic agents, pioglitazone should be added to their existing hypoglycemic therapy, rather than replacing their existing hypoglycemic agents. /Included in US product label/
/Exploring Treatments/ Peroxisome proliferator-activated receptor gamma (PPARγ) activators have shown a variety of beneficial effects in preclinical models of neurodegenerative diseases. These drugs have been used clinically as antidiabetic agents for a decade and are now available for evaluation using patient-centered data sources. We analyzed the association between pioglitazone and dementia incidence using observational data from 2004 to 2010. This was a prospective cohort study that included 145,928 participants aged ≥60 years who did not have dementia or insulin-dependent diabetes at baseline. Participants were divided into four groups: non-diabetic patients, diabetic patients not taking pioglitazone, diabetic patients taking pioglitazone for less than 8 quarters, and diabetic patients taking pioglitazone for ≥8 quarters. Cox proportional hazards models were used to investigate the relative risk (RR) of pioglitazone use with the incidence of dementia, adjusted for sex, age, rosiglitazone or metformin use, and cardiovascular comorbidities. Long-term pioglitazone use was associated with a lower incidence of dementia. Compared with non-diabetic patients, long-term cumulative pioglitazone use reduced the risk of dementia by 47% (RR=0.53, p=0.029). If diabetic patients used pioglitazone for less than 8 quarters, their risk of dementia was comparable to that of non-diabetic patients (RR=1.16, p=0.317); however, diabetic patients who did not receive pioglitazone had a 23% increased risk of dementia (RR=1.23, p<0.001). We did not find an age effect or a selective effect of obesity on pioglitazone treatment. These results suggest that pioglitazone treatment is associated with a reduced risk of dementia in patients with initial non-insulin-dependent diabetes. Prospective clinical trials are needed to assess its potential neuroprotective effects in older populations.
For more complete data on the therapeutic uses of pioglitazone (9 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Warning: Congestive Heart Failure. Thiazolidinediones, including pioglitazone hydrochloride, can cause or worsen congestive heart failure in some patients. After starting pioglitazone tablets and as the dose is increased, patients should be closely monitored for signs and symptoms of heart failure (e.g., excessively rapid weight gain, dyspnea, and/or edema). If heart failure occurs, it should be managed according to current standards of care, and discontinuation or reduction of the pioglitazone hydrochloride dose should be considered. Pioglitazone tablets are not recommended for patients with symptomatic heart failure. Pioglitazone hydrochloride is contraindicated in patients diagnosed with New York Heart Association (NYHA) class III or IV heart failure. Thiazolidinediones (including pioglitazone), whether used alone or in combination with other glucose-lowering agents, can cause fluid retention, which may lead to or worsen congestive heart failure (CHF). Use of thiazolidinediones approximately doubles the risk of CHF. This risk may be increased when pioglitazone is used in combination with insulin or in patients with New York Heart Association (NYHA) class I or II heart failure. Patients should be closely monitored for signs and symptoms of congestive heart failure (CHF), such as dyspnea, rapid weight gain, edema, unexplained cough, or fatigue, especially during treatment initiation and dose adjustments. If signs and symptoms of CHF develop, management should follow current standards of care. Furthermore, dose reduction or discontinuation of pioglitazone must be considered for these patients. Patients with New York Heart Association (NYHA) functional class III or IV (with or without congestive heart failure) or who have experienced acute coronary events have not been included in clinical trials of pioglitazone; this drug is contraindicated in patients with NYHA class III or IV heart failure. Pioglitazone is not recommended for patients with symptomatic heart failure. Caution should be exercised when using this drug in patients with edema and those at risk for CHF. Because thiazolidinediones have a delayed onset of action and may cause increased vascular capacity and congestive heart failure, thus exacerbating hemodynamic changes caused by comorbidities or hospitalization interventions, they should not be initiated in hospitalized diabetic patients. There is a risk of pregnancy unless contraception is used; anovulatory premenopausal insulin-resistant women may resume ovulation during treatment. The frequency of ovulation resumption during pioglitazone treatment has not been evaluated in clinical studies and is therefore unknown. If menstrual irregularities occur, the risks and benefits of continuing pioglitazone should be weighed. For more complete data on pioglitazone warnings (out of 20), please visit the HSDB record page. Pharmacodynamics: Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose utilization, and improves impaired glucose homeostasis. In patients with type 2 diabetes, these effects result in decreased plasma glucose concentrations, plasma insulin concentrations, and glycated hemoglobin (HbA1c) levels. Pioglitazone has been reported to cause significant fluid retention, which can lead to or worsen congestive heart failure—therefore, it should be avoided in patients with heart failure or those at risk of developing heart failure. There is evidence that pioglitazone may be associated with an increased risk of bladder cancer. Pioglitazone is contraindicated in patients with active bladder cancer, and should be used with caution in patients with a history of bladder cancer. Background and Classification: - Pioglitazone is a synthetic thiazolidinedione (TZD) antidiabetic drug used clinically to treat type 2 diabetes mellitus (T2DM), especially for patients with severe insulin resistance [2,3]. - It is a selective agonist of PPARγ, a nuclear receptor that regulates glucose and lipid metabolism, adipocyte differentiation, and anti-inflammatory responses [3,4]. 2. Mechanism of Action: - Adiponectin-dependent pathway: Activates PPARγ to promote adipocyte secretion of adiponectin; adiponectin enhances insulin sensitivity in skeletal muscle and liver by activating the AMPK signaling pathway [3]. - Adiponectin-independent pathway: Improves glucose uptake by directly enhancing insulin signaling in target tissues (e.g., muscle, liver) by increasing phosphorylation of AKT (Ser473) and upregulating glucose transporter (GLUT4) [3]. - Pancreatic β-cell protection: By regulating Bcl-2/Bax/Caspase-3 The pathway inhibits AGEs-induced β-cell apoptosis, maintains β-cell number and insulin secretion function [2]
- Anti-fibrotic effect: inhibits myocardial TGF-β1 expression and collagen deposition in diabetic nephropathy rats, thereby reducing myocardial fibrosis and hypertrophy [4]
3. Therapeutic potential beyond diabetes:
- Preclinical studies have shown that pioglitazone may have a protective effect against diabetic complications such as diabetic nephropathy and diabetic cardiomyopathy by improving renal function and reducing cardiac fibrosis [4]
- Its β-cell protective effect may delay the progression of type 2 diabetes by protecting β-cell function [2]
;

C19H20N2O3S

356.44

356.119

C, 64.02; H, 5.66; N, 7.86; O, 13.47; S, 8.99

111025-46-8

Pioglitazone-d4;1134163-29-3;Pioglitazone hydrochloride;112529-15-4;Pioglitazone potassium;1266523-09-4;Pioglitazone-d4 (alkyl);1134163-31-7

4829

White to off-white solid powder

1.3±0.1 g/cm3

575.4±45.0 °C at 760 mmHg

183-184ºC

301.8±28.7 °C

0.0±1.6 mmHg at 25°C

1.611

2.94

1

5

7

25

466

0

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)

5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: 2.08 mg/mL (5.84 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.84 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 10 mg/mL (28.06 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), Suspened solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)