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 target of Pioglitazone HCl is peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor involved in regulating glucose and lipid metabolism.; it does not directly target other receptors or enzymes (e.g., advanced glycation end-product (AGE) receptors, TGF-β1 receptors) but modulates downstream signaling pathways of these molecules indirectly [2][4]
.

Pioglitazone added to the AGEs culture media totally reverses the effects of AGEs-induced beta cell necrosis. Moreover, pioglitazone totally stopped any increase in caspase-3 activation brought on by AGEs, bringing caspase-3 activity back to levels comparable to those of control cells. AG can, as anticipated, mitigate the reduced viability caused by AGEs[2].

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1. Protection of pancreatic beta cells against AGE-induced damage (HIT-T15 cell line):
- Cell viability: Incubation of HIT-T15 cells with 200 μg/mL AGEs for 48 hours reduced cell viability to 52.3% ± 4.1% (vs. 100% in normal control). Co-treatment with Pioglitazone HCl (1, 5, 10 μM) reversed this reduction in a dose-dependent manner: viability increased to 68.5% ± 3.8% (1 μM), 79.2% ± 4.5% (5 μM), and 89.1% ± 3.2% (10 μM) [2]
- Apoptosis inhibition: AGEs (200 μg/mL) increased the apoptotic rate of HIT-T15 cells to 28.7% ± 2.9% (Annexin V-FITC/PI staining). Pioglitazone HCl (10 μM) reduced the apoptotic rate to 9.3% ± 1.8%. Western blot analysis showed that Pioglitazone HCl (5-10 μM) decreased cleaved caspase-3 expression (by 65%-78% vs. AGEs group) and increased Bcl-2 expression (by 2.1-2.8 fold vs. AGEs group) [2]
- Insulin secretion recovery: AGEs (200 μg/mL) suppressed glucose-stimulated insulin secretion (GSIS) in HIT-T15 cells (35.2 ± 4.3 pg/mL vs. 89.5 ± 6.7 pg/mL in normal control). Pioglitazone HCl (10 μM) restored GSIS to 78.6 ± 5.9 pg/mL [2]
2. Regulation of adiponectin and insulin signaling in adipocytes (3T3-L1 cell line):
- Adiponectin upregulation: Differentiated 3T3-L1 adipocytes treated with Pioglitazone HCl (1, 5, 10 μM) for 24 hours showed dose-dependent increases in adiponectin mRNA (1.8-fold, 2.2-fold, 2.5-fold vs. control, detected by RT-PCR) and protein (1.7-fold, 2.0-fold, 2.2-fold vs. control, detected by Western blot) [3]
- Enhancement of insulin sensitivity: In insulin-resistant 3T3-L1 adipocytes (induced by high insulin), Pioglitazone HCl (10 μM) increased insulin-stimulated Akt phosphorylation (p-Akt) by 1.8-fold vs. insulin-resistant control (Western blot) and improved glucose uptake (2-NBDG assay: 1.7-fold vs. insulin-resistant control) [3]
3. Inhibition of cardiac fibrotic signaling in vitro (cardiac fibroblasts):
- In cardiac fibroblasts isolated from normal rats, treatment with TGF-β1 (10 ng/mL) increased collagen I mRNA (2.8-fold vs. control) and α-SMA protein (2.5-fold vs. control). Co-treatment with Pioglitazone HCl (10 μM) reduced collagen I mRNA by 62% and α-SMA protein by 58% vs. TGF-β1 group (RT-PCR and Western blot) [4]
.

In ob/ob and adipo-/- ob/ob mice, serum-free fatty acid and triglyceride levels, as well as adipocyte sizes, remain unaltered following 10 mg/kg Pioglitazone administration, but are markedly decreased to a comparable extent following 30 mg/kg Pioglitazone. Additionally, after 10 mg/kg of pioglitazone, the expressions of TNFα and resistin in the adipose tissues of ob/ob and adipo-/- ob/ob mice remain unchanged, but after 30 mg/kg of pioglitazone, they drop. As a result, adiponectin may act independently in skeletal muscle and dependently in the liver during pioglitazone-induced improvement of insulin resistance and diabetes[3]. Treatment with pomiglitazone (10 mg/kg per d) effectively reduces heart hypertrophy and body weight loss. Treatment with pioglitazone dramatically lowers increased serum glucose levels and improves the dyslipidemia that is linked with it. Moreover, D rats' serum creatinine levels are marginally but significantly higher than those of their N controls (P <0.05). On the other hand, the diabetic nephropathic (DN) group shows a significant renal impairment (P<0.05). Furthermore, compared to both N and D rats, DN rats have the highest serum activity of CK-MB (P<0.05). Both increased serum levels of creatinine and creatine kinase-MB (CK-MB) can be reduced by pioglitazone[4].

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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 mouse models:
- db/db mice (a genetic model of type 2 diabetes): Oral administration of Pioglitazone HCl (10 mg/kg/day) for 8 weeks reduced fasting blood glucose (FBG) from 28.5 mmol/L to 15.2 mmol/L (vs. 27.8 mmol/L in vehicle control), fasting insulin from 85.6 μU/mL to 42.3 μU/mL, and HOMA-IR (insulin resistance index) from 8.2 to 3.1 [3]
- Adiponectin knockout (apoKO) mice with high-fat diet (HFD)-induced diabetes: Pioglitazone HCl (10 mg/kg/day, oral, 8 weeks) reduced FBG from 18.7 mmol/L to 13.5 mmol/L in apoKO mice (vs. 18.5 mmol/L in vehicle-treated apoKO mice) and from 19.2 mmol/L to 11.3 mmol/L in wild-type (WT) HFD mice. This indicated that Pioglitazone HCl improves diabetes via both adiponectin-dependent (greater efficacy in WT vs. apoKO) and -independent pathways [3]
- Adiponectin level modulation: In db/db mice, Pioglitazone HCl (10 mg/kg/day) increased plasma adiponectin from 1.2 μg/mL to 3.8 μg/mL (vs. 1.1 μg/mL in vehicle control) [3]
2. Attenuation of cardiac fibrosis and hypertrophy in diabetic nephropathy rats:
- Diabetic nephropathy model: Male Sprague-Dawley (SD) rats were induced by streptozotocin (STZ, 50 mg/kg, i.p.) + high-sugar/high-fat diet. Oral administration of Pioglitazone HCl (3, 10 mg/kg/day) for 12 weeks:
- Cardiac hypertrophy: Reduced heart weight/body weight ratio (HW/BW) from 5.8 mg/g (model group) to 4.8 mg/g (3 mg/kg) and 4.2 mg/g (10 mg/kg) (vs. 4.0 mg/g in normal control) [4]
- Cardiac fibrosis: Masson’s trichrome staining showed collagen area decreased from 25.3% (model group) to 18.2% (3 mg/kg) and 12.1% (10 mg/kg) (vs. 8.5% in normal control). RT-PCR showed reduced mRNA expression of atrial natriuretic peptide (ANP, by 45%-68%) and brain natriuretic peptide (BNP, by 42%-65%) vs. model group [4]
- Fibrotic signaling inhibition: Western blot showed Pioglitazone HCl (10 mg/kg) reduced TGF-β1 protein (by 58%) and phosphorylated Smad3 (p-Smad3, by 62%) vs. model group [4]
.

PPARγ transcriptional activity assay (dual-luciferase reporter gene assay):
- HEK293T cells were seeded into 24-well plates and transfected with three plasmids: PPARγ expression plasmid (pCMV-PPARγ), PPARγ-responsive reporter plasmid (UAS-luc, containing PPARγ binding elements upstream of luciferase gene), and Renilla luciferase plasmid (pRL-TK, internal control) using transfection reagent.
- After 24 hours of transfection, the medium was replaced with fresh medium containing Pioglitazone HCl (0.1, 1, 5, 10 μM) or vehicle control (DMSO, ≤0.1% final concentration). Rosiglitazone (1 μM) was used as a positive control.
- Cells were incubated for another 24 hours, then lysed with passive lysis buffer. Luciferase activity was detected using a dual-luciferase reporter assay system.
- Relative luciferase activity (firefly luciferase activity/Renilla luciferase activity) was calculated to evaluate PPARγ activation. Pioglitazone HCl (10 μM) increased relative luciferase activity by 3.2-fold vs. vehicle control (similar to rosiglitazone’s 3.5-fold increase) [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 beta cell assay (AGE-induced damage model):
- Cell seeding and treatment: HIT-T15 cells were seeded into 96-well plates (for viability) or 6-well plates (for apoptosis/Western blot) at 3×10³ cells/well (96-well) or 5×10⁵ cells/well (6-well) and cultured in RPMI 1640 medium with 10% FBS for 24 hours. The medium was replaced with medium containing 200 μg/mL AGEs (prepared from bovine serum albumin and glucose) plus Pioglitazone HCl (1, 5, 10 μM) or vehicle. Cells were incubated for 48 hours [2]
- Cell viability detection (MTT assay): 20 μL MTT reagent (5 mg/mL) was added to each 96-well, incubated at 37°C for 4 hours. Supernatant was removed, 150 μL DMSO was added to dissolve formazan crystals, and absorbance was measured at 570 nm. Cell viability = (OD of drug group / OD of normal control) × 100% [2]
- Apoptosis detection (Annexin V-FITC/PI staining): Cells in 6-well plates were trypsinized, washed with PBS, resuspended in binding buffer, and stained with Annexin V-FITC and PI for 15 minutes in the dark. Apoptotic rate was analyzed by flow cytometry [2]
- Insulin secretion detection (ELISA): After 48-hour treatment, cells were incubated with Krebs-Ringer bicarbonate buffer (KRBB) containing 2.8 mM glucose for 1 hour, then with KRBB containing 16.7 mM glucose for 2 hours. Supernatant was collected, and insulin concentration was measured by insulin ELISA kit [2]
2. 3T3-L1 adipocyte assay (insulin resistance model):
- Adipocyte differentiation: 3T3-L1 preadipocytes were cultured in DMEM with 10% FBS. Differentiation was induced by medium containing 0.5 mM isobutylmethylxanthine, 1 μM dexamethasone, and 10 μg/mL insulin for 2 days, then maintained in medium with 10 μg/mL insulin for another 2 days, followed by normal medium until 80% differentiation (day 8) [3]
- Insulin resistance induction: Differentiated adipocytes were treated with 100 nM insulin for 24 hours to induce insulin resistance [3]
- Drug treatment and detection: Insulin-resistant adipocytes were treated with Pioglitazone HCl (1, 5, 10 μM) for 24 hours. RT-PCR was used to detect adiponectin mRNA (primers targeting adiponectin and GAPDH), Western blot to detect adiponectin protein and p-Akt, and 2-NBDG (a fluorescent glucose analog) to measure glucose uptake (fluorescence intensity measured by microplate reader) [3]
3. Cardiac fibroblast assay (TGF-β1-induced fibrosis model):
- Cardiac fibroblast isolation: Cardiac fibroblasts were isolated from 1-3 day-old SD rat pups by collagenase digestion, cultured in DMEM with 10% FBS, and used at passage 3 [4]
- Treatment and detection: Fibroblasts were treated with TGF-β1 (10 ng/mL) plus Pioglitazone HCl (10 μM) or vehicle for 48 hours. RT-PCR detected collagen I mRNA, and Western blot detected α-SMA protein (a marker of myofibroblast activation) [4]
.

Mice: 10 mg/kg Pioglitazone HCl or vehicle (0.25% carboxymethylcellulose) is adnimistered to ob/ob and adipo -/- ob/ob mice by oral gavage once daily for 14 consecutive days. 30 mg/kg Pioglitazone or vehicle is also adnimistered to ob/ob and adipo -/- ob/ob mice by oral gavage once daily for 14 consecutive days.
Rats: Male Wistar albino rats (weighing 250±20 g) are ued.Rats that achieved serum glucose level ≥250 mg/dL and serum creatinine level ≥1.5 mg/dL are divided into 2 groups (n=10 per each group): diabetic nephropathic (DN) group in which rats received an equal amount of vehicle (0.5% carboxy methyl cellulose) and Pioglitazone-treated (DN+Pio) group in which rats treated with Pioglitazone. Pioglitazone (10 mg/kg BW) is given orally by gastric gavage, once daily, for 4 weeks.
Mice and rats

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1. db/db mouse and adiponectin knockout (apoKO) mouse protocol (diabetes/insulin resistance model):
- Animals: Male db/db mice (6 weeks old), male apoKO mice (6 weeks old), and age-matched male C57BL/6 WT mice. ApoKO and WT mice were fed a high-fat diet (HFD, 60% fat) for 4 weeks to induce insulin resistance before drug treatment [3]
- Grouping and administration: Mice were randomly divided into groups (n=8 per group):
- db/db mice: Vehicle control (0.5% methylcellulose, oral gavage), Pioglitazone HCl (10 mg/kg/day, oral gavage) [3]
- ApoKO and WT HFD mice: Vehicle control, Pioglitazone HCl (10 mg/kg/day, oral gavage) [3]
- Treatment duration: 8 weeks. Body weight was measured weekly. Fasting blood samples were collected from tail vein every 2 weeks to detect FBG (glucose meter) and fasting insulin (ELISA). At the end of treatment, mice were euthanized, and plasma adiponectin was measured by ELISA [3]
2. Diabetic nephropathy rat protocol (cardiac fibrosis/hypertrophy model):
- Animals: Male SD rats (8 weeks old, 200-220 g). Normal control group (n=6) was fed a normal diet; diabetic nephropathy groups (n=24) were induced by a single intraperitoneal injection of STZ (50 mg/kg, dissolved in 0.1 M citrate buffer, pH 4.5) and fed a high-sugar/high-fat diet (40% sugar, 20% fat) [4]
- Grouping and administration: After 1 week of STZ injection (FBG >16.7 mmol/L confirmed diabetes), rats were randomly divided into 4 groups (n=6 per group):
- Normal control: Normal diet, vehicle (0.5% methylcellulose, oral gavage) [4]
- Model control: High-sugar/high-fat diet, vehicle [4]
- Pioglitazone HCl low dose: High-sugar/high-fat diet, 3 mg/kg/day (oral gavage) [4]
- Pioglitazone HCl high dose: High-sugar/high-fat diet, 10 mg/kg/day (oral gavage) [4]
- Treatment duration: 12 weeks. Body weight and blood pressure were measured monthly. At the end of treatment, rats were euthanized:
- Heart weight was measured to calculate HW/BW ratio [4]
- Heart tissues were fixed in 4% formalin for Masson’s trichrome staining (collagen detection) [4]
- Fresh heart tissues were used for RT-PCR (ANP, BNP, TGF-β1 mRNA) and Western blot (TGF-β1, p-Smad3 protein) [4]
.

Absorption, Distribution, and Excretion
Absorption
After oral administration of pioglitazone, peak serum concentrations (Tmax) are reached within 2 hours. Food slightly delays the time to peak serum concentration, extending Tmax to approximately 3-4 hours, but does not affect the extent of 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.
Excretion
Approximately 15-30% of orally administered pioglitazone is excreted in the urine. Therefore, the majority of its excretion is considered to be either as the parent drug via bile or as metabolites via feces.
Volume of Distribution
The mean apparent volume of distribution of pioglitazone is 0.63 ± 0.41 L/kg.
Clearance
The apparent clearance of orally administered pioglitazone is 5-7 L/h.
There were no significant differences in the pharmacokinetic characteristics of pioglitazone among subjects with normal or moderately impaired renal function. Although the mean concentrations of pioglitazone and its metabolites in serum are elevated in patients with moderate to severe renal impairment, no dose adjustment is required. Compared to healthy subjects with normal renal function, patients with severe renal impairment show a decreased mean AUC after multiple oral doses of pioglitazone. Approximately 15% to 30% of the oral dose of pioglitazone is excreted in the urine. Renal clearance of pioglitazone is negligible; the drug is primarily excreted as metabolites and their conjugates. It is presumed that most of the oral dose is excreted unchanged or as metabolites via bile and ultimately in feces. Pioglitazone is a thiazolidinedione insulin sensitizer that has been shown to be effective in human type 2 diabetes and non-alcoholic fatty liver disease. It may also be effective in similar diseases 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. A 2×2 Latin square design with a 4-week washout period was used to administer pioglitazone intravenously (median dose 0.2 mg/kg) or orally (3 mg/kg) to six healthy lean cats (3.96 ± 0.56 kg) and six obese cats (6.43 ± 0.48 kg). Blood samples were collected within 24 hours, and pioglitazone concentrations were determined by a validated high-performance liquid chromatography (HPLC). A two-compartment model was used to analyze intravenous administration data, and a non-compartment model was used to analyze oral administration data. Pharmacokinetic parameters were determined. After oral administration, the mean bioavailability was 55%, t_1/2 was 3.5 h, T_max was 3.6 hr, C_max was 2131 ng/mL, and 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. Following oral administration of 3 mg/kg pioglitazone to cats, the systemic exposure was similar to that at human therapeutic doses. PMID: 22612529. The mean apparent volume of distribution (V_d/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. It also binds to other serum proteins, but with lower affinity. M-III (a ketone derivative of pioglitazone) and M-IV (a hydroxyl derivative of pioglitazone) also extensively bind to serum albumin (>98%).

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Metabolism/Metabolites
Pioglitazone is primarily metabolized via hydroxylation and oxidation—the resulting metabolites are partially 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 concentration. The specific CYP isoenzyme involved in pioglitazone metabolism is CYP2C8, followed by CYP3A4. There is also some evidence that extrahepatic CYP1A1 is involved. Cytochrome P450 (CYP) isoenzymes are involved in the metabolism of pioglitazone, including CYP2C8, followed by CYP3A4. CYP2C9 plays a negligible role in pioglitazone clearance. Pioglitazone is not a strong inducer of CYP3A4, and there is no evidence that pioglitazone induces CYP. Pioglitazone is primarily metabolized through hydroxylation and oxidation; some metabolites are also 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-(1-hydroxyethyl)pyridin-2-yl]ethoxy}phenyl)methyl]-1,3-thiazolidin-2,4-dione, and 5-({4-[2-(5-ethylpyridin-2-yl)-2-hydroxyethoxy]phenyl}methyl)-1,3-thiazolidin-2,4-dione.

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Biological 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 Overview
Identification and Uses: Pioglitazone is a solid dosage form. 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 is insulin-dependent. 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 PPARγ nuclear receptors regulates the transcription of various insulin-responsive genes involved in the regulation of glucose and lipid metabolism. To date, clinical studies have not identified hepatotoxicity with pioglitazone. However, post-marketing surveillance data have shown adverse reactions including 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 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 in mice (100 mg/kg), rats (4 mg/kg and above), and dogs (3 mg/kg) after oral administration of pioglitazone hydrochloride. 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 other than 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, daily oral doses of pioglitazone hydrochloride up to 40 mg/kg did not show any adverse effects on fertility in male and female rats. During organogenesis, administration of pioglitazone at a dose of 20 mg/kg to pregnant rats did not cause adverse developmental effects. During late pregnancy and lactation, administration of pioglitazone to pregnant rats at maternal doses of 10 mg/kg or higher resulted in postnatal growth retardation in offspring, attributed to weight loss. During organogenesis, no adverse developmental 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 genotoxicological studies have demonstrated that pioglitazone hydrochloride is non-mutagenic; these studies include the Ames bacterial assay, mammalian cell forward mutation assay, in vitro cytogenetic assays using CHL cells, unplanned DNA synthesis assays, and in vivo micronucleus assays. Pioglitazone acts as a peroxisome proliferator-activated receptor (PPAR) agonist on insulin target tissues such as adipose tissue, skeletal muscle, and liver. Activation of the PPAR-γ receptor increases the transcription of insulin-responsive 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, it can improve insulin resistance associated with type 2 diabetes without increasing insulin secretion from pancreatic β-cells.

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Hepatotoxicity
Unlike troglitazone, pioglitazone treatment does not cause elevated transaminases. In clinical trials, only 0.26% of pioglitazone patients 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 liver injury caused by pioglitazone 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, and all patterns of serum enzyme elevation have been described, including hepatocellular, cholestatic, and mixed types. Allergic reactions are rare, and autoantibodies are usually not present. Case reports of pioglitazone causing acute liver failure have been documented, typically associated with hepatocellular injury. In most cases, patients recover completely within 2 to 3 months. Probability Score: C (Possibly a rare cause of clinically significant liver injury). ◉ Summary 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 premature infants, alternative medications may be preferred.
◉ Effects on Breastfed Infants
No relevant published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No relevant published information found as of the revision date.
Route of Exposure
After oral administration on an empty stomach, pioglitazone is detectable in serum within 30 minutes and reaches peak concentrations within 2 hours. Food slightly delays the peak serum concentration by 3 to 4 hours, but does not affect absorption.

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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 50 mg empagliflozin monotherapy for 5 days, followed by 50 mg empagliflozin combined with 45 mg pioglitazone for 7 days, and finally 45 mg pioglitazone monotherapy for 7 days, using one of two treatment sequences. In Study 2, 20 volunteers received 45 mg pioglitazone monotherapy for 7 days, followed by 10 mg, 25 mg, and 50 mg empagliflozin combined with 45 mg pioglitazone for 9 days, using one of four treatment sequences. In Study 1, pioglitazone exposure (Cmax and AUC) increased when used in combination with empagliflozin compared to monotherapy. The geometric mean ratios (GMRs) of steady-state Cmax (Cmax,ss) and steady-state AUC (AUCt,ss) were 187.89% (95% CI, 166.35%–212.23%) and 157.97% (95% CI, 148.02%–168.58%), respectively, when used in combination with empagliflozin, compared to monotherapy. Because no increase in pioglitazone exposure was expected based on in vitro data, a second study was conducted using the empagliflozin dose tested in a Phase III clinical trial. In Study 2, pioglitazone exposure decreased slightly when used in combination with empagliflozin. Compared with monotherapy, the GMR of pioglitazone in combination with empagliflozin were as follows: 87.74% (95% CI, 73.88%-104.21%) for empagliflozin 10 mg, 90.23% (95% CI, 66.84%-121.82%) for empagliflozin 25 mg, and 89.85% (95% CI, 71.03%-113.66%) for 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 19 subjects taking empagliflozin 50 mg alone reported an adverse event, four of 20 subjects taking pioglitazone alone reported adverse events, and five of 18 subjects receiving combination therapy reported adverse events. In Study 2, eight of 20 subjects taking pioglitazone alone reported adverse events, ten of 18 subjects receiving pioglitazone in combination with empagliflozin 10 mg reported adverse events, five of 17 subjects receiving pioglitazone in combination with empagliflozin 25 mg reported adverse events, and six of 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. PMID: 26051874
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, studies in diabetic patients are needed to determine the clinical significance of the gemfibrozil-pioglitazone interaction. PMID: 15900286
In the treatment of gastroparesis, domperidone (a prokinetic drug) 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 the possibility of interactions and adverse reactions exists. This study monitored the concentration-dependent inhibition of domperidone hydroxylation by pioglitazone and ondansetron in mixed human liver microsomes (HLM). We further evaluated the role of pioglitazone as a mechanism inhibitor. This study assessed its microsomal binding. In human liver microsomes (HLM), the presence of pioglitazone reduced the Vmax/Km value for monohydroxydomperidone production. Diagnostic plots showed that pioglitazone inhibits domperidone metabolism 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 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. PMID: 24641107
The aim of this study was to investigate potential drug interactions between topiramate and metformin and pioglitazone at steady state. Two open-label studies were conducted in healthy adult men and women. In Study 1, eligible participants initially received metformin monotherapy (500 mg twice daily) for 3 days, followed by metformin and topiramate in combination from day 4 to day 10 (dose gradually increased to 100 mg twice daily). In Study 2, eligible participants were randomly assigned to two groups: Group 1 received pioglitazone monotherapy (30 mg once daily) for 8 days, followed by pioglitazone and topiramate in combination from day 9 to day 22 (dose gradually increased to 96 mg twice daily); Group 2 received topiramate monotherapy (dose gradually increased to 96 mg twice daily) for 11 days, followed by 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 (CIs) of geometric least squares mean (LSM) ratios, including maximum plasma concentration (Cmax), area under the concentration-time curve at dosing intervals (AUC12 or AUC24), and oral clearance (CL/F), evaluated with and without concomitant administration. Comparison with historical data showed a slight increase in oral clearance of topiramate when used in combination with metformin. Concomitant administration of topiramate with metformin reduced the oral clearance of metformin at steady state, resulting in a slight increase in systemic exposure to metformin. The geometric LSM ratios and 90% CIs for metformin CL/F and AUC12 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. Pioglitazone 30 mg QD does not affect the steady-state pharmacokinetics of topiramate, while topiramate 96 mg BID combined 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 and routinely observed. Topiramate combined with metformin or pioglitazone is generally well-tolerated, and no new safety issues have been observed. PMID: 25219351

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

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Ecological Information
Environmental Fate/Exposure Overview
The production and pharmaceutical use of pioglitazone may result in its release into the environment through various waste streams. If released into the air, based on an estimated vapor pressure of 2.9 × 10⁻¹⁴ mmHg at 25 °C, pioglitazone will exist only in the atmosphere as a particulate phase. Particulate pioglitazone will be removed from the atmosphere by dry and wet deposition. Pioglitazone contains pyridine and anisole functional groups, which do not absorb ultraviolet light with wavelengths greater than 290 nm, and therefore may be susceptible to direct photolysis by sunlight. If released into soil, based on an estimated Koc value of 9000, pioglitazone is not expected to migrate. Based on an estimated Henry's Law constant of 1.7 × 10⁻¹² atm·m³/mol, volatilization from moist soil surfaces is not expected to be a significant fate process. Based on its vapor pressure, pioglitazone is not expected to volatilize from dry soil surfaces. Biodegradation data (soil or water) are provided in the absence of data. Based on the estimated adsorption coefficient (Koc), pioglitazone is expected to adsorb onto suspended solids and sediments after being released into water. Based on the estimated Henry's Law constant for this compound, surface volatilization is not expected to be a significant fate process. The estimated bioaccumulation factor (BCF) is 190, indicating a high bioaccumulation potential in aquatic organisms. Hydrolysis is also not expected to be a significant environmental fate process, as the compound lacks functional groups that would undergo hydrolysis under environmental conditions (pH 5 to 9). In workplaces where pioglitazone is produced or used, people may be exposed to the compound through inhalation and skin contact. Public exposure to pioglitazone is unlikely unless direct medical treatment is received. (Source)

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History and Events
Rosiglitazone was approved by the U.S. Food and Drug Administration (FDA) in 1999 for the treatment of type 2 diabetes. Its unique mechanism of action and the risk of hypoglycemia facilitated its rapid marketization, but safety concerns began to emerge in 2007. In 2007, five major events related to the safety of rosiglitazone in certain patients occurred within four calendar days: (1) On May 21, 2007, a meta-analysis of rosiglitazone conducted by Nissen and Wolski was published online, and the FDA also issued a safety warning on the same day; (2) On July 30, 2007, an FDA advisory committee meeting concluded that rosiglitazone increases the risk of myocardial ischemia; (3) On August 14, 2007, the label of thiazolidinediones (TZDs) was updated to include a boxed warning about heart failure; (4) On November 14, 2007, the warnings and precautions section of the rosiglitazone package insert was updated regarding its use in combination with nitrates or insulin. The purpose of this study is to: (1) describe the trends in the use of thiazolidinediones (rosiglitazone and pioglitazone) in the context of publicly announced safety concerns during the period from January 1, 2007 to May 2008; and (2) determine how many thiazolidinedione users had medical claims indicating an increased cardiovascular (CV) risk before and after the FDA issued a safety warning and the online publication of the meta-analysis conducted by Nissen and Wolski (May 21, 2007). This study retrospectively analyzed pharmacy claims data from nine commercial insurance plans (totaling 9 million eligible members), including a cohort of 1.4 million members from one of the plans for which medical claims data were available. We assessed the monthly trends in thiazolidinedione (TZD) use during the 17-month period from January 1, 2007 to May 31, 2008, including the proportion of TZD users with increased cardiovascular risk. In the trend analysis, we calculated the average number of pharmacy prescriptions per million members per calendar month in 2007 for the two TZD drugs and one control drug—sitagliptin (a novel oral hypoglycemic agent belonging to the dipeptidyl peptidase-IV inhibitor class). For cardiovascular risk analysis, we used a comprehensive medical and pharmacy claims database comprising a cohort of 1.4 million members to identify patients who had TZD drugs available on May 20, 2007, December 7, 2007, or May 20, 2008. We traced the medical claims records of all identified patients back two years from May 20, 2007, December 7, 2007, or May 20, 2008, respectively. Increased cardiovascular risk for rosiglitazone users is defined as: a primary diagnosis of congestive heart failure (CHF; ICD-9-CM code 428.xx or 398.91) in a medical claim record, current treatment with nitrates or insulin, or ischemic heart disease (including myocardial infarction [MI; ICD-9-CM codes 410.xx to 414.xx, or a surgical code [36.0x to 36.3x, for clearing blockages and implanting stents, bypass surgery, and revascularization]) in the primary diagnosis field. Increased cardiovascular risk for pioglitazone users is defined as: a CHF diagnosis code in a medical claim record. In January 2007, the average number of claims per million members per day was 97.3 for rosiglitazone and 107.2 for pioglitazone. In May 2007, the average number of rosiglitazone claims per million members per day began to decline, falling to 41.0 by December 2007, a 58.6% decrease from the peak of 99.1 in February 2007, and further decreasing to 31.8 by May 2008. Pioglitazone usage increased by 8.0% from January to June 2007 (from 107.2 to 115.8), and remained relatively stable in December 2007 (114.6) and May 2008 (108.9). Sitagliptin claims increased fivefold at a steady pace, from an average of 8.6 claims per million members per day in January 2007 to 43.4 in December 2007, and continued to grow to 48.7 in May 2008. Of the 5,117 rosiglitazone users on May 20, 2007, 1,296 (25.3%) were identified as having increased cardiovascular risk, compared to 590 (22.5%) of the 2,621 users on December 7, 2007 (P = 0.006), and 336 (21.8%) of the 1,541 users in May 2008 (P = 0.005). On May 20, 2007, 170 out of 6,056 pioglitazone users (2.8%) were diagnosed with congestive heart failure; while on December 7, 2007, 160 out of 6,275 users (2.5%) were diagnosed with congestive heart failure (P = 0.376); and in May 2008, 122 out of 5,998 users were diagnosed with congestive heart failure (P = 0.006). Although rosiglitazone usage per million members decreased by more than half in 2007 (when cardiovascular safety issues began to emerge), approximately one-fifth of rosiglitazone users had increased cardiovascular risk by the end of 2007 and May 2008. In May 2007, approximately 3% of pioglitazone users were diagnosed with congestive heart failure in their claims records, a figure that decreased to 2% in May 2008. When developing a drug catalog, insurance companies should consider the impact of members with cardiovascular risk factors on the continued use of thiazolidinediones.

[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.

Pioglitazone hydrochloride is an aromatic ether. Pioglitazone hydrochloride is the hydrochloride salt of an orally active thiazolidinedione drug with antidiabetic properties and potential antitumor activity. Pioglitazone activates peroxisome proliferator-activated receptor γ (PPAR-γ), a ligand-activated transcription factor, thereby inducing cell differentiation and inhibiting cell growth and angiogenesis. The drug also regulates the transcription of insulin-responsive genes, inhibits macrophage and monocyte activation, and stimulates adipocyte differentiation. (NCI05) A thiazolidinedione and PPARγ agonist used to treat type 2 diabetes. See also: Pioglitazone (active fraction); Glimepiride; Pioglitazone hydrochloride (ingredient); Alogliptin benzoate; Pioglitazone hydrochloride (ingredient).

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Drug Indications
Pioglitazone is indicated for the treatment of type 2 diabetes: Monotherapy: for patients with poor glycemic control due to diet and exercise and who are unsuitable for metformin due to contraindications or intolerance (especially overweight patients); Dual oral therapy, in combination with metformin, for patients with poor glycemic control despite using the maximum tolerated dose of metformin monotherapy (especially overweight patients); Sulfonylureas, only for patients who are intolerant to or have contraindications to metformin and whose glycemic control is poor despite using the maximum tolerated dose of sulfonylurea monotherapy; Triple oral therapy, in combination with metformin and sulfonylureas, for patients with poor glycemic control despite using dual oral therapy (especially overweight patients). Pioglitazone is also indicated for patients with type 2 diabetes who are unsuitable for glycemic control with insulin alone and who are unsuitable for metformin due to contraindications or intolerance.
Pioglitazone can be used as a second- or third-line treatment for type 2 diabetes, specifically as follows: Monotherapy: For adult patients with poor glycemic control due to diet and exercise (especially overweight patients) who are unable to use metformin due to contraindications or intolerance. Dual oral therapy: In combination with metformin for adult patients (especially overweight patients) with poor glycemic control despite using the maximum tolerated dose of metformin monotherapy. Sulfonylureas: Only for adult patients who are intolerant to or have contraindications to metformin and whose glycemic control is poor despite using the maximum tolerated dose of sulfonylurea monotherapy. Pioglitazone can be used in combination with metformin and sulfonylureas for adult patients (especially overweight patients) with poor glycemic control despite dual oral hypoglycemic therapy. Pioglitazone is also indicated for adult patients with type 2 diabetes whose glycemic control is poor with insulin therapy and who are unsuitable for metformin due to contraindications or intolerance (see Section 4.4). After starting pioglitazone treatment, patients should be followed up 3 to 6 months later to assess treatment response (e.g., reduction in HbA1c). Pioglitazone should be discontinued in patients with poor treatment response. Given the potential risks of long-term treatment, the prescribing physician should confirm the maintenance of pioglitazone efficacy during subsequent routine follow-up visits (see Section 4.4). Pioglitazone is indicated for the treatment of type 2 diabetes: Monotherapy – for adult patients with poorly controlled blood glucose levels due to diet and exercise and who are unsuitable for metformin due to contraindications or intolerance (especially overweight patients); Dual oral therapy – in combination with metformin for adult patients with poor glycemic control despite receiving the maximum tolerated dose of metformin monotherapy (especially overweight patients); In combination with sulfonylureas, only for adult patients who are intolerant to or have contraindicated with metformin and who have poor glycemic control despite receiving the maximum tolerated dose of sulfonylurea monotherapy; Triple oral therapy – in combination with metformin and sulfonylureas for adult patients with poor glycemic control despite receiving dual oral therapy (especially overweight patients). Oral therapy is also indicated for adult patients with type 2 diabetes who are uncontrolled with insulin alone and who are unsuitable for metformin due to contraindications or intolerance. After starting pioglitazone treatment, patients should be followed up 3 to 6 months later to assess the adequacy of the treatment response (e.g., a decrease in HbA1c). For patients who do not show an adequate response, pioglitazone should be discontinued. Given the potential risks of long-term treatment, the prescribing physician should confirm the maintenance of pioglitazone's efficacy during subsequent routine follow-up visits. Pioglitazone can be used as a second- or third-line treatment for type 2 diabetes, specifically as follows: Monotherapy: Suitable for adult patients with poor glycemic control due to diet and exercise (especially overweight patients) who cannot use metformin due to contraindications or intolerance. Pioglitazone can be used in combination with the following drugs for dual oral therapy: Metformin, suitable for adult patients with poor glycemic control despite receiving the maximum tolerated dose of metformin monotherapy (especially overweight patients); Sulfonylureas, only suitable for adult patients who are intolerant to or have contraindications to metformin, and whose glycemic control is poor despite receiving the maximum tolerated dose of sulfonylurea monotherapy. Pioglitazone can be used in combination with the following drugs for triple oral therapy: Metformin and sulfonylureas, suitable for adult patients with poor glycemic control despite receiving dual oral therapy (especially overweight patients). Pioglitazone is also suitable in combination with insulin for adult patients with type 2 diabetes whose glycemic control is poor with insulin therapy and who cannot use metformin due to contraindications or intolerance. After starting pioglitazone treatment, patients should be followed up 3 to 6 months later to assess treatment response (e.g., reduction in HbA1c). Pioglitazone should be discontinued in patients with poor response. Given the potential risks of long-term treatment, the prescribing physician should confirm the maintenance of pioglitazone efficacy during subsequent routine follow-up visits. Pioglitazone is indicated for the following second- or third-line treatments of type 2 diabetes: Monotherapy: For adult patients (especially overweight) with poorly controlled diet and exercise and who cannot use metformin due to contraindications or intolerance. Combined oral dual therapy: Metformin, for adult patients (especially overweight) with poor glycemic control despite receiving the maximum tolerated dose of metformin monotherapy; Sulfonylureas, only for adult patients who are intolerant to or have contraindications to metformin and who have poor glycemic control despite receiving the maximum tolerated dose of sulfonylurea monotherapy. Pioglitazone can be used in combination with metformin and sulfonylureas in adult patients (especially overweight patients) whose glycemic control is poor despite dual oral hypoglycemic agents. Pioglitazone is also suitable for adult patients with type 2 diabetes whose glycemic control is poor with insulin therapy, and who cannot use metformin due to contraindications or intolerance. After starting pioglitazone treatment, patients should be followed up after 3 to 6 months to assess treatment response (e.g., HbA1c reduction). Pioglitazone should be discontinued in patients with poor treatment response. Given the potential risks of long-term treatment, the prescribing physician should confirm the maintenance of pioglitazone's efficacy during subsequent routine follow-up visits. Pioglitazone is suitable as monotherapy for type 2 diabetes in the following situations: adult patients with poor diet and exercise control who are unsuitable for metformin due to contraindications or intolerance (especially overweight patients). For adult patients whose glycemic control is inadequate with insulin therapy and who are unsuitable for metformin due to contraindications or intolerance, pioglitazone can also be used in combination with insulin. After starting pioglitazone treatment, patients should be followed up 3 to 6 months later to assess the adequacy of the treatment response (e.g., HbA1c reduction). Pioglitazone should be discontinued in patients with an inadequate response. Given the potential risks of long-term treatment, the prescribing physician should confirm the maintenance of pioglitazone efficacy during subsequent routine follow-up visits. Pioglitazone is indicated for the treatment of type 2 diabetes: as monotherapy for adult patients (especially overweight patients) with poorly controlled diet and exercise and who are unsuitable for metformin due to contraindications or intolerance. After starting pioglitazone treatment, patients should be followed up 3 to 6 months later to assess the adequacy of the treatment response (e.g., HbA1c reduction). Pioglitazone should be discontinued in patients with an inadequate response. Given the potential risks of long-term treatment, prescribing physicians should confirm the maintenance of pioglitazone's efficacy during routine follow-up visits. Pioglitazone is indicated for second- or third-line treatment of type 2 diabetes in the following ways: monotherapy for adult patients (especially overweight patients) with poorly controlled diabetes due to diet and exercise and who are unsuitable for metformin due to contraindications or intolerance; dual therapy with metformin in combination with oral medication for adult patients (especially overweight patients) with poor glycemic control despite receiving the maximum tolerated dose of metformin monotherapy; combination therapy with sulfonylureas only for adult patients who are intolerant to or have contraindicated with metformin and whose glycemic control is poor despite receiving the maximum tolerated dose of sulfonylurea monotherapy; and triple therapy with metformin and sulfonylureas in combination with oral medication for adult patients (especially overweight patients) with poor glycemic control despite receiving dual oral therapy. Pioglitazone is also indicated for use in combination with insulin in adult patients with type 2 diabetes whose glycemic control is inadequate with insulin alone and who are unsuitable for metformin due to contraindications or intolerance. After initiating pioglitazone treatment, patients should be followed up after 3 to 6 months to assess adequacy of the treatment response (e.g., a decrease in HbA1c). Pioglitazone should be discontinued in patients who do not show an adequate response. Given the potential risks of long-term treatment, prescribing physicians should confirm the maintenance of pioglitazone's efficacy during subsequent routine follow-up visits. Pioglitazone can be used as a second- or third-line treatment for type 2 diabetes, specifically as follows: Monotherapy – suitable for adult patients with poorly controlled diabetes through diet and exercise (especially overweight patients) who are unsuitable for metformin due to contraindications or intolerance; Pioglitazone can be used in combination with sulfonylureas for dual oral therapy, only suitable for adult patients who are intolerant to or have contraindications to metformin, and whose glycemic control remains poor even with the maximum tolerated dose of sulfonylurea monotherapy; Pioglitazone is also suitable for use in combination with insulin for adult patients with type 2 diabetes whose glycemic control is poor with insulin therapy and who are unsuitable for metformin due to contraindications or intolerance. After starting pioglitazone treatment, patients should be followed up after 3 to 6 months to assess treatment response (e.g., HbA1c reduction). Pioglitazone should be discontinued in patients with poor treatment response. Given the potential risks of long-term treatment, the prescribing physician should confirm the maintenance of pioglitazone efficacy during subsequent routine follow-up visits. Pioglitazone is indicated for second- or third-line treatment of type 2 diabetes in the following ways: Monotherapy: for adult patients (especially overweight patients) whose blood glucose control is poorly controlled by diet and exercise and who are unsuitable for metformin due to contraindications or intolerance; Dual oral therapy, in combination with: metformin, for adult patients (especially overweight patients) whose glycemic control is poor despite receiving the maximum tolerated dose of metformin monotherapy; sulfonylureas, only for adult patients who are intolerant to or have contraindications to metformin and whose glycemic control is poor despite receiving the maximum tolerated dose of sulfonylurea monotherapy. Pioglitazone can be used in combination with metformin and sulfonylureas in adult patients (especially overweight patients) whose glycemic control is poor despite receiving dual oral hypoglycemic therapy. Pioglitazone is also indicated for adult patients with type 2 diabetes whose glycemic control is poorly controlled with insulin therapy and who are unsuitable for metformin due to contraindications or intolerance (see Section 4.4). After starting pioglitazone treatment, patients should be followed up 3 to 6 months later to assess the adequacy of the treatment response (e.g., HbA1c reduction). Pioglitazone should be discontinued in patients who do not show an adequate response. Given the potential risks of long-term treatment, the prescribing physician should confirm the maintenance of pioglitazone's efficacy during subsequent routine follow-up visits (see Section 4.4). Mechanism of action: - Improves insulin resistance: Pioglitazone hydrochloride activates PPARγ, upregulating adiponectin expression in adipocytes. Adiponectin enhances insulin sensitivity by promoting AMPK activation and glucose uptake in skeletal muscle and the liver (adiponectin-dependent pathway). It can also directly regulate insulin signaling (e.g., increase Akt phosphorylation) without adiponectin [3] - Protect pancreatic β cells: Pioglitazone hydrochloride inhibits AGE-induced β cell apoptosis and restores glucose-stimulated insulin secretion by downregulating cleaved caspase-3 and upregulating Bcl-2 [2] - Reduce cardiac fibrosis/hypertrophy: Pioglitazone hydrochloride inhibits the TGF-β1/Smad3 signaling pathway in cardiac fibroblasts, reduces collagen synthesis and myofibroblast activation, thereby reducing cardiac fibrosis and hypertrophy in diabetic nephropathy [4] 2. Therapeutic significance: - Pioglitazone hydrochloride is mainly used to treat type 2 diabetes (T2DM), especially suitable for patients with insulin resistance. It improves glycemic control by reducing fasting blood glucose, fasting insulin and HOMA-IR[3] - It has a protective effect against T2DM-related complications, such as diabetic cardiomyopathy (by reducing myocardial fibrosis/hypertrophy) and pancreatic β-cell dysfunction (by resisting AGE-induced damage)[2][4] 3. Comparison with other PPARγ agonists: - Unlike non-selective PPAR agonists (e.g., bezafibrate that activates PPARα/γ/δ), pioglitazone hydrochloride is a selective PPARγ agonist that minimizes off-target effects on PPARα/δ-mediated lipid metabolism[3] - Its efficacy in adiponectin knockout mice demonstrates a unique dual pathway (adiponectin-dependent and non-adiponectin-dependent) to improve diabetes, which distinguishes it from PPARγ agonists that depend solely on adiponectin[3]

C19H20N2O3S.HCL

392.9

392.096

C, 58.08; H, 5.39; Cl, 9.02; N, 7.13; O, 12.22; S, 8.16

112529-15-4

Pioglitazone;111025-46-8

60560

White to off-white solid powder

1.26 g/cm3

575.4ºC at 760 mmHg

193-194ºC

301.8ºC

0mmHg at 25°C

1.64

4.29

2

5

7

26

466

0

GHUUBYQTCDQWRA-UHFFFAOYSA-N

InChI=1S/C19H20N2O3S.ClH/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);1H

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

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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: ≥ 2.5 mg/mL (6.36 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 25.0 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: ≥ 2.5 mg/mL (6.36 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.36 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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