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Pioglitazone potassium (U-72107) is a PPARγ (peroxisome proliferator-activated receptor) agonist with anti-diabetic effects. It has EC50s of 0.93 μM and 0.99 μM for human and mouse PPARγ, respectively.
| Targets |
hPPARγ (EC50 = 0.93 μM) mouse PPARγ (EC50 = 0.99 μM); hPPARδ (EC50 = 43 μM); hPPARα (EC50 = 100 μM); mouse PPARα (EC50 = 100 μM)
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| ln Vitro |
The pancreatic β-cell line T15 can avoid AGEs-induced HIT-impaired cell viability by totally preventing AGEs-induced β-cell necrosis and the rise of caspase-3, with pioglitazone potassium (0.5 or 1 μM, 5 days) being the most effective treatment to prevent these events [2]. Pioglitazone potassium (1 μM, 1 h) can lower the GSSG/GSH ratio in AGE-cultured cells and increase insulin secretion triggered by low glucose concentrations [2].
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| ln Vivo |
Pioglitazone potassium (oral gavage, 10 or 30 mg/kg once daily for 14 days) reduces insulin resistance and diabetes, perhaps in a lipocalin-dependent way in the liver but not in skeletal muscle[3] . Pioglitazone potassium (oral gavage, 10 mg/kg, once day, 4 weeks) can dramatically reduce body weight (BW), cardiac hypertrophy, increased blood glucose levels and ameliorate associated dyslipidemia [4].
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]. 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] 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]. |
| Cell Assay |
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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| Animal Protocol |
Animal/Disease Models: ob/ob and adipo-/- ob/ob mice on C57Bl/6 background [3]
Doses: 10 or 30 mg/kg Route of Administration: po (oral gavage); one time/day; 14-day Experimental Results: ob/ Serum free fatty acid and triglyceride levels and adipocyte size were unchanged in ob and adipo-/- ob/ob C57BL/6 mice at the 10 mg/kg dose, but were Dramatically diminished to similar levels at the 10 mg/kg dose. degree. 30 mg/kg. It was also shown that the expression of TNFα and resistin in the adipose tissue of ob/ob and adipo-/- ob/ob mice was unchanged at the 10 mg/kg dose but diminished at the 30 mg/kg dose. Animal/Disease Models: Male Wistar albino rat [4] Doses: 10 mg/kg Route of Administration: po (oral gavage); one time/day; 4-week Experimental Results: Reduce elevated serum creatinine and creatine kinase MB (CK-MB) levels, TGF-β1 gene expression and regulates the expression of MMP-2/TIMP-2 system. |
| ADME/Pharmacokinetics |
Absorption, Distribution, and Excretion
Absorption After oral administration of pioglitazone, peak serum concentrations (Tmax) are reached within 2 hours. Food slightly delays the occurrence of peak serum concentrations, 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 Routes Approximately 15-30% of orally administered pioglitazone is excreted in the urine. Therefore, the majority of its elimination is considered to be via bile excretion of the parent drug or fecal excretion of metabolites. 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 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 doses 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 negligible; the drug is primarily excreted as metabolites and their conjugates. It is presumed that the majority 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 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 (t1/2) was 3.5 h, the time to peak concentration (Tmax) was 3.6 h, the peak concentration (Cmax) was 2131 ng/mL, and the area under the curve (AUC0-8) 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. The systemic exposure of cats after oral administration of 3 mg/kg pioglitazone was similar to that of humans after receiving therapeutic doses. PMID:22612529 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) also extensively bind to serum albumin (>98%). View MoreMetabolism/Metabolites Pioglitazone is primarily metabolized through hydroxylation and oxidation, with some of its metabolites being 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 the clearance of pioglitazone. Pioglitazone is not a strong inducer of CYP3A4, and it has not been shown to induce CYP. Pioglitazone is primarily metabolized through hydroxylation and oxidation; some of its metabolites are 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. Biological Half-Life The mean serum half-life of pioglitazone and its metabolites is 3–7 hours and 16–24 hours, respectively. 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/Toxicokinetics |
Toxicity Overview
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 PPARγ nuclear receptors regulates the transcription of many insulin-responsive genes involved in the control of glucose and lipid metabolism. No hepatotoxicity of pioglitazone has been observed in clinical studies to date. 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 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 forward 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, as an agonist of peroxisome proliferator-activated receptor (PPAR), acts on insulin target tissues such as adipose tissue, skeletal muscle, and liver. Activation of the PPAR-γ receptor 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, insulin resistance associated with type 2 diabetes is improved without increasing insulin secretion from pancreatic β cells. View MoreHepatotoxicity Toxicity Data Hypoglycemia; LD50 = mg/kg (oral in rats) Interactions This study aimed to investigate the effects of combined use of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin and 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 45 mg 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, combination therapy with empagliflozin increased pioglitazone exposure (Cmax and AUC). The geometric mean ratios (GMRs) of steady-state Cmax (Cmax,ss) and steady-state AUC (AUCt,ss) with combination therapy with empagliflozin were 187.89% (95% CI, 166.35%–212.23%) and 157.97% (95% CI, 148.02%–168.58%), respectively, compared with monotherapy. 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 combined 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 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 indicate 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. Our objective was 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-phase crossover study, 12 healthy volunteers received either 600 mg of gemfibrozil or 100 mg of itraconazole (initial dose 200 mg), gemfibrozil in combination with itraconazole, or placebo, twice daily for four consecutive days. On day 3, they received a single 15 mg dose of 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 mean area under the plasma concentration-time curve (AUC0-∞) of pioglitazone by 3.2-fold (range: 2.3-fold to 6.5-fold; P < 0.001) and prolonged its elimination half-life (t1/2) from 8.3 hours to 22.7 hours (P < 0.001), but had no significant effect on peak concentration (Cmax) 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 inhibited 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 lead to in vivo drug interactions. PMID:24641107 This study aimed to investigate potential drug interactions between topiramate, metformin, and pioglitazone at steady state. We conducted two open-label studies 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. Topiramate combined with metformin or pioglitazone is generally well-tolerated, and no new safety issues have been observed. PMID: 25219351 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 pioglitazone metabolites M-III and M-IV have a protein binding rate of >98% (also primarily binding to albumin). Ecological Information Environmental Fate/Exposure Overview The production and use of pioglitazone as a medicine 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 as a particulate phase in the atmosphere. Particulate pioglitazone will be removed from the atmosphere through wet and dry sedimentation. 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 released into water is expected to adsorb onto suspended solids and sediments. 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) 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 became more prominent 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. |
| References |
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| Additional Infomation |
According to California labor law, pioglitazone may be carcinogenic. Pioglitazone belongs to the thiazolidinedione class of drugs, with the structure 1,3-thiazolidinedione-2,4-dione, where a benzyl group is substituted at the 5-position and a 2-(5-ethylpyridin-2-yl)ethoxy group is substituted at the 4-position of the benzene ring. It has hypoglycemic activity. Pioglitazone hydrochloride is an aromatic ether with various pharmacological effects, including insulin sensitizer, EC 2.7.1.33 (pantothenic acid kinase) inhibitor, xenobiotic inhibitor, EC 6.2.1.3 (long-chain fatty acid-CoA ligase) inhibitor, ferroptosis inhibitor, cardioprotective agent, PPARγ agonist, and antidepressant. Pioglitazone hydrochloride is the hydrochloride salt of an orally active thiazolidinedione drug, possessing antidiabetic properties and potential antitumor activity. Pioglitazone can activate the ligand-activated transcription factor peroxisome proliferator-activated receptor γ (PPAR-γ), thereby inducing cell differentiation and inhibiting cell growth and angiogenesis. In addition, this drug can regulate the transcription of insulin response genes, inhibit macrophage and monocyte activation, and stimulate adipocyte differentiation. Pioglitazone is a thiazolidinedione drug and a peroxisome proliferator-activated receptor γ (PPARγ) agonist used to treat type 2 diabetes. Pioglitazone is a hypoglycemic agent used as adjunctive therapy to diet, exercise, and other hypoglycemic agents to control type 2 diabetes. It is administered as a racemic mixture, although there are no pharmacological differences between its enantiomers, and they appear to interconvert in vivo with minimal effect. Thiazolidinediones, including rosiglitazone and troglitazone, primarily work by activating peroxisome proliferator-activated receptor γ (PPARγ) to promote insulin sensitivity and improve glucose uptake. PPARγ is a ligand-activated transcription factor involved in the expression of more than 100 genes and affecting a variety of metabolic processes, particularly lipid and glucose homeostasis. In recent years, due to various adverse reactions and usage warnings (such as congestive heart failure and bladder cancer), and the emergence of safer and more effective alternative drugs for patients with type 2 diabetes, thiazolidinediones, including pioglitazone, have become less commonly used. Pioglitazone is a peroxisome proliferator-activated receptor alpha (PPAR-γ) agonist, belonging to the thiazolidinedione class of drugs. Its mechanism of action is as a PPAR-γ agonist. Pioglitazone is an insulin sensitizer and a thiazolidinedione drug suitable for the treatment of type 2 diabetes. Pioglitazone has been associated with rare cases of acute liver injury. Pioglitazone is an orally effective 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. This drug also regulates the transcription of insulin-responsive genes, inhibits macrophage and monocyte activation, and stimulates adipocyte differentiation. Pioglitazone is used to treat type 2 diabetes. Pioglitazone selectively stimulates the nuclear receptor peroxisome proliferator-activated receptor γ (PPAR-γ). It regulates the transcription of insulin-sensitive genes involved in the control of glucose and lipid metabolism in lipids, muscle tissue, and the liver. A thiazolidinedione and PPARγ agonist used to treat type 2 diabetes.
View MoreDrug Indications Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It can also be used in combination with metformin, glimepiride, or alogliptin for the same 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. Therapeutic Uses Hydroxyglycemic Agents /Clinical Trials/ ClinicalTrials.gov is a registry and results database that tracks human clinical studies funded by public and private institutions worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); 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 NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Pioglitazone is indexed in the database. Pioglitazone can be used alone (monotherapy) or in combination with sulfonylureas, metformin (which can be used as a combination therapy or alone), or insulin as an adjunct to diet and exercise for the treatment of type 2 diabetes. For patients with type 2 diabetes who are not adequately glycemicly controlled with pioglitazone and sulfonylureas alone, or with sulfonylureas or pioglitazone alone, pioglitazone can also be used in combination with glimepiride. For patients whose hyperglycemia cannot be controlled by other hypoglycemic agents, pioglitazone should be added to the existing hypoglycemic treatment, rather than replacing the existing hypoglycemic agent. /Included in US product label/ /Exploring Treatment/ 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 the incidence of dementia 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. We divided the participants into four groups: non-diabetic patients, diabetic patients who did not take pioglitazone, diabetic patients who took pioglitazone for less than 8 quarters, and diabetic patients who took pioglitazone for ≥8 quarters. Cox proportional hazards models investigated the relative risk (RR) of pioglitazone use with the incidence of dementia, adjusting 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); while in diabetic patients not receiving pioglitazone, the risk of dementia increased by 23% (RR=1.23, p<0.001). We found no age effect or 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 evaluate its potential neuroprotective effects in older adults. Drug Warning /Black Box Warning/ Warning: Congestive Heart Failure. Thiazolidinediones, including pioglitazone hydrochloride, can cause or worsen congestive heart failure in some patients. Patients should be closely monitored for signs and symptoms of heart failure (e.g., excessively rapid weight gain, dyspnea, and/or edema) after starting pioglitazone tablets and after dose increases. If heart failure occurs, it should be managed according to current standards of care, and discontinuation or dose reduction of pioglitazone hydrochloride should be considered. Pioglitazone tablets are not recommended for patients with symptomatic heart failure. Pioglitazone hydrochloride is contraindicated in patients with heart failure diagnosed with New York Heart Association (NYHA) functional class III or IV. Thiazolidinediones, including pioglitazone, can cause fluid retention, alone or in combination with other hypoglycemic agents, which may lead to or worsen congestive heart failure (CHF). Use of thiazolidinediones approximately doubles the risk of CHF. Pioglitazone used in combination with insulin, or in patients with NYHA class I or II heart failure, may increase the risk of CHF. Patients should be closely monitored for signs and symptoms of CHF (e.g., dyspnea, rapid weight gain, edema, unexplained cough, or fatigue), especially during treatment initiation and dose adjustments. If signs and symptoms of CHF occur, treatment should be administered according to current standards of care. Furthermore, dose reduction or discontinuation of pioglitazone must be considered for these patients. Patients with NYHA class III or IV heart failure (with or without congestive heart failure (CHF)) 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 of congestive heart failure. Because thiazolidinediones have a delayed onset of action and can cause increased vascular capacity and congestive heart failure, they should not be initiated in hospitalized diabetic patients, as they may complicate the condition of patients with comorbidities or hemodynamic changes resulting from hospitalization interventions. There is a risk of pregnancy unless contraception is used; anovulatory premenopausal women with insulin resistance may resume ovulation during treatment. The frequency of ovulation resumption after pioglitazone treatment has not been assessed in clinical studies and is therefore unclear. If menstrual dysfunction occurs, the risks and benefits of continuing pioglitazone should be weighed. 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 can decrease plasma glucose concentrations, plasma insulin concentrations, and glycated hemoglobin (HbA1c) levels. It has been reported that pioglitazone can cause significant fluid retention, leading to the onset or exacerbation of congestive heart failure—therefore, its use should be avoided in patients with heart failure or at risk of developing heart failure. There is evidence that pioglitazone may be associated with an increased risk of bladder cancer. Pioglitazone should not be used in patients with active bladder cancer, and caution should be exercised in patients with a history of bladder cancer. Mechanism of Action Pioglitazone is a selective agonist of peroxisome proliferator-activated receptor γ (PPARγ), acting on insulin target tissues such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ increases the transcription of insulin-response genes involved in the regulation of glucose and lipid production, transport, and utilization. Through this mechanism, pioglitazone can both enhance tissue sensitivity to insulin and reduce hepatic glucose production (i.e., gluconeogenesis)—thus improving insulin resistance associated with type 2 diabetes without increasing insulin secretion from pancreatic β-cells. Repeated administration of peroxisome proliferator-activated receptor gamma (PPARγ) agonists reduced neuropathic pain-like behaviors and associated changes in spinal dorsal horn glial cell activation. Since PPARγ is a nuclear receptor, persistent changes in gene expression are generally considered to be its pain-reducing mechanism. However, we recently reported that a single intrathecal injection of the PPARγ agonist pioglitazone reduced hyperalgesia within 30 minutes, a time typically shorter than that required by genomic mechanisms. To determine the rapid anti-hyperalgesic effect of PPARγ activation, we administered pioglitazone to rats with intact nerve damage and assessed their hyperalgesia. Hyperalgesia was suppressed within 5 minutes of pioglitazone injection, consistent with a non-genomic mechanism. Systemic or intrathecal administration of the PPARγ antagonist GW9662 inhibited the anti-hyperalgesic effect of intraperitoneal or intrathecal pioglitazone, suggesting a spinal PPARγ-dependent mechanism. To further investigate the role of non-genomic mechanisms, we used anisin to block the synthesis of new proteins in the spinal cord. When administered intrathecally, anisin did not alter the anti-hyperalgesic effect of pioglitazone in the early stages (7.5 minutes), further supporting a rapid non-genomic mechanism. At a later time point, anisin reduced the anti-hyperalgesic effect of pioglitazone, suggesting a delayed activation of the genomic mechanism. Pioglitazone inhibited the increase in GFAP expression induced by preserved nerve injury more rapidly than expected, achieving this effect within 60 minutes. We demonstrate for the first time that activation of spinal PPARγ can rapidly alleviate neuropathic pain, and that this process is independent of classical genomic activity. We conclude that the acute mechanism by which pioglitazone inhibits neuropathic pain is partly through reducing astrocyte activation, and partly through genomic and non-genomic PPARγ mechanisms. PMID: 25599238 Full text: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329091 Pioglitazone hydrochloride is a thiazolidinedione drug whose mechanism of action is dependent on the presence of insulin. Pioglitazone hydrochloride reduces insulin resistance in the periphery and liver, thereby increasing insulin-dependent glucose utilization and reducing hepatic glucose output. Pioglitazone is not an insulin secretagogue. It is an agonist of peroxisome proliferator-activated receptor γ (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 various insulin-responsive genes involved in the regulation of glucose and lipid metabolism. Thiazolidinediones not only reduce insulin resistance in patients with type 2 diabetes but also in patients with non-diabetic diseases associated with insulin resistance, such as obesity. Their mechanism of action involves binding to peroxisome proliferator-activated receptor (PPARγ), a transcription factor that regulates the expression of specific genes, particularly in adipocytes, but also present in other tissues. Thiazolidinediones likely act primarily on adipose tissue with high PPARγ expression. Thiazolidinediones have been shown to interfere with the expression and release of insulin resistance mediators (such as free fatty acids, adipokines like tumor necrosis factor-α, resistin, and adiponectin) in adipose tissue, thereby net improving insulin sensitivity (i.e., in muscle and liver). However, direct molecular effects on skeletal muscle cannot be ruled out. ...PMID: 12173692 Pioglitazone is a complete peroxisome proliferator-activated receptor (PPAR)-γ agonist that improves insulin sensitivity by increasing circulating adiponectin levels. However, the molecular mechanism by which pioglitazone induces insulin sensitization is not fully elucidated. In this study, we investigated whether pioglitazone improves insulin resistance by upregulating the expression of two different adiponectin receptors (AdipoR1 or AdipoR2) in 3T3-L1 adipocytes. In this study, the glucose uptake of 3T3-L1 adipocytes after pioglitazone treatment was assessed using a 2-[(3)H]deoxyglucose uptake assay. Simultaneously, qRT-PCR was used to analyze the mRNA expression levels of AdipoR1 and AdipoR2. The researchers first confirmed that pioglitazone significantly enhanced the uptake of 2-deoxyglucose (2-DOG) by insulin-induced 3T3-L1 adipocytes. Next, we investigated the mRNA expression of AdipoR1 and AdipoR2 after pioglitazone treatment and its regulation. Interestingly, pioglitazone significantly induced AdipoR2 expression but had no effect on AdipoR1 expression. Furthermore, adenovirus-mediated PPARγ expression significantly enhanced the effects of pioglitazone on 2-DOG uptake and AdipoR2 expression in insulin-stimulated 3T3-L1 adipocytes. These data indicate that pioglitazone enhances the autocrine and paracrine effects of adiponectin in 3T3-L1 adipocytes by upregulating PPARγ-mediated AdipoR2 expression. Furthermore, we found that pioglitazone significantly increased the phosphorylation level of AMP-activated protein kinase (AMPK) in insulin-stimulated 3T3-L1 adipocytes, but did not lead to phosphorylation of IRS-1, Akt, or other protein kinases… Pioglitazone enhances insulin sensitivity in 3T3-L1 adipocytes at least partially through PPARγ-AdipoR2-mediated AMPK phosphorylation. In conclusion, the upregulation of AdipoR2 expression may be one of the mechanisms by which pioglitazone improves insulin resistance in 3T3-L1 adipocytes. |
| Molecular Formula |
C19H21KN2O3S
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|---|---|
| Molecular Weight |
396.544944524765
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| Exact Mass |
394.075
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| CAS # |
1266523-09-4
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| Related CAS # |
Pioglitazone;111025-46-8
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| PubChem CID |
56653040
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| Appearance |
Typically exists as solid at room temperature
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
7
|
| Heavy Atom Count |
26
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| Complexity |
472
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(C1C=CC(OCCC2N=CC(CC)=CC=2)=CC=1)C1SC(=O)NC1=O.[KH]
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| InChi Key |
YRUUYXLNBAJFIM-UHFFFAOYSA-M
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| InChi Code |
InChI=1S/C19H20N2O3S.K/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);/q;+1/p-1
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| Chemical Name |
potassium;5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidin-3-ide-2,4-dione
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| Synonyms |
Pioglitazone (potassium salt); 1266523-09-4; Pioglitazone potassium; X1ZX7RX9WU; Pioglitazone (potassium); UNII-X1ZX7RX9WU; potassium;5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyl]methyl]-1,3-thiazolidin-3-ide-2,4-dione; 2,4-Thiazolidinedione, 5-((4-(2-(5-ethyl-2-pyridinyl)ethoxy)phenyl)methyl)-, potassium salt (1:1);
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5218 mL | 12.6088 mL | 25.2175 mL | |
| 5 mM | 0.5044 mL | 2.5218 mL | 5.0435 mL | |
| 10 mM | 0.2522 mL | 1.2609 mL | 2.5218 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04501406 | Recruiting | Drug: Pioglitazone Other: Placebo |
Type 2 Diabetes Mellitus (T2DM) Nonalcoholic Steatohepatitis |
University of Florida | December 15, 2020 | Phase 2 |
| NCT01873001 | Completed | Drug: Pioglitazone HCl Drug: Abiraterone acetate |
Healthy Volunteers | Janssen Research & Development, LLC | May 2013 | Phase 1 |
| NCT02958956 | Completed Has Results | Drug: Pioglitazone | Diabetes Mellitus, Type 2, Cancer | Takeda | January 1, 1997 | |
| NCT03080480 | Terminated | Drug: Pioglitazone | Chronic Granulomatous Disease | Children's Hospital of Fudan University | September 1, 2017 | Phase 1 Phase 2 |
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