HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
Pioglitazone
U 72107 · PINEPOLLEN · Pioglitazone · Pioglitozaone · D4-Pioglitazone · Pioglitazone (Actos) · Pioglitazone free base · Pioglitazone USP/EP/BP
Identifikatoren & physikalische Daten
| CAS No. | 111025-46-8 |
|---|---|
| Summenformel | C19H20N2O3S |
| Durchschnittliche Molmasse | 356,4 g/mol |
| Monoisotopische Masse | 356,1194635 g/mol |
| SMILES | CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1 |
| InChIKey | HYAFETHFCAUJAY-UHFFFAOYSA-N |
| PubChem CID | 4829 |
| ChEMBL | CHEMBL595 |
| ChEBI | CHEBI:8228 |
| EC No. | 601-029-7 |
| DTXSID | DTXSID3037129 |
Chemische & physikalische Eigenschaften
| XLogP | 3,8 |
|---|---|
| Polarare Oberfläche (TPSA) | 93,6 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 5 |
| Frei drehbare Bindungen | 7 |
| Schwere Atome | 25 |
| Formalladung | 0 |
| Komplexität | 466 |
| Arzneimittel | Pharmaceuticals |
| LogP (Verteilungskoeffizient) | 2.33.39 |
| Color/Form | Colorless needles from dimethylformamide and water |
| Löslichkeit | Practically insoluble4.42e-03 g/LDMSO (Slightly, Heated) |
| Human Drugs | Breast FeedingLactationMilk, HumanHypoglycemic AgentsThiazolidinedionesEMA approved medicines: Human medicine |
| Decomposition | Hazardous decomposition products formed under fire conditions: Carbon oxides, Nitrogen oxides (NOx), Sulfur oxides, Hydrogen chloride gas. /Pioglitazone hydrochloride/ |
| Schmelzpunkt | 193-194C183-184 °CColorless prisms from ethanol, MP: 193-194 °C. Soluble in dimethyl formamideslightly soluble in ethanolvery slightly soluble in acetone, acetonitrile. Practically insoluble in waterinsoluble in ether. /Pioglitazone hydrochloride/183 - 184 °C183-184 C |
| Physical Description | Solid |
| Stability/Shelf Life | Stable under recommended storage conditions. /Pioglitazone hydrochloride/ |
| Dissociation Constants | 5.19pKa = 5.19 (pyridine) |
| Collision Cross Section | 178.8 Ų [M+H]+ [CCS Type: DTBuffer gas: N2Ionization: APCI+Dataset: TOXCASTSource Identifier: DTXSID3044203]176.88 Ų [M+H]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards] |
| Other Experimental Properties | White crystalline powder. Odorless. MW: 392.90 daltons. Soluble in N,N-dimethylformamide, slightly soluble in anhdydrous ethanol, very slightly soluble in acetone, acetonitrile, practically insoluble in water, insoluble in ether /Pioglitazone hydrochloride/ |
| Siedepunkt | 575.4±45.0 °C(Predicted) |
| Dichte | 1.260±0.06 g/cm3(Predicted) |
| Lagerbedingungen | under inert gas (nitrogen or Argon) at 2-8°C |
| pKa (Säurekonstante) | 6.35±0.50(Predicted) |
| Aggregatzustand | White to off-white solid. |
| Farbe | White to Off-White |
| Henry-Konstante | 5.8×106 mol/(m3Pa) at 25℃, HSDB (2015) |
| InChI | InChI=1S/C19H20N2O3S/c1-2-13-3-6-15(20-12-13)9-10-24-16-7-4-14(5-8-16)11-17-18(22)21-19(23)25-17/h3-8,12,17H,2,9-11H2,1H3,(H,21,22,23) |
| InChIKey | HYAFETHFCAUJAY-UHFFFAOYSA-N |
| SMILES | S1C(CC2=CC=C(OCCC3=NC=C(CC)C=C3)C=C2)C(=O)NC1=O |
Sicherheit & Vorschriften
| GHS-Einstufung | WarningH302+H312+H332 (16.7%): Harmful if swallowed, in contact with skin or if inhaled [Warning Acute toxicity, oralacute toxicity, dermalacute toxicity, inhalation]P203, P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 6 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies. |
|---|---|
| Regulatorische Informationen | Hazard Traits - CarcinogenicityStatus: Active Update: 08-11-2019 https://echa.europa.eu/registration-dossier/-/registered-dossier/30090 |
| FDA-Anforderungen | The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including pioglitazone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Pioglitazone hydrochloride/ |
| History and Incidents | Rosiglitazone was approved by the U.S. Food and Drug Administration (FDA) for type 2 diabetes in 1999. The unique mechanism of action and low risk of hypoglycemia contributed to rapid market uptake of rosiglitazone, but safety concerns became more prominent in 2007. There were 5 major events on 4 calendar days in 2007 regarding safety concerns related to rosiglitazone in certain patients: (1) the May 21, 2007, online release of the rosiglitazone meta-analysis performed by Nissen and Wolski and the FDA safety warning on the same day(2) the July 30, 2007, conclusion of an FDA advisory committee meeting that rosiglitazone increased cardiac ischemic risk(3) the August 14, 2007, update of thiazolidinedione (TZD) labels with a black-box warning for heart failureand (4) the November 14, 2007, update to the warnings and precautions section of the rosiglitazone label for coadministration of nitrate or insulin. /The purpose of this paper was/ to (1) describe TZD (rosiglitazone and pioglitazone) utilization trends from January 1, 2007, continuing through May 2008 amid public announcements of safety concerns and (2) determine the percentage of TZD users who had medical claims indicating increased cardiovascular (CV) risk before and after release (May 21, 2007) of the FDA safety warning and online release of the meta-analysis performed by Nissen and Wolski. A retrospective analysis of pharmacy claims was performed from 9 commercial plans with a combined 9 million eligible members, including a 1.4 million-member cohort from 1 of the plans for which medical claims data were available. We evaluated trends in TZD use for each month for the 17-month period from January 1, 2007, through May 31, 2008, including the percentage of TZD users at increased CV risk. In the trend analysis, for each calendar month of 2007, we calculated mean pharmacy claim counts per day per million members for each of the 2 TZD drugs and for a comparison drug, sitagliptin, a new oral hypoglycemic agent in a different class (dipeptidyl-peptidase-IV inhibitors). For the CV risk analysis, we used the database of integrated medical and pharmacy claims for the 1.4 million-member cohort to identify patients with a current days supply of a TZD on May 20, 2007, December 7, 2007, or May 20, 2008. The medical claims for all identified patients were queried back 2 years from May 20, 2007, December 7, 2007, or May 20, 2008, respectively. Rosiglitazone users at increased CV rsk were defined as those with a medical claim with a primary diagnosis for congestive heart failure (CHFInternational Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 428.xx or 398.91), those with a current supply of nitrate or insulin therapy, or those with ischemic heart disease, including myocardial infarction (MIICD-9-CM codes 410.xx through 414.xx, or surgical procedure codes [36.0x through 36.3x for removal of obstruction and insertion of stents, bypass surgery, and revascularization] in the primary diagnosis field). Pioglitazone users at increased risk were identified from medical claims with a CHF diagnosis code. The average number of claims per day per million members in January 2007 was 97.3 for rosiglitazone and 107.2 for pioglitazone. The average number of claims for rosiglitazone per day per million members began to decrease in May 2007, falling to 41.0 in December 2007, for a total decrease of 58.6% from the February 2007 peak (99.1), and fell further to 31.8 in May 2008. Pioglitazone use increased 8.0% from January to June 2007 (107.2 to 115.8) and remained relatively flat through December 2007 (114.6) and through May 2008 (108.9). Sitagliptin claims increased 5-fold, at a consistent rate, from an average of 8.6 claims per day per million members in January 2007 to 43.4 in December 2007, and continued to increase to 48.7, in May 2008. Of the 5,117 rosiglitazone users on May 20, 2007, 1,296 (25.3%) were identified at increased CV risk versus 590 (22.5%) of 2,621 users on December 7, 2007 (P = 0.006), and 336 (21.8%) of 1,541 users in May 2008 (P = 0.005). Of 6,056 pioglitazone users on May 20, 2007, 170 (2.8%) had a CHF diagnosis versus 160 (2.5%) of 6,275 users on December 7, 2007 (P = 0.376), and 122 of 5,998 users in May 2008 (P = 0.006). Although rosiglitazone utilization per million members declined by more than half in 2007, when CV safety concerns started to emerge, about 1 in 5 rosiglitazone users had elevated CV risk at year-end 2007 and in May 2008. About 3% of pioglitazone users in May 2007 had a diagnosis of CHF in claims history, which declined to 2% in May 2008. Insurers should consider the impact of persistent utilization of TZDs among members with CV risk factors when making formulary decisions. |
| Hazard Classes and Categories | Acute Tox. 4 (100%) |
| Shipment Methods and Regulations | PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped & will resist attack from the carcinogen. Both bottle & the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies & airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary & secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen & is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container & the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest & most secure form of transport & notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ |
| Firefighting Hazards | Hazardous decomposition products formed under fire conditions: Carbon oxides, Nitrogen oxides (NOx), Sulfur oxides, Hydrogen chloride gas. /Pioglitazone hydrochloride/ |
| Brandbekämpfungsverfahren | Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Pioglitazone hydrochloride/Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Pioglitazone hydrochloride/ |
| Lagerbedingungen | Storage: Store at 20 °C to 25 °C (68 °F to 77 °F)excursions permitted to 15 °C to 30 °C (59 °F to 86 °F).Keep container tightly closed in a dry and well-ventilated place. /Pioglitazone hydrochloride/PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen & date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ |
| Reinigungsverfahren | ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: No special environmental precautions required. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Pioglitazone hydrochloride/PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured & the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed & labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ |
| Entsorgungsverfahren | SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. /Pioglitazone hydrochloride/PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds & specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods & recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous & organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/For more Disposal Methods (Complete) data for Pioglitazone (7 total), please visit the HSDB record page. |
| Preventive Measures | Precautions for safe handling: Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. /Pioglitazone hydrochloride/Appropriate engineering controls: General industrial hygiene practice. /Pioglitazone hydrochloride/Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Pioglitazone hydrochloride/SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.For more Preventive Measures (Complete) data for Pioglitazone (14 total), please visit the HSDB record page. |
| Personal Protective Equipment (PPE) | Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Pioglitazone hydrochloride/Skin protection: Handle with gloves. /Pioglitazone hydrochloride/Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. /Pioglitazone hydrochloride/Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Pioglitazone hydrochloride/PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece & close-fitting at ankles & wrists), gloves, hair covering & overshoes. ... In chemical laboratory, gloves & gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, & disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ |
| Wechselwirkungen | The aim was to investigate the effects of coadministration of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with the thiazolidinedione pioglitazone. In study 1, 20 healthy volunteers received 50 mg of empagliflozin alone for 5 days, followed by 50 mg of empagliflozin coadministered with 45 mg of pioglitazone for 7 days and 45 mg of pioglitazone alone for 7 days in 1 of 2 treatment sequences. In study 2, 20 volunteers received 45 mg of pioglitazone alone for 7 days and 10, 25, and 50 mg of empagliflozin for 9 days coadministered with 45 mg of pioglitazone for the first 7 days in 1 of 4 treatment sequences. Pioglitazone exposure (Cmax and AUC) increased when coadministered with empagliflozin versus monotherapy in study 1. The geometric mean ratio (GMR) for pioglitazone Cmax at steady state (Cmax,ss) and for AUC during the dosing interval at steady state (AUCt,ss) when coadministered with empagliflozin versus administration alone was 187.89% (95% CI, 166.35%-212.23%) and 157.97% (95% CI, 148.02%-168.58%), respectively. Because an increase in pioglitazone exposure was not expected, based on in vitro data, a second study was conducted with the empagliflozin doses tested in Phase III trials. In study 2, pioglitazone exposure decreased marginally when coadministered with empagliflozin. The GMR for pioglitazone Cmax,ss when coadministered with empagliflozin versus administration alone was 87.74% (95% CI, 73.88%-104.21%) with empagliflozin 10 mg, 90.23% (95% CI, 66.84%-121.82%) with empagliflozin 25 mg, and 89.85% (95% CI, 71.03%-113.66%) with empagliflozin 50 mg. The GMR for pioglitazone AUCt,ss when coadministered with empagliflozin versus administration alone was 90.01% (95% CI, 77.91%-103.99%) with empagliflozin 10 mg, 88.98% (95% CI, 72.69%-108.92%) with empagliflozin 25 mg, and 91.10% (95% CI, 77.40%-107.22%) with empagliflozin 50 mg. The effects of empagliflozin on pioglitazone exposure are not considered to be clinically relevant. Empagliflozin exposure was unaffected by coadministration with pioglitazone. Empagliflozin and pioglitazone were well tolerated when administered alone or in combination. In study 1, adverse events were reported in 1 of 19 participants on empagliflozin 50 mg alone, 4 of 20 on pioglitazone alone, and 5 of 18 on combination treatment. In study 2, adverse events were reported in 8 of 20 participants on pioglitazone alone, 10 of 18 when coadministered with empagliflozin 10 mg, 5 of 17 when coadministered with empagliflozin 25 mg, and 6 of 16 when coadministered with empagliflozin 50 mg. These results indicate that pioglitazone and empagliflozin can be coadministered without dose adjustments.The thiazolidinedione antidiabetic drug pioglitazone is metabolized mainly by cytochrome P450 (CYP) 2C8 and CYP3A4 in vitro. Our objective was to study the effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics of pioglitazone to determine the role of these enzymes in the fate of pioglitazone in humans. In a randomized, double-blind, 4-phase crossover study, 12 healthy volunteers took either 600 mg gemfibrozil or 100 mg itraconazole (first dose, 200 mg), both gemfibrozil and itraconazole, or placebo twice daily for 4 days. On day 3, they received a single dose of 15 mg pioglitazone. Plasma drug concentrations and the cumulative excretion of pioglitazone and its metabolites into urine were measured for up to 48 hours. RESULTS: Gemfibrozil alone raised the mean total area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] of pioglitazone 3.2-fold (range, 2.3-fold to 6.5-foldP < 0.001) and prolonged its elimination half-life (t (1/2) ) from 8.3 to 22.7 hours ( P < .001) but had no significant effect on its peak concentration (C max ) compared with placebo (control). Gemfibrozil increased the 48-hour excretion of pioglitazone into urine by 2.5-fold ( P < 0.001) and reduced the ratios of the active metabolites M-III and M-IV to pioglitazone in plasma and urine. Gemfibrozil decreased the area under the plasma concentration-time curve from time 0 to 48 hours [AUC(0-48)] of the metabolites M-III and M-IV by 42% ( P < 0.05) and 45% ( P < 0.001), respectively, but their total AUC(0-infinity) values were reduced by less or not at all. Itraconazole had no significant effect on the pharmacokinetics of pioglitazone and did not alter the effect of gemfibrozil on pioglitazone pharmacokinetics. The mean area under the concentration versus time curve to 49 hours [AUC(0-49)] of itraconazole was 46% lower ( P <0.001) during the gemfibrozil-itraconazole phase than during the itraconazole phase. Gemfibrozil elevates the plasma concentrations of pioglitazone, probably by inhibition of its CYP2C8-mediated metabolism. CYP2C8 appears to be of major importance and CYP3A4 of minor importance in pioglitazone metabolism in vivo in humans. Concomitant use of gemfibrozil with pioglitazone may increase the effects and risk of dose-related adverse effects of pioglitazone. However, studies in diabetic patients are needed to determine the clinical significance of the gemfibrozil-pioglitazone interaction.Domperidone (prokinetic agent) is frequently co-administered with pioglitazone (anitidiabetic) or ondansetron (antiemetic) in gastroparesis management. These drugs are metabolized via cytochome P-450 (CYP) 3A4, raising the possibility of interaction and adverse reactions. The concentration-dependent inhibitory effect of pioglitazone and ondansetron on domperidone hydroxylation was monitored in pooled human liver microsomes (HLM). Pioglitazone was further assessed as a mechanism-based inhibitor. Microsomal binding was evaluated in our assessment. In HLM, Vmax/Km estimates for monohydroxy domperidone formation decreased in presence of pioglitazone. Diagnostic plots indicated that pioglitazone inhibited domperidone in a partial mixed-type manner. The in vitro Ki was 1.52 uM. Predicted in vivo AUCi/AUC ratio was 1.98. Pioglitazone also exerted time-dependent inhibition on the metabolism of domperidone and the average remaining enzymatic activity decreased significantly upon preincubation with pioglitazone over 0-40 min. Diagnostic plots showed no inhibitory effect of ondansetron on domperidone hydroxylation. In conclusion, pioglitazone inhibited domperidone metabolism in vitro through different complex mechanisms. Our in vitro data predict that the co-administration of these drugs can potentially trigger an in vivo drug-drug interaction./The objective of this study was/ to investigate potential drug-drug interactions between topiramate and metformin and pioglitazone at steady state. Two open-label studies were performed in healthy adult men and women. In Study 1, eligible participants were given metformin alone for 3 days (500 mg twice daily (BID)) followed by concomitant metformin and topiramate (titrated to 100 mg BID) from days 4 to 10. In Study 2, eligible participants were randomly assigned to treatment with pioglitazone 30 mg once daily (QD) alone for 8 days followed by concomitant pioglitazone and topiramate (titrated to 96 mg BID) from days 9 to 22 (Group 1) or to topiramate (titrated to 96 mg BID) alone for 11 days followed by concomitant pioglitazone 30 mg QD and topiramate 96 mg BID from days 12 to 22 (Group 2). An analysis of variance was used to evaluate differences in pharmacokinetics with and without concomitant treatment90% confidence intervals (CI) for the ratio of the geometric least squares mean (LSM) estimates for maximum plasma concentration (Cmax), area under concentration-time curve for dosing interval (AUC12 or AUC24), and oral clearance (CL/F) with and without concomitant treatment were used to assess a drug interaction. A comparison to historical data suggested a modest increase in topiramate oral clearance when given concomitantly with metformin. Coadministration with topiramate reduced metformin oral clearance at steady state, resulting in a modest increase in systemic metformin exposure. Geometric LSM ratios and 90% CI for metformin CL/F and AUC12 were 80% (75%, 85%) and 125% (117%, 134%), respectively. Pioglitazone had no effect on topiramate pharmacokinetics at steady state. Concomitant topiramate resulted in decreased systemic exposure to pioglitazone and its active metabolites, with geometric LSM ratios and 90% CI for AUC24 of 85.0% (75.7%, 95.6%) for pioglitazone, 40.5% (36.8%, 44.6%) for M-III, and 83.8% (76.1%, 91.2%) for M-IV, respectively. This effect appeared more pronounced in women than in men. Coadministration of topiramate with metformin or pioglitazone was generally well tolerated by healthy participants in these studies. A modest increase in metformin exposure and decrease in topiramate exposure was observed at steady state following coadministration of metformin 500 mg BID and topiramate 100mg BID. The clinical significance of the observed interaction is unclear but is not likely to require a dose adjustment of either agent. Pioglitazone 30 mg QD did not affect the pharmacokinetics of topiramate at steady state, while coadministration of topiramate 96 mg BID with pioglitazone decreased steady-state systemic exposure to pioglitazone, M-III, and M-IV. While the clinical consequence of this interaction is unknown, careful attention should be given to the routine monitoring for adequate glycemic control of patients receiving this concomitant therapy. Concomitant administration of topiramate with metformin or pioglitazone was generally well tolerated and no new safety concerns were observed.For more Interactions (Complete) data for Pioglitazone (20 total), please visit the HSDB record page. |
| Hepatotoxicity | In contrast to troglitazone, pioglitazone is not associated with an increased frequency of aminotransferase elevations during therapy. In clinical trials, ALT elevations above 3 times the ULN occurred in only 0.26% of patients on pioglitazone, compared to 0.25% of placebo recipients (and 1.9% of troglitazone recipients in similar studies). In addition, clinically apparent liver injury attributed to pioglitazone is very rare, fewer than a dozen cases having been described in the literature despite extensive use of this agent. The liver injury usually arises between 1 and 6 months after starting therapy and all patterns of serum enzymes elevations have been described including hepatocellular, cholestatic and mixed. Allergic phenomena are rare and autoantibodies have not been typically present. Cases of acute liver failure attributed to pioglitazone have been reported, usually in association with a hepatocellular pattern of injury. In most instances, recovery is complete within 2 to 3 months. |
| Umweltverhalten | TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 9000(SRC), determined from a structure estimation method(2), indicates that pioglitazone is expected to be immobile in soil(SRC). Volatilization of pioglitazone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.7X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Pioglitazone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.9X10-19 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 9000(SRC), determined from a structure estimation method(2), indicates that pioglitazone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.7X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(6), an estimated BCF of 190(SRC), from an estimated log Kow of 3.96(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Biodegradation data in water were not available(SRC, 2018).ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), pioglitazone, which has an estimated vapor pressure of 2.9X10-14 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase pioglitazone may be removed from the air by wet and dry deposition(SRC). Pioglitazone contains pyridine- and anisole-like functional groups that do not absorb UV light at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC). |
| Unerwünschte Wirkungen | The common adverse effects of pioglitazone are edema, weight gain, macular edema, osteoporosis, and congestive heart failure (CHF). It may cause hypoglycemia when combined with other antidiabetic drugs and decrease hematocrit and hemoglobin levels. |
| Expositionspfade | Following oral administration, in the fasting state, pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption. |
| Toxizitätsübersicht | IDENTIFICATION AND USE: Pioglitazone is a solid. It is used as hypoglycemic agent as an adjunct to diet and exercise for the management of type 2 diabetes mellitus. HUMAN STUDIES: Pioglitazone hydrochloride is a thiazolidinedione that depends on the presence of insulin for its mechanism of action. Pioglitazone hydrochloride decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is an agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARgamma nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism. No evidence of hepatotoxicity has been noted with pioglitazone in clinical studies to date. However, hepatitis, liver function test abnormalities (such as elevations in hepatic enzymes to at least 3 times the upper limit of normal), mixed hepatocellular-cholestatic liver injury, and liver failure with or without fatalities have been reported during postmarketing experience with the drug. Thiazolidinediones, including pioglitazone hydrochloride, cause or exacerbate congestive heart failure in some patients. Pioglitazone-induced heart failure is known in patients with underlying heart disease, but is not well documented in patients with normal left ventricular function. It has been however reported that a patient developed congestive heart failure and pulmonary edema with normal left ventricular function within 1 year of starting pioglitazone therapy. Patients treated with pioglitazone have increased risk of bladder cancer compared to general population. There was also described an association of pioglitazone use with an increased risk of newly developed chronic kidney disease. ANIMAL STUDIES: Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above, but not in a 52-week study at oral doses up to 32 mg/kg. Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone hydrochloride. In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day. A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg. Drug-induced tumors were not observed in any organ except for the urinary 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. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone hydrochloride daily prior to and throughout mating and gestation. Pioglitazone administered to pregnant rats during organogenesis did not cause adverse developmental effects at a dose of 20 mg/kg. When pregnant rats received pioglitazone during late gestation and lactation, delayed postnatal development, attributed to decreased body weight, occurred in offspring at maternal doses of 10 mg/kg and above. In pregnant rabbits administered pioglitazone during organogenesis, no adverse developmental effects were observed at 80 mg/kg, but reduced embryofetal viability at 160 mg/kg. Pioglitazone hydrochloride was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay, an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.There is no known antidote for pioglitazone overdosethe only treatment in such cases is supportive management.Pioglitazone acts as an agonist at peroxisome proliferator activated receptors (PPAR) in target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR-gamma receptors increases the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, pioglitazone both enhances tissue sensitivity to insulin and reduces hepatic gluconeogenesis. Thus, insulin resistance associated with type 2 diabetes mellitus is improved without an increase in insulin secretion by pancreatic β cells. |
| Medical Surveillance | PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ |
| Soil Adsorption/Mobility | Using a structure estimation method based on molecular connectivity indices(1), the Koc of pioglitazone can be estimated to be 9000(SRC). According to a classification scheme(2), this estimated Koc value suggests that pioglitazone is expected to be immobile in soil. |
| Human Toxicity Excerpts | /SIGNS AND SYMPTOMS/ No evidence of hepatotoxicity has been noted with pioglitazone in clinical studies to date. However, hepatitis, liver function test abnormalities (i.e., elevations in hepatic enzymes to at least 3 times the upper limit of normal), mixed hepatocellular-cholestatic liver injury, and liver failure with or without fatalities have been reported during postmarketing experience with the drug./SIGNS AND SYMPTOMS/ Thiazolidinediones, including pioglitazone hydrochloride, cause or exacerbate congestive heart failure in some patients./CASE REPORTS/ /The objective of this paper was/ to report 2 cases of thiazolidinedione (TZD)-associated congestive heart failure (CHF). ... A 57-year-old obese white man with type 2 diabetes was treated with pioglitazone 30 mg/day and insulin. He had no prior history of CHF and had an excellent exercise tolerance. Over the first 4 weeks of pioglitazone therapy, the patient experienced significant weight gain and subsequently developed CHF and pulmonary edema. A 50-year-old obese white man with type 2 diabetes presented with cardiogenic shock. Rosiglitazone 4 mg once daily had been initiated 6 weeks prior to presentation. He had no prior history of cardiac disease, and investigations did not reveal a cause for the cardiogenic shock. Rosiglitazone therapy was discontinued on admission. He improved and was discharged 21 days later. TZDs are oral agents used for the treatment of type 2 diabetes. TZD-associated CHF and pulmonary edema have been reported in patients with a prior history of CHF. These 2 cases highlight that this adverse event can occur even in the absence of any preexisting history of clinical heart failure or cardiac disease. ... In both cases, an objective causality assessment using the Naranjo probability scale revealed that the adverse drug reaction between cardiomyopathy and rosiglitazone in this patient was probable. TZD should be considered as a cause in the differential diagnosis of CHF and pulmonary edema in patients without a prior history of clinical CHF or cardiac disease. Healthcare professionals should be aware of the possible association between TZDs and cardiomyopathy./CASE REPORTS/ A 39-year-old black woman with type 2 diabetes mellitus, hypertension, and congestive heart failure presented to a pharmacist-staffed diabetes comanagement service. She reported fatigue, dark brown urine, nausea, itching, and loss of appetite. Pioglitazone was promptly discontinued because her symptoms were consistent with those of hepatic dysfunction and pioglitazone was identified as a potential cause. The patient was referred to her physician. Liver enzyme levels were checked 13 days after initial presentation and found to be abnormal: alanine aminotransferase 490 U/L, aspartate aminotransferase 360 U/L, alkaline phosphatase 851 U/L, total bilirubin 3.1 mg/dL, direct bilirubin 2.0 mg/dL, and indirect bilirubin 1.1 mg/dL. Within 2 (1/2) months of discontinuing pioglitazone, the patient's symptoms resolved and liver enzyme levels returned to normal. Troglitazone, a thiazolidinedione (TZD), was removed from the market because of hepatotoxicity. Reported cases involving the newer TZDs, rosiglitazone and pioglitazone, have been few in number and less severe in consequence. Six cases of rosiglitazone-induced hepatotoxicity and 5 of pioglitazone-induced hepatotoxicity have been reported. Most patients improved symptomatically 2-4 weeks following discontinuation of the offending TZD, with normalization of liver enzyme levels in 2 weeks to 6 months following TZD discontinuation. Although the timeline and extent of liver enzyme elevation in this case are unclear, the Naranjo probability scale suggests that a causal relationship between pioglitazone and liver disease is probable. Patients with previous TZD-induced hepatotoxicity should not be rechallenged. Cases of hepatotoxicity with second generation TZDs, although clearly linked, have been few in number and less severe in consequence when compared to troglitazone. /Current package labeling requires/ baseline and then periodic measurement of liver enzymes in patients taking pioglitazone or rosiglitazone.For more Human Toxicity Excerpts (Complete) data for Pioglitazone (24 total), please visit the HSDB record page. |
| Artificial Pollution Sources | Pioglitazone's production and administration as a medication(1) may result in its release to the environment through various waste streams(SRC). |
| Carcinogen Classification | PioglitazoneGroup 2A: Probably carcinogenic to humansVolume 108: (2016) Some Drugs and Herbal Products20132A, probably carcinogenic to humans. (L135) |
| Drug Induced Liver Injury | Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)pioglitazoneActos®Antidiabetics3less-DILI-concern drugs |
| R-Sätze (R) | 11-34 |
| Gefahrensymbole | F,C |
| Sicherheitshinweise (S) | 16-26-36/37/39-45 |
| Gefahrstoffdaten | 111025-46-8(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Pioglitazone is an agonist of the peroxisome proliferator-activated receptor γ (PPARγ; EC50 = ~500-600 nM for both human and murine PPARγ). It is selective for PPARγ over PPARα, exhibiting low level activation of PPARα at 1 μM and 5.4-fold activation at a concentration of 10 μM. Pioglitazone inhibits pyruvate oxidation and glucose production in hepatocytes when used at a concentration of 10 μM. In vivo, pioglitazone (0.3-3 mg/kg per day) reduces hyperglycemia, hyperlipidemia, and hyperinsulinemia in a dose-dependent manner in male Wistar fatty rats. It reduces the number of lesions in a transgenic rat adenocarcinoma of prostate (TRAP) model. Pioglitazone (2.5 mg/kg) also decreases production of neuroinflammatory cytokines and reduces immobility in the forced swim and tail suspension tests in a mouse model of chronic mild stress, indicating antidepressant-like activity that can be reversed by the PPARγ antagonist GW9662 .
Verwenden
Pioglitazone shows antidiabetic activity in patients with type 2 diabetes mellitus.