Rosiglitazone

122-123 °C

153-155 °C

172.4 Ų [M+H]+ [CCS Type: DT; Buffer gas: N2; Ionization: APCI+; Dataset: TOXCAST; Source Identifier: DTXSID2023569]

172.6 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

172.19 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Warning

H315 (50%): Causes skin irritation [Warning Skin corrosion/irritation]

P203, P261, P264, P264+P265, P271, P273, P280, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P332+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including rosiglitazone maleate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Rosiglitazone maleate/

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 failure; and (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 (CHF; International 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 (MI; ICD-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.

Eye Irrit. 2 (100%)

Eye Irrit. 2 (100%)

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2 - 8 °C.

Store at 25 °C (77 °F) with excursions 15 °C to 30 °C (59 °F to 86 °F). Protect from light.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

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.

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed.

Appropriate engineering controls: General industrial hygiene practice.

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.

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.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place.

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).

An inhibitor of CYP2C8 (e.g., gemfibrozil) may increase the AUC of rosiglitazone and an inducer of CYP2C8 (e.g., rifampin) may decrease the AUC of rosiglitazone. Therefore, if an inhibitor or an inducer of CYP2C8 is started or stopped during treatment with rosiglitazone, changes in diabetes treatment may be needed based upon clinical response.

/The authors/ investigated the possible effect of ketoconazole on the pharmacokinetics of rosiglitazone in humans. Ten healthy Korean male volunteers were treated twice daily for 5 days with 200 mg ketoconazole or with placebo, using a randomized, open-label, two-way crossover study. On day 5, a single dose of 8 mg rosiglitazone was administered orally, and plasma rosiglitazone concentrations were measured. Ketoconazole increased the mean area under the plasma concentration-time curve for rosiglitazone by 47%[P = 0.0003; 95% confidence interval (CI) 23, 70] and the mean elimination half-life from 3.55 to 5.50 hr (P = 0.0003; 95% CI in difference 1.1, 2.4). The peak plasma concentration of rosiglitazone was increased by ketoconazole treatment by 17% (P = 0.03; 95% CI 5, 29). The apparent oral clearance of rosiglitazone decreased by 28% after ketoconazole treatment (P = 0.0005; 95% CI 18, 38). This study revealed that ketoconazole affected the disposition of rosiglitazone in humans, probably by the inhibition of CYP2C8 and CYP2C9, leading to increasing rosiglitazone concentrations that could increase the efficacy of rosiglitazone or its adverse events.

Endothelial dysfunction is implicated in the initiation and progression of atherosclerosis. Whether atorvastatin combined with rosiglitazone has synergistic effects on endothelial function improvement in the setting of dyslipidemia is unknown. Dyslipidemia rat model was produced with high-fat and high-cholesterol diet administration. Thereafter, atorvastatin, rosiglitazone or atorvastatin combined with rosiglitazone were prescribed for 2 weeks. At baseline, 6 weeks of dyslipidemia model production, and 2 weeks of medical intervention, fasting blood was drawn for parameters of interest evaluation. At the end, myocardium was used for 15-deoxy-delta-12,14-PGJ2 (15-d-PGJ2) assessment. Initially, there was no significant difference of parameters between sham and dyslipidemia groups. With 6 weeks' high-fat and high-cholesterol diet administration, as compared to sham group, serum levels of triglyceride (TG), total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) were significantly increased. Additionally, nitric oxide (NO) production was reduced and serum levels of malondialdehyde (MDA), C-reactive protein (CRP) and asymmetric dimethylarginine (ADMA) were profoundly elevated in dyslipidemia group. After 2 weeks' medical intervention, lipid profile was slightly improved in atorvastatin and combined groups as compared to control group. Nevertheless, in comparison to control group, NO production was profoundly increased and serum levels of MDA, CRP and ADMA were significantly decreased with atorvastatin or rosiglitazone therapy. 15-d-PGJ2 expression of myocardium was also significantly elevated with atorvastatin or rosiglitazone treatment. Notably, these effects were further enhanced with combined therapy, suggesting that atorvastatin and rosiglitazone had synergistic effects on endothelial protection, and inflammation and oxidation amelioration. Atorvastatin and rosiglitazone therapy had synergistic effects on endothelium protection as well as amelioration of oxidative stress and inflammatory reaction in rats with dyslipidemia.

Avandia (2 mg twice daily) taken concomitantly with glyburide (3.75 to 10 mg/day) for 7 days did not alter the mean steady-state 24-hour plasma glucose concentrations in diabetic patients stabilized on glyburide therapy. Repeat doses of Avandia (8 mg once daily) for 8 days in healthy adult Caucasian subjects caused a decrease in glyburide AUC and Cmax of approximately 30%. In Japanese subjects, glyburide AUC and Cmax slightly increased following coadministration of Avandia.

Rifampin administration (600 mg once a day), an inducer of CYP2C8, for 6 days is reported to decrease rosiglitazone AUC by 66%, compared with the administration of rosiglitazone (8 mg) alone.

In contrast to troglitazone, rosiglitazone 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 0.25% of patients on rosiglitazone, compared to 0.25% of placebo recipients (and 1.9% of troglitazone recipients in similar studies). In addition, clinically apparent liver injury attributed to rosiglitazone 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 12 weeks after starting therapy (thus, a shorter latency than typically occurs with troglitazone) and all patterns of serum enzyme elevations have been described including hepatocellular, cholestatic and mixed. Allergic phenomena are rare and autoantibodies have not been typically present. Fatal instances have been reported usually in cases with a hepatocellular pattern of injury. In most instances, recovery is complete within 1 to 2 months.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1000(SRC), determined from a structure estimation method(2), indicates that rosiglitazone is expected to have low mobility in soil(SRC). The pKa1, pKa2 values of rosiglitazone maleate are 6.1, 6.8(3), suggesting that rosiglitazone will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of rosiglitazone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.7X10-14 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Rosiglitazone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.0X10-14 mm Hg(SRC), determined from a fragment constant method(2). Biodegradation data for rosiglitazone in soil were not available(SRC, 2018).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1000(SRC), determined from a structure estimation method(2), indicates that rosiglitazone 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 1.7X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 58(SRC), from an estimated log Kow of 3.2(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation data for rosiglitazone 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), rosiglitazone, which has an estimated vapor pressure of 3.0X-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 rosiglitazone may be removed from the air by wet or dry deposition(SRC). Rosiglitazone does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

The most common adverse effects reported are increased LDL-cholesterol, increased HDL-cholesterol, increased total cholesterol. Less common adverse effects are edema, hypertension, heart failure/congestive heart failure, myocardial ischemia, diarrhea, upper respiratory tract infection. Uncommon adverse effects reported include anemia, back pain, fatigue, headache, hypoglycemia, myalgia, sinusitis, weight gain.

IDENTIFICATION AND USE: Rosiglitazone is a solid. It is used as an antidiabetic agent as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. HUMAN STUDIES: Thiazolidinediones, including rosiglitazone, alone or in combination with other antidiabetic agents, can cause fluid retention and may lead to or exacerbate congestive heart failure (CHF). Use of thiazolidinediones is associated with an approximately twofold increased risk of CHF. No evidence of hepatotoxicity has been noted with rosiglitazone in clinical studies to date, including a long-term (4-6 years) study in patients with recently diagnosed type 2 diabetes mellitus. However, hepatitis, elevations in hepatic enzymes to at least 3 times the upper limit of normal, and liver failure with or without fatalities have been reported during postmarketing experience with rosiglitazone. Rosiglitazone was not mutagenic or clastogenic in the in vitro chromosome aberration test in human lymphocytes. ANIMAL STUDIES: Rosiglitazone was not carcinogenic in the mouse. There was an increase in incidence of adipose hyperplasia in the mouse at doses >/= 1.5 mg/kg/day. Heart weights were increased in mice (3 mg/kg/day), rats (5 mg/kg/day), and dogs (2 mg/kg/day) with rosiglitazone treatments. Effects in juvenile rats were consistent with those seen in adults. Morphometric measurement indicated that there was hypertrophy in cardiac ventricular tissues, which may be due to increased heart work as a result of plasma volume expansion. Rosiglitazone had no effects on mating or fertility of male rats given up to 40 mg/kg/day. In juvenile rats dosed from 27 days of age through to sexual maturity (at up to 40 mg/kg/day), there was no effect on male reproductive performance, or on estrous cyclicity, mating performance, or pregnancy incidence in females. Rosiglitazone was not mutagenic or clastogenic in the in vitro bacterial assays for gene mutation, the in vivo mouse micronucleus test, and the in vivo/in vitro rat UDS assay. There was a small (about 2-fold) increase in mutation in the in vitro mouse lymphoma assay in the presence of metabolic activation.

For patients with impaired liver function test who reports ALT greater than three times the normal upper limit, it is recommended to stop the treatment. In cases of ALT showing 1.5 to 3 times the upper normal limit, it is recommended to re-test every week until normalization of liver function test.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of March 27, 2018: http://actor.epa.gov/dashboard/]

Using a structure estimation method based on molecular connectivity indices(1), the Koc of rosiglitazone can be estimated to be 3,600(SRC). According to a classification scheme(2), this estimated Koc value suggests that rosiglitazone is expected to have slight mobility in soil. The pKa1, pKa2 values of rosiglitazone maleate are 6.1, 6.8(3), suggesting that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ Limited data are available with regard to overdosage in humans. In clinical studies in volunteers, Avandia has been administered at single oral doses of up to 20 mg and was well-tolerated.

/SIGNS AND SYMPTOMS/ Thiazolidinedione use is associated with bone loss and fractures in women and possibly in men with type 2 diabetes mellitus. In long-term comparative clinical trials in patients with type 2 diabetes mellitus, the incidence of bone fracture was increased in patients (particularly women) receiving rosiglitazone versus comparator agents (glyburide and/or metformin). Such effects were noted after the first year of treatment and persisted throughout the study. The majority of fractures observed in patients taking thiazolidinediones were in a distal upper limb (i.e., forearm, hand, wrist) or distal lower limb (i.e., foot, ankle, fibula, tibia). In an observational study in the United Kingdom in men and women (mean age: 60.7 years) with diabetes mellitus, use of pioglitazone or rosiglitazone for approximately 12-18 months (as estimated from prescription records) was associated with a twofold to threefold increase in fractures, particularly of the hip and wrist. The overall risk of fracture was similar among men and women and was independent of body mass index, comorbid conditions, diabetic complications, duration of diabetes mellitus, and use of other oral antidiabetic drugs.145 Risk of fractures should be considered when initiating or continuing thiazolidinedione therapy in female patients with type 2 diabetes mellitus. Bone health should be assessed and maintained according to current standards of care. Although increased risk of fracture may also apply to men, the risk appears to be higher among women than men.

/SIGNS AND SYMPTOMS/ Thiazolidinediones, including rosiglitazone, alone or in combination with other antidiabetic agents, can cause fluid retention and may lead to or exacerbate congestive heart failure (CHF). Use of thiazolidinediones is associated with an approximately twofold increased risk of CHF. Patients should be observed for signs and symptoms of CHF (e.g., dyspnea, rapid weight gain, edema, unexplained cough or fatigue), especially during initiation of therapy and dosage titration. If signs and symptoms of CHF develop, the disorder should be managed according to current standards of care. In addition, a decrease in the dosage of rosiglitazone or discontinuance of the drug should be considered.

/SIGNS AND SYMPTOMS/ No evidence of hepatotoxicity has been noted with rosiglitazone in clinical studies to date, including a long-term (4-6 years) study (ADOPT) in patients with recently diagnosed type 2 diabetes mellitus. In the ADOPT study, the incidence of ALT elevation exceeding 3 times the upper limit of normal was similar in patients receiving rosiglitazone or active comparators (i.e., glyburide or metformin). However, hepatitis, elevations in hepatic enzymes to at least 3 times the upper limit of normal, and liver failure with or without fatalities have been reported during postmarketing experience with rosiglitazone.

For more Human Toxicity Excerpts (Complete) data for Rosiglitazone (28 total), please visit the HSDB record page.

Rosiglitazone

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 108: (2016) Some Drugs and Herbal Products

2016

2013

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

rosiglitazone

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

An estimated BCF of 58 was calculated for rosiglitazone(SRC), using an estimated log Kow of 3.2(1) and a regression-derived equation(1). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including rosiglitazone maleate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Rosiglitazone maleate/

A - Alimentary tract and metabolism

QA - Alimentary tract and metabolism

When rosiglitazone is used as monotherapy, it is associated with increases in total cholesterol, LDL, and HDL. It is also associated with decreases in free fatty acids. Increases in LDL occurred primarily during the first 1 to 2 months of therapy with AVANDIA and LDL levels remained elevated above baseline throughout the trials. In contrast, HDL continued to rise over time. As a result, the LDL/HDL ratio peaked after 2 months of therapy and then appeared to decrease over time.

Rosiglitazone acts as a highly selective and potent 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 regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In this way, rosiglitazone enhances tissue sensitivity to insulin.

Because osteoblasts and marrow adipocytes are derived from a common mesenchymal progenitor, increased adipogenesis may occur at the expense of osteoblasts, leading to bone loss. Our previous in vitro studies indicated that activation of the proadipogenic transcription factor peroxisome proliferator-activated receptor isoform gamma 2 with rosiglitazone suppressed osteoblast differentiation. Here, we show that 5-month-old Swiss-Webster mice receiving rosiglitazone for 28 day exhibited bone loss associated with an increase in marrow adipocytes, a decrease in the ratio of osteoblasts to osteoclasts, a reduction in bone formation rate, and a reduction in wall width--an index of the amount of bone formed by each team of osteoblasts. Rosiglitazone had no effect on the number of early osteoblast or osteoclast progenitors, or on osteoblast life span, but decreased the expression of the key osteoblastogenic transcription factors Runx2 and Osterix in cultures of marrow-derived mesenchymal progenitors. These effects were associated with diversion of bipotential progenitors from the osteoblast to the adipocyte lineage, and suppression of the differentiation of monopotential osteoblast progenitors. However, rosiglitazone had no effect on osteoblastic cells at later stages of differentiation. Hence, rosiglitazone attenuates osteoblast differentiation and thereby reduces bone formation rate in vivo, leading to bone loss. These findings provide a mechanistic explanation for the recent evidence that peroxisome proliferator-activated receptor isoform gamma activation is a negative regulator of bone mass and suggest that the increased production of oxidized fatty acids with age may indeed be an important mechanism for age-related osteoporosis in humans.

Brain peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, is involved in neuroprotection. It is activated by the drug rosiglitazone, which then can increase the pro-survival protein B-cell lymphoma 2 (BCL-2), to mediate neuroprotection. However, the mechanism underlying this molecular cascade remains unknown. Here, we show that the neuroprotective protein neurotrophic factor-a1 (NF-a1), which also induces the expression of BCL-2, has a promoter that contains PPARgamma-binding sites that are activated by rosiglitazone. Treatment of Neuro2a cells and primary hippocampal neurons with rosiglitazone increased endogenous NF-a1 expression and prevented H2 O2 -induced cytotoxicity. Concomitant with the increase in NF-a1, BCL-2 was also increased in these cells. When siRNA against NF-a1 was used, the induction of BCL-2 by rosiglitazone was prevented, and the neuroprotective effect of rosiglitazone was reduced. These results demonstrate that rosiglitazone-activated PPARgamma directly induces the transcription of NF-a1, contributing to neuroprotection in neurons. We proposed the following cascade for neuroprotection against oxidative stress by rosiglitazone: Rosiglitazone enters the neuron and binds to peroxisome proliferator-activated receptor gamma (PPARgamma) in the nucleus. The PPARgamma-rosiglitazone complex binds to the neurotrophic factor-a1 (NF-a1) promoter and activates the transcription of NF-a1 mRNA which is then translated to the protein. NF-a1 is the secreted, binds to a cognate receptor and activates the extracellular signal-regulated kinases (ERK) pathway. This in turn enhances the expression of the pro-survival protein, B-cell lymphoma 2 (BCL-2) and inhibition of caspase 3 (Csp-3) to mediate neuroprotection under oxidative stress. Akt, protein kinase B (PKB).

Rosiglitazone, a member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARgamma). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARgamma nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPARgamma- responsive genes also participate in the regulation of fatty acid metabolism

Rosiglitazone acts principally by increasing insulin sensitivity in target tissues, as well as decreasing hepatic gluconeogenesis. Rosiglitazone is a peroxisome proliferator-activated receptorgamma (PPARgamma) agonist that increases transcription of insulin-responsive genes and increases insulin sensitivity. Rosiglitazone, like other thiazolidinediones, ameliorates insulin resistance associated with type diabetes mellitus without stimulating insulin release from pancreatic beta cells, thus avoiding the risk of hypoglycemia. Because rosiglitazone does not lower glucose concentrations below euglycemia, the drug is appropriately referred to as an antidiabetic agent rather than a hypoglycemic agent. Some evidence suggests that the glucoregulatory effects of thiazolidinediones are mediated in part via reduced systemic and tissue lipid availability. Circulating concentrations of insulin and C-peptide are reduced during rosiglitazone therapy.

3-4 hours (single oral dose, independent of dose)

The elimination half-life of rosiglitazone was 3-4 hours and was independent of dose. The time to Cmax and the elimination half-life for two metabolites in plasma were significantly longer than for rosiglitazone itself (4-6 hours versus 0.5-1 hours, and about 5 days versus 3-7 hours).

The plasma half life of (14)C-related material ranged from 103 to 158 hours.

Hepatic. Rosiglitazone is extensively metabolized in the liver to inactive metabolites via N-demethylation, hydroxylation, and conjugation with sulfate and glucuronic acid. In vitro data have shown that Cytochrome (CYP) P450 isoenzyme 2C8 (CYP2C8) and to a minor extent CYP2C9 are involved in the hepatic metabolism of rosiglitazone.

The main metabolites observed in humans are also observed in rats; however, the clearance in rats was almost ten times higher than in humans, probably due to the higher levels of CYP2C in rat microsomes.

In vitro data demonstrate that rosiglitazone is predominantly metabolized by Cytochrome P450 (CYP) isoenzyme 2C8, with CYP2C9 contributing as a minor pathway.

Rosiglitazone is extensively metabolized with no unchanged drug excreted in the urine. The major routes of metabolism were N-demethylation and hydroxylation, followed by conjugation with sulfate and glucuronic acid. All the circulating metabolites are considerably less potent than parent and, therefore, are not expected to contribute to the insulin-sensitizing activity of rosiglitazone.

Rosiglitazone has known human metabolites that include ortho-hydroxyrosiglitazone, para-hydroxyrosiglitazone, and N-Desmethylrosiglitazone.

05V02F2KDG

ROSIGLITAZONE

Established Pharmacologic Class [EPC] - Peroxisome Proliferator Receptor gamma Agonist

Mechanisms of Action [MoA] - Peroxisome Proliferator-activated Receptor gamma Agonists

Established Pharmacologic Class [EPC] - Thiazolidinedione

Chemical Structure [CS] - Thiazolidinediones

The absolute bioavailability of rosiglitazone is 99%. Peak plasma concentrations are observed about 1 hour after dosing. Administration of rosiglitazone with food resulted in no change in overall exposure (AUC), but there was an approximately 28% decrease in Cmax and a delay in Tmax (1.75 hours). These changes are not likely to be clinically significant; therefore, rosiglitazone may be administered with or without food. Maximum plasma concentration (Cmax) and the area under the curve (AUC) of rosiglitazone increase in a dose-proportional manner over the therapeutic dose range.

Following oral or intravenous administration of [14C]rosiglitazone maleate, approximately 64% and 23% of the dose was eliminated in the urine and in the feces, respectively.

17.6 L [oral volume of distribution Vss/F]

Oral clearance (CL) = 3.03 ± 0.87 L/hr [1 mg Fasting]

In a study in healthy volunteers, the absorption of rosiglitazone was relatively rapid, with 99% oral bioavailability after oral absorption.

Severe forms of non-alcoholic fatty liver disease (NAFLD) adversely affect the liver physiology and hence the pharmacokinetics of drugs. Here, we investigated the effect of NAFLD on the pharmacokinetics of rosiglitazone, an insulin sensitizer used in the treatment of type 2 diabetes. Male C57BL/6 mice were divided into two groups. The first group (n=14) was fed with normal chow feed and the second group (n=14) was fed with 60% high-fat diet (HFD) and 40% high fructose liquid (HFL) for 60 days to induce NAFLD. The development of NAFLD was confirmed by histopathology, liver triglyceride levels and biochemical estimations, and used for pharmacokinetic investigations. Rosiglitazone was administered orally at 30 mg/kg dose. At predetermined time points, blood was collected and rosiglitazone concentrations were determined using LC/MS/MS. Plasma concentrations were subjected to non-compartmental analysis using Phoenix WinNonlin (6.3), and the area under the plasma concentration-time curve (AUC) was calculated by the linear-up log-down method. HFD and HFL diet successfully induced NAFLD in mice. Rosiglitazone pharmacokinetics in NAFLD animals were altered significantly as compared to healthy mice. Rosiglitazone exposure increased significantly in NAFLD mice (2.5-fold higher AUC than healthy mice). The rosiglitazone oral clearance was significantly lower and the mean plasma half-life was significantly longer in NAFLD mice as compared to healthy mice. The NAFLD mouse model showed profound effects on rosiglitazone pharmacokinetics. The magnitude of change in rosiglitazone pharmacokinetics is similar to that observed in humans with moderate to severe liver disease. The present animal model can be utilized to study the NAFLD-induced changes in the pharmacokinetics of different drugs.

Antidiabetic agent

MEDICATION

Use (kg; approx.) in Germany (2009): >100

Rosiglitazone is produced by dissolving 2-N-methyl-2-pyridylaminoethanol in dim- ethylformamide and adding sodium hydroxide under atmospheric nitrogen. 4-Fluorobenzaldehyde is added. The resulting mixture is then dissolved in toluene and piperidine is added. The compound obtained is dissolved in dioxane and hydrogenated at room temperature and atmospheric pressure. Rosiglitazone is separated by filtration, vacuum concentration and recrystallization.

Preparation: R.M. Hindley, European Patent Office patent 306228; idem, United States of America patent 5002953 (1989, 1991 both to Beecham).

Table: Rosiglitazone Maleate Preparations [Table#7259]

Table: Rosiglitazone Maleate Combinations [Table#7260]