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PubMed1997

Effects of troglitazone on insulin action and cardiovascular risk factors in patients with non-insulin-dependent diabetes.

OBJECTIVE: Insulin resistance is a potential target for pharmacologic intervention in non-insulin-dependent diabetes. Troglitazone is being evaluated as an insulin enhancer in insulin resistant states. RESEARCH DESIGN AND METHODS: We randomized 40 patients with non-insulin-dependent diabetes to diet plus placebo (n = 15) or diet plus troglitazone (n = 25; 200 mg/day) treatment for 8 weeks. Fasting endogenous glucose production (EGP, by the stable isotope technique) and whole-body insulin sensitivity (by the insulin suppression test) were measured at baseline and on days 3, 7, 14, 28, and 56 of treatment. RESULTS: By day 56, fasting plasma glucose had risen from 12.0 +/- 0.9 to 12.8 +/- 1.2 mmol/L in the placebo group and had fallen from 12.4 +/- 0.6 to 11.3 +/- 0.6 mmol/L in the troglitazone group (p = 0.03). This was the result of small improvements in whole-body insulin sensitivity (steady-state plasma glucose during the insulin suppression test: from 11.09 +/- 1.1 to 10.3 +/- 0.8 mmol/L versus 13.8 +/- 1.0 to 10.0 +/- 0.9 mmol/L, placebo versus troglitazone; p = 0.01) and EGP (from 103% +/- 3% versus 96% +/- 2% of baseline, placebo versus troglitazone; p = 0.09). The time course of insulin action showed an early (first week of treatment) decrease in EGP in the troglitazone group that was maintained throughout, whereas steady-state plasma glucose levels began to diverge toward the end of treatment. The effects of insulin on plasma free fatty acid and potassium concentrations were not different between placebo and troglitazone. The cardiovascular risk profile (heart rate; serum triglycerides; total, low-density lipoprotein, and high-density lipoprotein cholesterol; proinsulin; uric acid; plasminogen activator inhibitor-1 antigen and activity; 24-hour blood pressure monitoring and urinary albumin excretion) was unaltered by troglitazone treatment. CONCLUSIONS: Troglitazone as monotherapy for typical non-insulin-dependent diabetes had a modest anti-hyperglycemic effect and, at the dose used in this study, had no effect on cardiovascular risk factors.

Administration, Oral↗
PubMed2000

Troglitazone stimulates acetyl-CoA carboxylase activity through a post-translational mechanism.

Troglitazone, a thiazolidinedione, is known to act as an insulin sensitizer. The various effects of the drug include stimulation of glucose utilization and inhibition of gluconeogenesis and fatty acid oxidation. We studied the effect of troglitazone treatment on rat liver acetyl-CoA carboxylase (ACC), the key enzyme that catalyzes the formation of malonyl-CoA, the rate-limiting step in the synthesis of long chain fatty acids. Treatment of rats with troglitazone for 18 days resulted in more than 200% increase in the activity of hepatic acetyl-CoA carboxylase (1.01+/-0.14 and 2.33+/-0.28 mU/mg supernatant protein for control and troglitazone-treated rats, respectively) (p<0.001). The expression of acetyl-CoA carboxylase mRNA, as studied by RNAse protection assay, was not significantly different between the two groups of animals. The ACC from control and troglitazone-treated groups was purified by avidin-affinity chromatography. The purified enzyme migrated as a major protein band (Mr 262,000) on SDS-polyacrylamide gels. Troglitazone treatment was associated with increased citrate sensitivity of ACC. The specific activity of the purified preparation in troglitazone-treated rats was increased by 67% (2.5 vs. 1.5 U/mg). Quantitation of alkali-labile phosphate content of the purified preparation revealed 5.66+/-0.17 and 6.29+/-0.13 mol Pi/mol subunit of 262 Kda for control and troglitazone-treated rats, respectively (P<0.01). The subtle increase in phosphate content does not explain the observed activation of the enzyme. It is possible that additional mechanisms such as troglitazone related rearrangement of the occupancy of select phosphate binding sites or altered binding of the biotin cofactor may also contribute to the observed activation of ACC.

Acetyl-CoA Carboxylase↗
PubMed2003

Acute effects of troglitazone and nitric oxide on glucose uptake in L929 fibroblast cells.

The thiazolidinedione class of antidiabetic drugs, including troglitazone, has an insulin-sensitizing effect for patients with type 2 diabetes. However, in some tissues, studies have shown that troglitazone also has an acute insulin-independent effect on glucose uptake. To determine the extent of this acute action of troglitazone, the effect of troglitazone on 2-deoxyglucose (2DG) uptake in L929 fibroblast cells was measured. Troglitazone stimulated 2DG uptake in a dose dependent manner with a maximum stimulation of >300% at 5-10 microM. In addition, nitric oxide has been shown to stimulate glucose uptake in peripheral muscle tissue. Therefore, the effect of nitric oxide on 2DG uptake in L929 cells was also investigated using the nitric oxide donor, sodium nitroprusside (SNP). SNP stimulated 2DG uptake by >200% with a maximally effective concentration of 5 mM. The combined effect of maximally effective concentrations of both stimulants (10 microM troglitazone + 5 mM SNP) was not additive suggesting a shared pathway for 2DG uptake. However, the nitric oxide synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA, 50 microM) had no effect on troglitazone stimulated 2DG uptake, indicating that the troglitazone and nitric oxide pathways converge after nitric oxide production. In addition, 12.5 microM dantrolene was shown to have no effect on either troglitazone or SNP stimulated 2DG uptake suggesting that these stimulatory effects are independent of changes in calcium ion concentrations. These data provide important evidence for the acute regulation of glucose transport through GLUT 1 transporters.

Animals↗
PubMed2002

Troglitazone improves GLUT4 expression in adipose tissue in an animal model of obese type 2 diabetes mellitus.

Troglitazone has been shown to improve peripheral insulin resistance in type 2 diabetic patients and animal models. We examined the effect of troglitazone on the expression of glucose transporter 4 (GLUT4) in muscle and adipose tissue from Otsuka Long-Evans Tokushima Fatty (OLETF) rat, an animal model of obese type 2 diabetes mellitus. In addition, the effects of troglitazone on GLUT4 translocation and on glucose transport activity in adipocytes were also evaluated. Muscle and adipose tissues were isolated from 35-week-old male troglitazone-treated and untreated OLETF rats at a dose of 150 mg/kg per day for 14 days. In skeletal muscle, the protein and mRNA levels of GLUT4 were not significantly different between OLETF and control rats and they were not affected by troglitazone. On the other hand, GLUT4 protein and mRNA levels in adipose tissue from OLETF rats were significantly decreased (P<0.01) compared with control rats and they were significantly increased (1.5-fold, P<0.01) by troglitazone. Troglitazone had no major effect on GLUT4 translocation in adipocytes, but it significantly increased (1.4-fold, P<0.05) the basal and insulin-induced amounts of GLUT4 in plasma membrane (PM) in adipocytes from OLETF rats. Consistent with these results, the basal and insulin-induced glucose uptakes in adipocytes from troglitazone-treated OLETF rats were significantly increased (1.5-fold, P<0.05) compared with untreated OLETF rats. Our results suggest that troglitazone may exert beneficial effects on insulin resistance by increasing the expression of GLUT4 in adipose tissue.

Adipose Tissue↗
PubMed1999

Troglitazone. Is it all over?

In January 1997 a drug from a new pharmacological class, the thiazolidinediones, became available: troglitazone. Troglitazone indirectly enhances peripheral insulin sensitivity. In this way it lowers the levels of both glucose and insulin. Troglitazone also has a lowering effect on the levels of triglycerides. In clinical trials only mild side effects had been observed. Therefore, troglitazone seemed a promising drug. Recently, however, it became clear that troglitazone could cause liver dysfunction in some patients. Although this side effect is reversible in most cases, six deaths have been described due to liver damage. Troglitazone was to be introduced in Europe in 1998 but registration procedures and clinical trials have been stopped because of its side effects on the liver. In the United States and Japan troglitazone is still being used, albeit with extra precautions. Troglitazone is a valuable addition to the arsenal of antidiabetic drugs for type 2 diabetes. It can be particularly useful, both as an additive and as a replacement, in patients for whom metformin is not suitable because of contraindications or side effects. The risk of severe liver dysfunction is a reason to reserve troglitazone as a second-line drug.

Animals↗
PubMed2001

Combined effects of troglitazone and muscle contraction on insulin sensitization in Balb-c mouse muscle.

Thiazolidinediones, represented by troglitazone, are insulin-sensitizing agents with proven efficacy for the treatment of type 2 diabetes. Exercise is also recommended for patients with type 2 diabetes because it both stimulates glucose uptake directly and it increases insulin sensitivity following exercise. The purpose of this study was to investigate the effects of troglitazone combined with exercise on 2-deoxyglucose (2DG) uptake in both the epitrochlearis and soleus muscle of Balb-c mice. Acute, 1-h treatment with troglitazone (10 or 20 microM), in the presence or absence of insulin, had no effect on 2DG uptake in either muscle. Chronic treatment with troglitazone by feeding enhanced the insulin sensitivity and responsiveness of 2DG uptake primarily in the epitrochlearis. Direct electrical stimulation of in situ muscle was used to model exercise while the contralateral muscle was used as the unexercised control. This model mimicked exercise in that glycogen was depleted, immediate 2DG uptake was enhanced, and there was a post-exercise increase in insulin sensitivity. Troglitazone feeding had no effect on 2DG uptake in the soleus when measured immediately after electrical stimultion. However, 2DG uptake in the unstimulated epitrochlearis from troglitazone-fed mice was elevated when measured immediately after removal such that no additional effects of the electrical stimulation were measured. We found that the insulin-sensitizing effect of troglitazone was not additive to the insulin-sensitizing effect of exercise, which suggests that troglitazone and exercise share similar pathways. A unique finding in this study was the differential response to troglitazone between the epitrochlearis (fast twitch) and the soleus (slow twitch) muscle types. Possible mechanisms are discussed.

Animals↗
PubMed2000

Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus: a serial intravascular ultrasound study.

OBJECTIVES: The aim of the present study was to determine whether troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus (NIDDM). BACKGROUND: Increased in-stent restenosis in patients with diabetes mellitus is due to accelerated neointimal tissue proliferation after coronary stent implantation. Troglitazone inhibits intimal hyperplasia in experimental animal models. METHODS: We studied 62 stented lesions in 52 patients with plasma glucose levels (PG) > or = 11.1 mmol/liter at 2 h after 75 g oral glucose load. The study patients were randomized into two groups: the troglitazone group of 25 patients with 29 stents, who were treated with 400 mg of troglitazone, and the control group of 27 patients with 33 stents. All patients underwent oral glucose tolerance tests before and after their six-month treatment period. The sum of PG (sum of PG) and the sum of insulin levels (sum of IRI) were measured. Serial (postintervention and at six-month follow-up) intravascular ultrasound studies were performed. Cross-sectional images within stents were taken at every 1 mm, using an automatic pullback. Stent areas (SA), lumen areas (LA), and intimal areas (IA = SA - LA) were measured and averaged over a number of selected image slices. The intimal index was calculated as intimal index = averaged IA/averaged SA x 100%. RESULTS: There were no differences between the two groups before treatment in sum of PG (31.35 +/- 3.07 mmol/liter vs. 32.89 +/- 4.87 mmol/liter, respectively, p = 0.2998) and sum of IRI (219.6 +/- 106.2 mU/liter vs. 209.2 +/- 91.6 mU/liter, respectively, p = 0.8934). However, reductions in sum of PG at the six-month follow-up in the troglitazone group were significantly greater than those in the control group (-21.4 +/- 8.8% vs. -4.5 +/- 7.4%, respectively, p < 0.0001). Likewise, decreases in sum of IRI were greater in the troglitazone-treated group (-31.4 +/- 17.9% vs. -1.9 +/- 15.1%, respectively, p < 0.0001). Although, there were no differences between the two groups in SA at postintervention (7.4 +/- 2.2 mm2 vs. 7.3 +/- 1.7 mm2, respectively, p = 0.9482) and at follow-up (7.3 +/- 2.3 mm2 vs. 7.3 +/- 1.8 mm2, respectively, p = 0.2307), the LA at follow-up in the troglitazone group was significantly greater than that in the control group (5.3 +/- 1.7 mm2 vs. 3.7 +/- 1.7 mm2, respectively, p = 0.0002). The IA at follow-up in the troglitazone group was significantly smaller than that in the control group (2.0 +/- 0.9 mm2 vs. 3.5 +/- 1.8 mm2, respectively, p < 0.0001). This was also true for intimal index (27.1 +/- 11.5% vs. 49.0 +/- 14.4%, respectively, p < 0.0001). CONCLUSIONS: Serial intravascular ultrasound assessment shows that administration of troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with NIDDM.

Cell Division↗
PubMed1995

Effect of troglitazone, a new oral antidiabetic agent, on fructose-induced insulin resistance.

Troglitazone, a newly developed oral antidiabetic agent, improves hyperglycemia, and has been reported to improve insulin resistance and to decrease hepatic glucose production in diabetic animals. However, the exact mechanism of Troglitazone on the improvement of insulin resistance is not known. Chronic administration of fructose to normal rats leads to hyperglycemia, and hyperinsulinemia; it induces insulin resistance. To reveal the mechanism of Troglitazone, we studied the effect of Troglitazone on serum glucose and insulin in the fructose-induced, insulin-resistant rats. Male Sprague-Dawley (SD) rats were fed either on standard chow or one containing fructose. Troglitazone was administrated as a food admixture (150 mg/kg/day) for 8 weeks. The rats were fed on (1) standard chow, (2) standard chow and Troglitazone, (3) fructose-enriched chow, or (4) fructose-enriched chow and Troglitazone. Blood samples were obtained every two weeks, and the levels of serum glucose and insulin were measured. Fructose-enriched chow increased serum glucose and insulin levels and insulin-to-glucose ratios. Troglitazone improved the fructose-induced increases in serum glucose, insulin levels, and insulin/glucose ratios. In conclusion, Troglitazone improved the fructose-induced insulin resistance.

Aging↗
PubMed2000

Effect of troglitazone on cytochrome P450 enzymes in primary cultures of human and rat hepatocytes.

1. Troglitazone was the first thiazolidinedione approved for clinical use in the treatment of non-insulin-dependent diabetes mellitus. During clinical investigations of drug-drug interactions with therapeutics (terfenadine and cyclosporine) known to be metabolized by CYP3A4, pharmacokinetic interactions were noted upon troglitazone multiple-dose treatments. The nature of the interactions suggested induction of CYP3A enzymes. 2. Primary cultures of human hepatocytes were used to investigate the induction potential of troglitazone with respect to CYP3A4, CYP2B6 and CYP1A1/2. In human hepatocytes, troglitazone induced both immunoreactive CYP3A4 protein and testosterone 6beta-hydroxylase activity in a dose-dependent fashion (EC50 = 5-10 microM), accompanied by an increase in CYP3A4 mRNA. The capacity of troglitazone to induce CYP3A4 was between that of rifampin (EC50 = 0.8 microM) and dexamethasone (40-50 microM). Troglitazone increased CYP2B6 immunoreactive protein but did not significantly effect CYP1A1/2 activity, immunoreactive protein or mRNA. 3. Troglitazone produced significant increases in CYP3A message, protein and activity in primary rat hepatocytes, a slight increase in CYP2B1/2 activity and no change in CYP1A1/2 message or activity. 4. These results provide evidence that troglitazone can induce CYP3A and CYP2B enzymes while apparently not altering CYP1A. This provides a rationale for the clinically observed interactions of troglitazone with selected CYP3A4 substrates.

Animals↗
PubMed2006

Troglitazone-induced hepatic necrosis in an animal model of silent genetic mitochondrial abnormalities.

Troglitazone, a first-generation thiazolidinedione antidiabetic drug, was withdrawn from the market due to an unacceptable risk of idiosyncratic hepatotoxicity. Troglitazone does not cause hepatotoxicity in normal healthy rodents, but it produces mitochondrial injury in vitro at high concentrations. The aim of this study was to explore whether genetic mitochondrial abnormalities might sensitize mice to hepatic adverse effects of troglitazone. We used heterozygous superoxide dismutase 2 (Sod2(+/-)) mice as a model of clinically silent mitochondrial stress. Troglitazone was daily administered for 4 weeks (0, 10 or 30 mg/kg/day, ip). We found that troglitazone caused overt liver injury in the high-dose group, manifested by increased serum alanine aminotransferase activity (> twofold) and midzonal areas of hepatic necrosis, in Sod2(+/-) but not in wild-type mice. No signs of hepatotoxicity were apparent at 2 weeks of treatment. Hepatic mitochondria isolated from troglitazone-treated mice exhibited decreased activities of aconitase (by 45%) and complex I (by 46%) and increased (by 58%) protein carbonyls, indicative of enhanced mitochondrial oxidant stress. This was paralleled by compensatory increases in mitochondrial glutathione levels. Finally, in hepatocytes isolated from untreated Sod2(+/-), but not wild-type mice, troglitazone caused a concentration-dependent increase in superoxide anion levels as demonstrated with a selective mitochondria-targeting fluorescent probe. In conclusion, prolonged administration of troglitazone can superimpose oxidant stress, potentiate mitochondrial damage, and induce delayed hepatic necrosis in mice with genetically compromised mitochondrial function. These data are consistent with our hypothesis that inherited or acquired mitochondrial abnormalities may be one of the contributing determinants of susceptibility to troglitazone-induced idiosyncratic liver injury.

Aconitate Hydratase↗
PubMed2000

Effect of troglitazone on exocrine pancreas in rats with streptozotocin-induced diabetes mellitus.

Abnormality of pancreatic exocrine secretion has been observed in patients with diabetes mellitus. Troglitazone is a novel insulin-sensitizing agent that improves hyperglycemia and hyperinsulinemia in insulin-resistant diabetes mellitus. We investigated the effect of troglitazone on exocrine pancreas in streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced by intraperitoneal injection of STZ (25 mg/kg), and then 0.2% troglitazone containing rat chow was given for 2 weeks. Control diabetic animals received normal rat chow for 2 weeks. Glucose tolerance tests were performed before and after the administration of troglitazone. Pancreas weight, enzyme, protein, and insulin contents in the pancreas were measured. For the exocrine secretory study, pure pancreatic juice was collected hourly. Plasma glucose concentrations stimulated by the oral administration of 2.5 g/kg glucose in the troglitazone-treated group were significantly lower than those in the control group, but not plasma insulin concentrations. Pancreas weight in diabetic rats was less than that in normal rats. Administration of troglitazone resulted in a significant increase in pancreas weight and amylase and trypsin output. However, protein and insulin contents were not affected by the treatment with troglitazone. Both basal and cholecystokinin (CCK-8; 26 pmol/kg/h) stimulated exocrine secretion in juice volume, amylase, and trypsin output were markedly decreased in diabetic rats, compared with those in normal rats. Impaired basal and CCK-stimulated pancreatic exocrine secretion in diabetic rats recovered to the normal levels when troglitazone was given. In conclusion, troglitazone might be effective to restore exocrine pancreatic insufficiency in STZ-diabetic rats.

Animals↗
PubMed2004

Troglitazone inhibits the progression of chronic pancreatitis and the profibrogenic activity of pancreatic stellate cells via a PPARgamma-independent mechanism.

We have previously reported that troglitazone inhibits proinflammatory cytokine production in chronic pancreatitis. In the present study, we show that troglitazone prevents the progression of chronic pancreatitis by inhibiting the proliferation of pancreatic stellate cells (PSCs) via a PPARgamma-independent mechanism. WBN/Kob rats with spontaneous chronic pancreatitis were fed troglitazone-containing rat chow for 3 or 6 months. Pancreatic fibrosis and expression of alpha-SMA were markedly attenuated by troglitazone. Rat PSCs expressed a higher level of PPARgamma1 mRNA than of PPARgamma2 mRNA. PSCs were transiently cotransfected with a dominant negative mutant PPARgamma1 and a PPAR-driven reporter gene. Troglitazone increased reporter activity and the mutant receptor abrogated wild-type receptor activity in a dose-dependent manner. Troglitazone inhibited cell proliferation by blocking cell-cycle progression beyond the G1 phase. These effects were observed in mutant receptor-transfected cells as well as cells transfected with the control vector. The effect of troglitazone on alpha1(I) procollagen mRNA and MCP-1 mRNA was unaffected by inhibition of endogenous PPARgamma1 receptor activity. These results suggest that troglitazone may serve as novel therapeutic agent for the treatment of chronic pancreatitis. The antifibrotic effect of troglitazone appears to be mediated, in part, via a PPARgamma-independent mechanism.

Actins↗
PubMed1998

Synergistic actions of insulin and troglitazone on contractility in endothelium-denuded rat aortic rings.

Insulin attenuates vascular contraction via inhibition of voltage-operated Ca2+ channels and by enhancement of endothelium-dependent vasodilation. Thus it has been suggested that hypertension-associated insulin resistance results from an insensitivity to the hormone's effects on vascular reactivity. This hypothesis has been strengthened by reports that thiazolidinediones, a class of insulin-sensitizing agents, lower blood pressure and improve insulin responsiveness in hypertensive, insulin-resistant animal models. We tested the hypothesis that troglitazone enhances the vasodilating effect of insulin via inhibition of voltage-operated Ca2+ channels in vascular smooth muscle cells. Rat thoracic aortic rings (no endothelium) were suspended in tissue baths for isometric force measurement. Rings were incubated with 0.1 DMSO vehicle (control), troglitazone (10(-5) M), insulin (10(-7) U/l), or both troglitazone and insulin (1 h) and then contracted with phenylephrine (PE), KCl, or BAY K 8644. Troglitazone increased the EC50 values for PE and KCl. Contractions to BAY K 8644 in troglitazone-treated rings were virtually abolished. Insulin alone had no effect on contraction. However, when insulin was combined with troglitazone, the EC50 values for PE and KCl were further increased. Additionally, the maximum contractions to both PE (14 +/- 4% of control) and KCl (12 +/- 2% of control) were reduced. Measurement of Ca2+ concentration ([Ca2+]) with fura 2-AM in dispersed vascular smooth muscle cells indicated that neither insulin nor troglitazone alone altered PE-induced increases in intracellular [Ca2+]. However, troglitazone and insulin together caused a significant reduction in PE-induced increases in intracellular [Ca2+] (expressed as percentage of preincubation stimulation to PE: 47 +/- 10%, treated; 102 +/- 13%, vehicle). These results demonstrate that troglitazone inhibits Ca2+ influx and that it acts synergistically with insulin to attenuate further vascular contraction via inhibition of voltage-operated Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2003

Troglitazone acts by PPARgamma and PPARgamma-independent pathways on LLC-PK1-F+ acid-base metabolism.

Troglitazone was studied in pH-sensitive LLC-PK1-F+ cells to determine the effect on pHi and glutamine metabolism as well as the role of peroxisome proliferator-activated receptor (PPARgamma)-dependent and PPARgamma-independent signaling pathways. Troglitazone induces a dose-dependent cellular acidosis that occurs within 4 min and persists over 18 h as a result of inhibiting Na+/H+ exchanger-mediated acid extrusion. Cellular acidosis was associated with glutamine-dependent augmented [15N]ammonium production and decreased [15N]alanine formation from 15N-labeled glutamine. The shift in glutamine metabolism from alanine to ammoniagenesis appears within 3 h and is associated after 18 h with both a reduction in assayable alanine aminotransferase (ALT) activity as well as cellular acidosis. The relative contribution of troglitazone-induced cellular acidosis vs. the decrease in assayable ALT activity to alanine production could be demonstrated. The PPARgamma antagonist bisphenol A diglycide ether (BADGE) reversed both the troglitazone-induced cellular acidosis and ammoniagenesis but enhanced the troglitazone reduction of assayable ALT activity; BADGE also blocked troglitazone induction of peroxisome proliferator response element-driven firefly luciferase activity. The protein kinase C (PKC) inhibitor chelerythrine mimics troglitazone effects, whereas phorbol ester reverses the effects on ammoniagenesis consistent with troglitazone negatively regulating the DAG/PKC/ERK pathway. Although functional PPARgamma signaling occurs in this cell line, the major troglitazone-induced acid-base responses appear to be mediated by pathway(s) involving PKC/ERK.

Acid-Base Equilibrium↗
PubMed2001

Interactions between simvastatin and troglitazone or pioglitazone in healthy subjects.

Two randomized, two-period crossover studies were conducted to evaluate the effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG-CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plasma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of once-daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg (Study II) for 24 days with coadministration of once-daily doses of simvastatin 40 mg (Study I) or 80 mg (Study II) on Days 15 through 24. Treatment B consisted of once-daily oral doses of simvastatin 40 mg (Study I) or 80 mg (Study II) for 10 days. In Study I, the area under the plasma concentration-time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG-CoA reductase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by approximately 30% for Cmax and approximately 40% for AUC), but time to reach Cmax (tmax) did not change, as compared with those who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or tmax (p > 0.5) but caused a small but clinically insignificant increase (approximately 25%) in Cmax for troglitazone. In Study II, pioglitazone, at the highest approved dose for clinical use, did not significantly alter any of the pharmacokinetic parameters (AUC, Cmax, and tmax) of simvastatin HMG-CoA reductase inhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either troglitazone or pioglitazone was well tolerated. The modest effect of troglitazone on simvastatin pharmacokinetics is in agreement with the suggestion that troglitazone is an inducer of CYP3A. The insignificant effect of simvastatin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug-metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely.

Administration, Oral↗
PubMed1998

Troglitazone increases system A amino acid transport in 3T3-L1 cells.

System A is one of the most highly regulated transport systems for transport of neutral amino acids into mammalian cells. Stimulation of uptake of alpha-[3H]methylaminoisobutyric acid (MeAIB), a nonmetabolizable system A substrate, by a novel insulin-sensitizing agent, troglitazone, in 3T3-L1 adipocytes was investigated. Treating adipocytes with troglitazone alone resulted in a time- and dose-dependent increase in the uptake of MeAIB. The peak stimulation appeared about 24 h after troglitazone addition. Both troglitazone- and insulin-stimulated transport activities increased markedly after the induction of differentiation of preadipocytes into adipocytes, and declined to a steady state level in adipocytes. The stimulated MeAIB uptake exhibited substrate specificity typical of system A and was mediated by a single component as determined by Eadie-Hofstee plots. The stimulation by troglitazone and that by insulin were similarly sensitive to actinomycin D and cycloheximide, suggesting that both agents may induce de novo synthesis of the same type of system A transport. Apart from the insulin-independent effect, troglitazone also showed an insulin-dependent action characterized by enhanced sensitivity to insulin. The synergistic stimulation of MeAIB uptake by coadministration of insulin and troglitazone was most prominent at the early stages of adipocyte differentiation. Pretreating cells with troglitazone during the differentiation attenuated the sensitivity of insulin to inhibition by actinomycin D, suggesting that troglitazone may enhance the insulin action by stabilizing messenger RNA involved in system A function.

3T3 Cells↗
PubMed2003

Troglitazone induces CYP3A4 activity leading to falsely abnormal dexamethasone suppression test.

After evaluating a patient who appeared to have a falsely abnormal response to the dexamethasone suppression test while taking troglitazone, we examined the effects of troglitazone on the activity of hepatic CYP3A4 and the screening tests for Cushing's syndrome. We studied five healthy women and three healthy men, aged 25 +/- 2 yr, before and after treatment with troglitazone (600 mg daily) for 28 d. Baseline 0800 h cortisol and corticosterone were similar before and after troglitazone treatment. Before troglitazone treatment, all subjects suppressed 0800 h cortisol below 1.8 micro g/dl (mean, 0.66 +/- 0.08 micro g/dl) during the 1-mg overnight dexamethasone suppression test (DST), whereas during troglitazone treatment none of the subjects suppressed 0800 h cortisol below 1.8 micro g/dl (mean, 9.0 +/- 1.8 micro g/dl). Serum dexamethasone levels decreased by 66 +/- 4%, and the erythromycin breath test measurements increased by 27 +/- 8%, indicating increased CYP3A4 activity during troglitazone treatment. The hydrocortisone suppression test (HST) was performed by administering 50 mg hydrocortisone at 2300 h. Using the criterion of suppression of 0800 h plasma corticosterone by more than 50%, the specificity of the HST was 100% both before and after troglitazone treatment. In conclusion, troglitazone induced the activity of CYP3A4 leading to falsely abnormal DST. HST is a useful alternative to the DST in patients taking medications that increase the activity of CYP3A4.

Adult↗
PubMed1998

Troglitazone: review and assessment of its role in the treatment of patients with impaired glucose tolerance and diabetes mellitus.

OBJECTIVE: To introduce troglitazone (CS-045, Rezulin), a new oral antidiabetic agent and discuss its pharmacology, therapeutics, pharmacokinetics, dosing guidelines, adverse effects, drug interactions, and clinical efficacy. DATA SOURCES: A MEDLINE database search was completed to identify relevant articles including reviews, recent studies and abstracts, and data from Parke-Davis. STUDY SELECTION: Due to the small number of published human studies available, some data are derived from animal studies and abstracts of human studies. Studies and abstracts chosen summarize the clinical action of troglitazone in healthy volunteers, in subjects with impaired glucose tolerance, and in patients with diabetes mellitus. Three of the six published human studies used subjects in a placebo-controlled, multicenter, randomized environment (type 2 diabetic patients or obese subjects with insulin resistance). DATA EXTRACTION: All clinical trials available, including unpublished reports, were reviewed. DATA SYNTHESIS: Troglitazone is the first member of a new class of medications, the thiazolidinediones, to be approved for clinical use. Troglitazone increases insulin sensitivity in skeletal muscle and in hepatic and adipose tissue. It has been shown to decrease hepatic glucose output while having no effect on stimulating insulin secretion from the pancreatic beta-cells. Its metabolic effects decrease fasting and postprandial hyperglycemia, insulin concentrations, and triglyceride concentrations, while increasing high-density lipoprotein concentrations. There is some evidence, based on short-term trials, that troglitazone causes only minimal decreases in glycosylated hemoglobin A1C (HbA1C) concentrations. Data suggest that troglitazone decreases impaired glucose tolerance in nondiabetic obese subjects and leads to a reduction in both systolic and diastolic blood pressure in hypertensive type 2 diabetes mellitus patients. Troglitazone has a mild adverse effect profile, with rare instances of abnormal liver function tests. CONCLUSIONS: Troglitazone appears to be a safe, effective, and useful new agent in the treatment of insulin-requiring type 2 diabetes mellitus patients, although its HbA1C-lowering effects have been minimal in short-term trials, and its insulin dosage-reduction activity remains unclear. The Food and Drug Administration has also approved its use as monotherapy and in combination with sulfonylureas for patients with type 2 diabetes. It may have use in the treatment of patients with impaired glucose tolerance, but more clinical experience is needed before definitive conclusions can be made. The role of troglitazone therapy in diabetes mellitus and impaired glucose intolerance will continue to evolve as the results of studies and our clinical experience with this agent become available.

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