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PubMed2001

Troglitazone-induced intrahepatic cholestasis by an interference with the hepatobiliary export of bile acids in male and female rats. Correlation with the gender difference in troglitazone sulfate formation and the inhibition of the canalicular bile salt export pump (Bsep) by troglitazone and troglitazone sulfate.

Troglitazone is a thiazolidinedione insulin sensitizer drug for the treatment of type 2 non-insulin-dependent diabetes mellitus (NIDDM). Based on an increasing number of reports on troglitazone-associated liver toxicity, the cholestatic potential of troglitazone and its major metabolite troglitazone sulfate has been investigated. In isolated perfused rat livers troglitazone (10 microM) reduced the bile flow by 25% (female) to 50% (male) within 60 min. After single intravenous administrations of troglitazone to rats of both genders, rapid and dose-dependent increases in the plasma bile acid concentrations were observed, with male rats being more sensitive than female rats. In male rat liver tissue fivefold higher troglitazone sulfate levels were measured as compared to female rat liver tissue. This difference was due to the formation rate of troglitazone sulfate, which was four times faster in cytosolic fractions of male rat liver as compared to female rat liver (Clint=132 and 35 microl min(-1) mg(-1), respectively). Troglitazone sulfate strongly inhibited the ATP-dependent taurocholate transport mediated by the canalicular bile salt export pump (Bsep) in isolated canalicular rat liver plasma membrane preparations of both genders (IC(50) value of 0.4-0.6 microM), while troglitazone was 10 times less potent (IC(50) values of 3.9 microM). This high Bsep inhibition potential and the efficient formation and accumulation of troglitazone sulfate in liver tissue, suggested that troglitazone sulfate was mainly responsible for the interaction with the hepatobiliary export of bile acids at the level of the canalicular Bsep in rats. Such an interaction might lead potentially also in man to a troglitazone-induced intrahepatic cholestasis, potentially contributing to the formation of troglitazone-induced liver injuries.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity: in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat.

Troglitazone is a thiazolidinedione insulin sensitizer drug for the treatment of type 2 non-insulin-dependent diabetes mellitus (NIDDM). Based on an increasing number of reports on troglitazone-associated liver toxicity, the cholestatic potential of troglitazone has been investigated. Rapid and dose-dependent increases in the plasma bile acid concentrations were observed in rats after a single intravenous administration of troglitazone. A radiolabeled taurocholic acid tracer accumulated in liver tissue, indicating an interference with the hepatobiliary export of bile acids. In isolated canalicular rat liver plasma membrane preparations, troglitazone competitively inhibited the ATP-dependent taurocholate transport (apparent K(i) value, 1.3 microM), mediated by the canalicular bile salt export pump (Bsep). Troglitazone sulfate, the main troglitazone metabolite eliminated into bile, also showed competitive Bsep inhibition with an apparent K(i) value of 0.23 microM. A comparable inhibition was observed for both compounds in canalicular plasma membrane vesicles prepared from Mrp2-deficient (TR(-)) rats, suggesting a direct (cis-) inhibition of Bsep by troglitazone and troglitazone sulfate. A high accumulation potential was observed for troglitazone sulfate in rat liver tissue, indicating that the hepatobiliary export of this conjugated metabolite might represent a rate-limiting step in the overall elimination process of troglitazone. This accumulation in combination with the high Bsep inhibition potential suggested that mainly troglitazone sulfate was responsible for the interaction with the hepatobiliary export of bile acids at the level of the canalicular Bsep in rats. Such an interaction might lead to a troglitazone-induced intrahepatic cholestasis in humans as well, contributing to the formation of a troglitazone-induced liver toxicity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group.

The effects of troglitazone, a novel thiazolidinedione, in non-insulin-dependent diabetic (NIDDM) patients were studied in a double-blind, parallel-group, placebo-controlled, dose-ranging trial. A total of 330 patients (63% male), mean age 57 years (range 39-72), with two fasting capillary blood glucose values > or = 7 and < or = 15 mmol/l (within 2.5 mmol/l of each other) were randomised to treatment with placebo or troglitazone at doses of 200, 400, 600 or 800 mg once daily, or 200 or 400 mg twice daily, for 12 weeks. Prior to the study, treatment had been with diet alone (38% patients) or with oral hypoglycaemic agents which were stopped 3-4 weeks before study treatment started. During treatment, HbA1c tended to rise in patients taking placebo (7.2-8.0%), but remained unchanged with all doses of troglitazone. After 12 weeks of treatment, HbA1c was significantly lower in the troglitazone-treated (mean 7.0-7.4%) compared to the placebo-treated (8.0%) patients (p = 0.055 to < 0.001), as was fasting serum glucose concentration (troglitazone, 9.3-11.0 mmol/l vs placebo, 12.9 mmol/l, p < 0.001). All doses of troglitazone were equally effective. Troglitazone also lowered fasting plasma insulin concentration, by 12-26% compared to placebo (p = 0.074 to < 0.001). Insulin sensitivity assessed by homeostasis model assessment (HOMA) was greater after 12 weeks of treatment in troglitazone-treated patients (troglitazone, 34.3-42.8% vs placebo, 29.9%, p < 0.05). In addition, serum triglyceride and non-esterified fatty acid concentrations were significantly lower and HDL cholesterol higher at troglitazone doses of 600 and 800 mg/day. LDL cholesterol increased at 400 and 600 mg doses only (from 4.3 and 3.9 mmol/l at baseline to 4.8 and 4.5 mmol/l, respectively at 12 weeks, p < 0.05), but not at doses of 800 mg once daily or 400 mg twice daily. LDL/HDL ratio did not change during treatment. All doses were well tolerated; incidence of adverse events in troglitazone-treated patients was no higher than in those treated with placebo. However, a tendency to reduced neutrophil counts was observed in patients taking the highest doses of troglitazone. We conclude that troglitazone is effective and well-tolerated and shows potential as a new therapeutic agent for the treatment of NIDDM.

Adult↗

PubMed1998

Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled study. The Troglitazone Study Group.

To assess the effects of troglitazone monotherapy on glycemic control in patients with type 2 diabetes mellitus, we carried out a 6-month, randomized, double-blind, placebo-controlled study in 24 hospital and outpatient clinics in the United States and Canada. Troglitazone 100, 200, 400, or 600 mg or placebo once daily with breakfast was administered to 402 patients with type 2 diabetes with fasting serum glucose (FSG) > 140 mg/dL, glycosylated hemoglobin (HbA1c) > 6.5%, and fasting C-peptide > or = 1.5 ng/mL. Prior oral hypoglycemic therapy was withdrawn in patients who received it before the study. FSG, HbA1c, C-peptide, and serum insulin were evaluated at baseline and the end of the study. Analysis was performed on two subsets of patients based on prestudy therapy: Patients treated with diet and exercise only before the study (22% of patients), and those who had been receiving sulfonylurea therapy (78% of patients). Patients treated with 400 and 600 mg troglitazone had significant decreases from baseline in mean FSG and HbA1c at month 6 compared with placebo-treated patients (FSG: -51 and -60 mg/dL, respectively; HbA1c: -0.7 and -1.1%, respectively). In the diet-only subset, 600 mg troglitazone therapy resulted in a significant (P < 0.05) reduction in HbA1c (-1.35%) and a significant reduction in FSG (-42 mg/dL) compared with placebo. Patients previously treated with sulfonylurea therapy had significant (P < 0.05) decreases in mean FSG with 200-600 mg troglitazone therapy compared with placebo (-48, -61, and -66 mg/dL, respectively). Significant (P < 0.05) decreases in mean HbA1c occurred with 400 and 600 mg troglitazone therapy at month 6 (-0.8 and -1.2%, respectively) compared with placebo in this same subset. Significant (P < 0.05) decreases in triglycerides and free fatty acids occurred with troglitazone 400 and 600 mg, and increased high-density lipoprotein occurred with 600 mg troglitazone. We conclude that troglitazone monotherapy significantly improves HbA1c and fasting serum glucose, while lowering insulin and C-peptide in patients with type 2 diabetes. Troglitazone 600 mg monotherapy is efficacious for patients who are newly diagnosed and have never received pharmacological intervention for diabetes.

Aged↗

PubMed1997

Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group.

Troglitazone is a thiazolidinedione under development for the treatment of NIDDM and potentially other insulin-resistant disease states. Treatment with troglitazone is associated with an improvement in hyperglycemia, hyperinsulinemia, and insulin-mediated glucose disposal. No significant side effects have been observed in humans. Because of reported cardiac changes in animals treated with drugs of this class, this multicenter 48-week study was conducted to evaluate whether NIDDM patients treated with troglitazone develop any cardiac mass increase or functional impairment. A total of 154 NIDDM patients were randomized to receive troglitazone 800 mg q.d. or glyburide titrated to achieve glycemic control (< or =20 mg b.i.d. or q.d.). Two-dimensional echocardiography and pulsed Doppler were used to measure left ventricular mass index (LVMI), cardiac index (CI), and stroke volume index (SVI). All echocardiograms were performed at each center (baseline, 12, 24, 36, and 48 weeks), recorded on videotape, and forwarded to a blinded central echocardiographic interpreter for analysis. The results showed that LVMI of patients treated with troglitazone was not statistically or clinically different from baseline after 24 or 48 weeks. Statistically significant increases in SVI and CI and a statistically significant decrease in diastolic pressure and estimated peripheral resistance were observed in troglitazone-treated patients. These results were not sex-specific. Glycemic benefits of troglitazone treatment were observed as evidenced by long-term improvement of HbA1c and C-peptide levels. Furthermore, triglycerides were significantly lower, and HDL was significantly higher at weeks 24 and 48. In conclusion, NIDDM patients treated with troglitazone do not show any cardiac mass increase or cardiac function impairment. Conversely, patients on troglitazone benefited from enhanced cardiac output and stroke volume, possibly as a result of decreased peripheral resistance. Treatment with troglitazone appears to have a favorable impact on known cardiovascular risk factors and could potentially lower cardiovascular morbidity in NIDDM patients.

Blood Glucose↗

PubMed1998

Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. Troglitazone and Exogenous Insulin Study Group.

BACKGROUND: Troglitazone is a new oral antidiabetic drug that increases the sensitivity of peripheral tissues to insulin. It may therefore increase the efficacy of exogenous insulin in patients with insulin-resistant diabetes mellitus. METHODS: We studied the effect of troglitazone or placebo in 350 patients with poorly controlled non-insulin-dependent (type 2) diabetes mellitus (glycosylated hemoglobin values, 8 to 12 percent; normal, 4.3 to 6.1 percent) despite therapy with at least 30 U of insulin daily. The patients were randomly assigned to receive 200 mg of troglitazone (116 patients), 600 mg of troglitazone (116 patients), or placebo (118 patients) daily for 26 weeks. Insulin doses were not increased and were reduced only to prevent hypoglycemia. Glycosylated hemoglobin, serum glucose while fasting, serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides were measured 5 times during an 8-week base-line period and 10 times during the 26-week treatment period. Daily insulin doses were recorded during both periods. RESULTS: Ninety percent of the patients completed the study. The adjusted mean glycosylated hemoglobin values decreased by 0.8 and 1.4 percentage points, respectively, in the group given 200 mg of troglitazone and the group given 600 mg of troglitazone, and fasting serum glucose concentrations decreased by 35 and 49 mg per deciliter (1.9 and 2.7 mmol per liter), respectively, despite decreases in the insulin dose of 11 percent and 29 percent (P<0.001 for all comparisons with the placebo group). Serum total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations increased slightly and serum triglyceride concentrations decreased slightly in the troglitazone-treated patients. CONCLUSIONS: When given in conjunction with insulin, troglitazone improves glycemic control in patients with type 2 diabetes mellitus.

Administration, Oral↗

PubMed2000

Intestinal absorption and excretion of troglitazone sulphate, a major biliary metabolite of troglitazone.

1. Deconjugation by sulphate transfer and intestinal absorption of troglitazone sulphate (M1), the major metabolite of a thiazolidinedione antidiabetic drug, troglitazone, were studied in the male F344 rat using 14C-troglitazone, 4C-M1 and 35S-M1. 2. Some part of M1, produced in the liver and excreted mostly in the bile, was deconjugated in the intestine to the parent compound, troglitazone, by arylsulphate sulphotransferase originated from intestinal flora. However, deconjugation of M1 was not catalyzed by arylsulphatases. Caecal injection of M1 led to the appearance of troglitazone and M1 in plasma. 3. Biliary excretion mostly as M1, and, following absorption, as M1 and troglitazone after deconjugation, were indicated as the basis for the enterohepatic circulation of troglitazone. 4. Enterohepatic circulation may prolong the pharmacological effects of troglitazone.

Animals↗

PubMed1998

Troglitazone use in insulin-treated type 2 diabetic patients. The Troglitazone Insulin Study Group.

OBJECTIVE: To determine the ability of troglitazone to reduce requirements for injected insulin while maintaining blood glucose levels in insulin-treated patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week double-blind study with open-label extension included patients who had failed previous oral antidiabetic medication and took > or =30 but <150 U of insulin daily The 222 patients in the double-blind study received 200 or 400 mg troglitazone once daily or matching placebo. The primary end point was the proportion of patients meeting the target of > or =50% reduction in injected insulin and either a 15% reduction in fasting blood glucose or a blood glucose <7.8 mmol/l. Insulin dose was reduced 25% based on a study-specific algorithm whenever fasting blood glucose was reduced 5% from baseline. Also of interest were changes in insulin dose and HbA1c. The open-label extension included 173 patients. They received 200 mg of troglitazone with optional titration to 400 mg, and insulin dose was adjusted based on investigators' standards of care. Open-label measures were change in insulin dose, HbA1c, and fasting serum glucose (FSG). RESULTS: In the double-blind phase, 22 and 27% of the 200- and 400-mg troglitazone groups, respectively, reached target, compared with placebo (7%) (P < 0.01). Insulin dose reductions of 13 +/- 3, 30 +/- 3, and 41 +/- 3 U were observed for placebo, 200-, and 400-mg troglitazone groups, respectively HbA1c decreased 0.09 +/- 0.14% for placebo, 0.13 +/- 0.14% for 200 mg, and 0.41 +/- 0.14% for 400 mg (P < 0.05) troglitazone. In the open-label extension, troglitazone treatment resulted in >50% reduction from baseline in daily insulin dose and decreases in HbA1c of 1% and in FSG of >17%. CONCLUSIONS: Troglitazone decreases daily injected insulin dose requirements and improves glycemic control in insulin-treated patients with type 2 diabetes.

Adult↗

PubMed1999

Troglitazone in combination with sulphonylurea improves glycaemic control in Type 2 diabetic patients inadequately controlled by sulphonylurea therapy alone. Troglitazone Study Group.

AIM: The aim of this study was to investigate the effectiveness of troglitazone (a peroxisome proliferator-activated receptor-gamma agonist developed primarily for the treatment of Type 2 diabetes mellitus (DM)), 100 or 200mg/day, in terms of glycaemic control, lipid profile and tolerability, when given in addition to existing sulphonylurea therapy. METHODS: A 16-week, randomized, parallel-group placebo-controlled trial in 259 Type 2 diabetic patients already on sulphonylurea therapy. RESULTS: At week 16, adjusted geometric mean HbA1c with troglitazone 100mg (7.7%; P=0.023) and 200mg (7.4%; P<0.001) was lower with sulphonylurea alone (8.2%). At all weeks, adjusted geometric mean fasting serum glucose levels were lower in both troglitazone groups, compared with sulphonylurea alone (P=0.007 to P<0.001). At week 16, both troglitazone groups showed reductions in immune reactive insulin compared with sulphonylurea alone (200mg, 13%; P=0.032: 100mg, 5%; NS). Troglitazone reduced serum levels of nonesterified fatty acids at week 16 (100 g, 12%; P=0.042) and at all weeks (200mg, 17-24%; P=0.014 to P<0.001). The incidence of drug-related adverse events was similar in all groups (23-24% of patients). There was no apparent association between hypoglycaemia and the addition of troglitazone to sulphonylurea therapy. CONCLUSIONS: Troglitazone 100 or 200 mg added to usual sulphonylurea therapy in patients with Type 2 DM is associated with a significant improvement in glycaemic control, without altering the adverse-event profile of the sulphonylurea.

Blood Glucose↗

PubMed1998

TRIPOD (TRoglitazone In the Prevention Of Diabetes): a randomized, placebo-controlled trial of troglitazone in women with prior gestational diabetes mellitus.

The TRoglitazone In the Prevention Of Diabetes (TRIPOD) trial is a single-center, randomized, placebo-controlled, double-masked study. The primary aim of the TRIPOD trial is to test the hypothesis that chronic administration of troglitazone to nondiabetic women with prior gestational diabetes mellitus (GDM) will improve whole-body insulin sensitivity and reduce the incidence of non-insulin-dependent diabetes (NIDDM). Because troglitazone is already known to lower blood glucose concentrations in persons who have developed NIDDM, an additional aim of the project will be to determine whether early intervention with troglitazone will achieve better final glycemic control than can be achieved by later intervention. In addition, since troglitazone treatment is expected to improve insulin sensitivity and may prevent or delay a decline in glucose tolerance, we also plan to determine whether long-term troglitazone treatment alters the development or progression of atherosclerosis. In this article we describe the experiment's design, the study's endpoints and methods for determining those endpoints, methods for assessing quality of life, and proposed methods for statistical analyses. The unique two-phase study design of the TRIPOD trial will permit testing not only of the biological question about reversal of insulin resistance and prevention of diabetes, but also of the clinical question about whether early intervention is superior to late intervention. Results from this trial will have an important impact on the monitoring and treatment of patients at high risk for NIDDM.

Adolescent↗

PubMed1998

Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The Troglitazone Study Group.

OBJECTIVE: To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone. RESEARCH DESIGN AND METHODS: There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed. RESULTS: Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy CONCLUSIONS: Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association.

Blood Glucose↗

PubMed2001

Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo.

Troglitazone (TGZ), a 2,4-thiazolidinedione antidiabetic, causes hepatotoxicity in 1.9% of patients. TGZ is an inducer of, and substrate for, hepatic P450 3A. Microsomal metabolism yields a benzoquinone (TGZQ) and reactive intermediates. Kassahun et al. [Kassahun et al. (2001) Chem. Res. Toxicol. 14, 62-70] have trapped the intermediates as thioester, thioether, and disulfide conjugates of glutathione and found five conjugates in rat bile. The thioether was substituted in the chromane moiety. We have investigated the effect of the P450 3A inducer, dexamethasone (DEX), on metabolism of TGZ and TGZQ in rats and assessed the compounds' cytotoxicity. TGZ-glucuronide and sulfonate were confirmed as principal biliary metabolites of TGZ (50 mg/kg, iv). Bile from noninduced animals also contained a TGZ-glutathione thioether adduct (ML3) but it was substituted in the thiazolidinedione moiety. Pretreatment with DEX (50 mg/kg/day for 3 days) resulted in a 2-5-fold increase in the biliary concentration of ML3 and a 2-fold increase in the concentration of TGZQ, which was commensurate with the induction of hepatic P450 3A. Three of the known glutathione-conjugated metabolites were also found. TGZQ (50 mg/kg, iv) was metabolized to an analogue of one of the TGZ-glutathione thioesters and a glutathione adduct of TGZQ hydroquinone after DEX pretreatment. TGZ quinol glucuronide was a biliary metabolite of TGZ and TGZQ. Its formation would represent deactivation of TGZQ. TGZ was toxic to rat hepatocytes and Hep-G2 cells at concentrations exceeding 50 and 25 microM, respectively, after 24 h. In contrast, TGZQ was nontoxic to rat hepatocytes and toxic to Hep G2 cells only at concentrations exceeding 100 microM. Our results show that TGZQ as well as TGZ yields reactive metabolites in vivo, and that bioactivation is enhanced by induction of P450 3A. However, hepatotoxicity is unlikely to be due to either TGZQ or its metabolites.

Animals↗

PubMed1997

Acute effect of troglitazone on glucose metabolism in the absence or presence of insulin in perfused rat hindlimb.

Troglitazone (CS-045) is a new type of antidiabetic agent that decreases plasma glucose by enhancing insulin action in insulin-resistant diabetic animals and non-insulin-dependent diabetes mellitus (NIDDM) patients. To examine the direct effect of troglitazone on glucose metabolism and insulin action in skeletal muscle, we infused troglitazone solution into perfused rat hindlimbs in the presence of 6 mmol/L glucose and in the absence or presence of insulin. In the absence of insulin, even 50 mumol/L troglitazone did not elicit glucose uptake. Troglitazone did increase lactate and pyruvate release at concentrations of 20 mumol/L and higher; however, it decreased the ratio of lactate to pyruvate (L/P ratio) and increased oxygen consumption at concentrations higher than 5 and 20 mumol/L, respectively. In hindlimb muscle, 20 mumol/L troglitazone decreased glycogen content without changing fructose 2,6-bisphosphate (F2,6P2) content in the absence of insulin. Insulin infusion with 250 microU/mL obtained half-maximal effects, causing a 2.8-fold increase in glucose uptake and a 1.5-fold increase in lactate and pyruvate release. When 20 mumol/L troglitazone was infused for 30 minutes together with 250 microU/mL insulin, insulin-induced glucose uptake significantly increased 30 minutes after troglitazone infusion, and this increase was further augmented after withdrawal of troglitazone. In insulin plus troglitazone infusion at 30 minutes after troglitazone removal, glycogen content in hindlimb muscle was significantly decreased compared with that obtained with insulin infusion alone. In summary, in the absence of insulin, troglitazone does not elicit glucose uptake, but causes an increase in glycolysis accompanied by a decrease in muscle glycogen content and L/P ratio and an increase in oxygen consumption. In the presence of insulin, troglitazone increases insulin-induced glucose uptake, and this increase is further augmented after troglitazone removal. Addition of troglitazone to insulin infusion decreased the glycogen content in hindlimb muscle. This decrease in muscle glycogen content may trigger an enhancement of insulin-induced glucose uptake similar to that observed during muscle contraction or epinephrine treatment.

Animals↗

PubMed1998

Concomitant administration of cholestyramine influences the absorption of troglitazone.

AIM: Troglitazone is an orally active anti-diabetic agent. Cholestyramine is an orally administered lipid-lowering agent which acts by binding to bile acids and removing them from enterohepatic circulation. Preclinical studies suggesting the potential for an interaction between troglitazone and cholestyramine require confirmation in a clinical setting. METHODS: In vitro and in vivo experiments in the dog were carried out prior to a clinical study. Twelve healthy volunteers (mean age 32 years, range 20-44 years) each received a single oral dose of troglitazone 400 mg alone and with cholestyramine 12 g (taken 1 h after troglitazone) in an open, two-way crossover study. RESULTS: In vitro, about 99% of troglitazone was adsorbed by cholestyramine at an incubate concentration of 3 microg ml(-1) whilst at 500 microg ml(-1) adsorption fell to about 90%. In vivo, AUC of troglitazone was reduced by an average of 42% (22.7 vs 12.2 microg ml(-1) h (95% CI for difference 28-57, P=0.01) in 11 beagle dogs receiving troglitazone 200 mg and cholestyramine 1 g compared with control values. Mean maximum plasma concentration (Cmax) was 49% of control values (7.08 vs 3.42 microg ml(-1) (95% CI for difference 14-85, P=0.05)). In the clinical study median AUC for troglitazone and its two major metabolites were statistically significantly lower when troglitazone was administered with cholestyramine (17.9 vs 5.2 microg ml(-1) h (95% CI for difference -20.5, -8.7), 133.7 vs 27 1 microg ml(-1) h (-166.4, -67.8) and 18.4 vs 2.5 microg ml(-1) h (-21.6, -10.6) for troglitazone, sulphate and quinone metabolite respectively (all P < 0.01) representing percentage decreases of 71, 80 and 86% respectively. A statistically significant reduction was also observed in Cmax for the sulphate metabolite (4.56 vs 1.28 microg ml(-1) (95% CI for difference -4.42, -1.99, P < 0.01)), but not for troglitazone (1.85 vs 1.23 microg ml(-1) (-1.13, 0.49) or the oxidative metabolite (0.84 vs 0.45 microg ml(-1) (-0.77, 0.09)). CONCLUSIONS: The results were indicative of an alteration in the extent of troglitazone's absorption. Concomitant administration of troglitazone and cholestyramine could severely impair troglitazone's clinical utility as an antihyperglycaemic agent.

Absorption↗

PubMed2000

Effect of troglitazone on the liver of a Gunn rat model of genetic enzyme polymorphism.

There is a possibility that serious liver dysfunction rarely observed in diabetic patients given troglitazone is attributable to idiosyncratic abnormalities in liver drug-metabolism. In addition, the results of blood biochemical examinations in serious cases of liver dysfunction showed a tendency for a high level of total bilirubin (T-Bil) over a long period compared with other indicators of liver dysfunction. Thus, we focused on genetic variation of UDP-glucuronosyltransferases (UGTs) that are involved in the conjugation of troglitazone and bilirubin. In this study, Gunn rats, which are hereditarily deficient in the UGT1 family of UGT isozymes, and Wistar rats, the parent strain of Gunn rats, were treated with troglitazone for 3 months at dose levels of 0, 100 or 400 mg/kg to investigate two possibilities: first, whether the genetic deficiency in UGT1s induces an alteration of the metabolic profile of troglitazone followed by liver dysfunction, and second, whether the dosing of troglitazone to Gunn rats which show hyperbilirubinemia result in liver dysfunction. As a result, the metabolic profile of troglitazone in Gunn rats was much the same as that of Wistar rats, suggesting that genetic deficiencies in UGT1s did not influence the metabolic profile of troglitazone. Moreover, no elevation of blood biochemical parameters, such as asparate aminotransferase (AST) and alanine aminotransferase (ALT), or histopathological liver injuries, such as hepatocellular degeneration and necrosis, were observed in either strain of rats, and hyperbilirubinemia in Gunn rats was not aggravated by the dosing of troglitazone. These results strongly suggest that troglitazone was not metabolized by UGT1s but by other UGT isozyme (s) in rats, and that glucuronidation of troglitazone did not compete with glucuronidation of bilirubin in vivo. Thus, it is suggested that high levels of total bilirubin in patients with liver dysfunction induced by troglitazone are attributable to hypofunction due to hepatocellular injury, not to metabolic competition of bilirubin with troglitazone. Moreover, it is also suggested that the deficiency in the UGT1 family of UGT isozymes itself may not be the cause of liver dysfunction associated with troglitazone treatment.

Animals↗

PubMed1999

Troglitazone: a review of its use in the management of type 2 diabetes mellitus.

UNLABELLED: Troglitazone is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is indicated for the treatment of patients with type 2 (non-insulin-dependent) diabetes mellitus. Troglitazone acts by enhancing the effects of insulin at peripheral target sites and, unlike the sulphonylurea drugs, is not associated with hypoglycaemia when administered as monotherapy. Clinical trials with troglitazone (usually 200 to 600 mg/day) in patients with type 2 diabetes mellitus consistently showed marked improvement in glycaemic control, as well as reductions in fasting serum insulin, C-peptide and triglyceride levels. Comparative studies with either glibenclamide (glyburide) or metformin indicated similar glycaemic control with troglitazone or these agents. Serum insulin levels were lower with troglitazone than with glibenclamide. Clinical trials of up to approximately 2 years' duration showed that glycaemic control is maintained with troglitazone on a long term basis. In general, troglitazone is well tolerated by the majority of patients. However, discontinuation of troglitazone because of elevated liver enzyme levels occurs in approximately 2% of patients receiving the drug, and frequent monitoring of liver enzymes is required (e.g. at least 11 times during the first year of therapy). Among patients who started troglitazone therapy in 1998 (after the incorporation of a boxed warning and increased monitoring requirements in the product labelling), the estimated risk of liver-related death is approximately 1 in 100,000. CONCLUSIONS: Troglitazone improves the ability of target cells to respond to insulin. The drug has been shown to improve glycaemic control in patients with type 2 diabetes mellitus when used as monotherapy or in combination with other oral antidiabetic drugs or insulin, and its efficacy is similar to that of glibenclamide or metformin. Although troglitazone is generally well tolerated, close monitoring of liver enzyme function is required to minimise the rare occurrence of serious hepatic dysfunction. Drug acquisition and liver function monitoring costs, as well as potential adverse effects, are important factors that may ultimately determine the precise place of troglitazone in the management of type 2 diabetes mellitus. Nevertheless, as the first member of a new class of oral antidiabetic agents, the thiazolidinediones, troglitazone offers an effective treatment option in patients with type 2 diabetes mellitus through its action of improving insulin sensitivity.

Adult↗

PubMed1999

Inhibition of LDL oxidation in vitro but not ex vivo by troglitazone.

Diabetic subjects are at increased risk for developing coronary artery disease, in part because of increased oxidation of LDL, which promotes atherogenesis. Troglitazone, a new antidiabetic drug of the thiazolidinedione class, acts as an insulin sensitizer and improves hyperglycemia. Structurally, it contains a tocopherol moiety similar to vitamin E and has been shown to have antioxidant properties in vitro. Therefore, we evaluated whether troglitazone inhibited LDL oxidation both in vitro and in type 2 diabetic subjects ex vivo. Troglitazone inhibited oxidation of LDL induced by Cu2+ or 2'2'-azobis-2-amidinopropane hydrochloride (AAPH) with 50% inhibition at 1 micromol/l and 100% inhibition at 5-10 micromol/l troglitazone. The inhibition of LDL oxidation by troglitazone also was time dependent. In addition, troglitazone inhibited oxidation of 125I-labeled LDL and its subsequent uptake and degradation by macrophages. To determine whether troglitazone was incorporated into LDL particles or acted in the aqueous milieu, troglitazone was incubated overnight at 37 degrees C with LDL or plasma before LDL re-isolation. After re-isolation, LDL that was incubated with troglitazone was no longer protected from oxidation, compared with probucol-treated LDL, which remained protected. Further, [14C]troglitazone did not get incorporated into LDL. This suggests that troglitazone exerts its antioxidant effect in the aqueous milieu of LDL. Consistent with this was the observation that the lag phases of copper-induced conjugated diene formation, a measure of the susceptibility in vivo, was similar for subjects taking troglitazone (76 +/- 5 min, n = 9) to subjects not taking the drug (77 +/- 3 min, n = 11; NS). Thus, troglitazone may be of value as an aqueous-phase antioxidant in addition to its effect on glucose homeostasis.

Antioxidants↗

PubMed2000

The role of conjugation in hepatotoxicity of troglitazone in human and porcine hepatocyte cultures.

In primary human and porcine hepatocyte cultures, we investigated the relationship between metabolism and cytotoxicity of troglitazone. Treatment of human hepatocytes for 2 h with 10, 20, 25, 35, and 50 microM troglitazone in protein-free medium resulted in concentration-dependent decreases in total protein synthesis. Decreases at 10 and 20 microM were reversible by 24 h, however protein synthesis did not recover at concentrations >/=25 microM. Troglitazone at 50 microM caused cellular death. In porcine hepatocytes, 100 microM troglitazone was lethal, whereas at 50 microM, protein synthesis completely recovered by 24 h. Recovery in protein synthesis was associated with metabolism of parent drug, whereas toxicity correlated (r(2) = 0.82) with accumulation of unmetabolized troglitazone. By 1 h, in human hepatocytes, troglitazone was metabolized to similar amounts of sulfate and quinone metabolites with little glucuronide detected. In contrast, porcine hepatocytes metabolized troglitazone to the similar amounts of glucuronide and the quinone metabolites with little sulfate detected. Exposure of human hepatocytes to a combination of 10 microM troglitazone and 10 microM 2,4-dichloro-4-nitrophenol resulted in a 70% decrease in protein synthesis, associated with 90% inhibition in the formation of troglitazone sulfate, a 4-fold increase in unmetabolized troglitazone, and no effect on formation of the quinone metabolite. Treatment with a combination of acetaminophen or phenobarbital with 20 microM troglitazone resulted in sustained decrease in protein synthesis associated with inhibition of sulfation and accumulation of troglitazone. These results suggest that inhibition of troglitazone sulfation may result in increased hepatotoxicity due to exposure to parent drug, or increased metabolism by alternate pathways.

Acetaminophen↗