Troglitazone is a PPARγ agonist; its EC50s for the human and murine PPARγ receptors are 550 nM and 780 nM, respectively[1]. With IC50s of 49.9 ± 1.2 and 51.3 ± 5.3 μM, respectively, troglitazone (2-200 μM) is cytotoxic to the pancreatic cancer cell lines (MIA Paca2 and PANC-1 cells). In MIA Paca2 and PANC-1 cells, troglitazone (50 μM) increases chromatin condensation, increases caspase-3 activity, and lowers Bcl-2 expression [2]. In human lung adenocarcinoma cells, troglitazone (0, 1, 2, and 4 μM) sensitizes TRAIL-mediated apoptosis. Autophagy inhibition prevents the enhancement of TRAIL-induced apoptosis by troglitazone. Additionally, PPARγ activation in A549 cells induces the effects of troglitazone[3].

The MIA Paca2 xenograft model exhibits growth inhibition in response to troglitazone (200 mg/kg, po)[2].

Absorption, Distribution and Excretion
Absorbed rapidly. Food increases the extent of absorption by 30% to 85%.

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Metabolism / Metabolites
A sulfate conjugate metabolite (Metabolite 1) and a quinone metabolite (Metabolite 3) have been detected in the plasma of healthy males. A glucuronide conjugate (Metabolite 2) has been detected in the urine and also in negligible amounts in the plasma. In healthy volunteers and in patients with type 2 diabetes, the steady-state concentration of Metabolite 1 is six to seven times that of troglitazone and Metabolite 3. In in vivo drug interaction studies, troglitazone has been shown to induce cytochrome P450 CYP3A4 at clinically relevant doses.
Troglitazone has known human metabolites that include (2S,3S,4S,5R)-6-[[2-[[4-[(2,4-dioxo-1,3-thiazolidin-5-yl)methyl]phenoxy]methyl]-2,5,7,8-tetramethyl-3,4-dihydrochromen-6-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid.
A sulfate conjugate metabolite (Metabolite 1) and a quinone metabolite (Metabolite 3) have been detected in the plasma of healthy males. A glucuronide conjugate (Metabolite 2) has been detected in the urine and also in negligible amounts in the plasma. In healthy volunteers and in patients with type 2 diabetes, the steady-state concentration of Metabolite 1 is six to seven times that of troglitazone and Metabolite 3. In in vivo drug interaction studies, troglitazone has been shown to induce cytochrome P450 CYP3A4 at clinically relevant doses.
Half Life: 16-34 hours

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Biological Half-Life
16-34 hours

Toxicity Summary
Troglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin. It has a unique mechanism of action that is dependent on the presence of insulin for activity. Troglitazone decreases hepatic glucose output and increases insulin dependent glucose disposal in skeletal muscle. Its mechanism of action is thought to involve binding to nuclear receptors (PPAR) that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism. Troglitazone is a ligand to both PPAR‘± and PPAR‘_, with a highter affinity for PPAR‘_. The drug also contains an ‘±-tocopheroyl moiety, potentially giving it vitamin E-like activity. Troglitazone has been shown to reduce inflammation, and is associated with a decrase in nuclear factor kappa-B (NF-‘_B) and a concomitant increase in its inhibitor (I‘_B). NF-‘_B is an important cellular transcription regulator for the immune response. Unlike sulfonylureas, troglitazone is not an insulin secretagogue.

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Hepatotoxicity
Large prospective studies showed that significant elevations in serum aminotransferase levels (equal to or greater than 3 times the upper limit of the normal range [ULN]) occurred in 1.9% of patients with diabetes treated with troglitazone for 24 to 48 weeks, compared to only 0.6% in placebo recipients. These enzyme elevations were usually asymptomatic and often resolved despite continuation of therapy. Nevertheless, elevations >10 times ULN occurred in 0.5% of patients (but in no placebo recipient) and a proportion of these developed symptoms of liver injury and jaundice. Soon after the approval of troglitazone as therapy for type 2 diabetes in the United States, cases of severe acute liver injury began to be reported, and dramatic case reports as well as small case series documented that clinically significant injury was occurring in 1:1000 to 1:10,000 recipients. The latency to onset of injury was typically 1 to 6 months and the onset was marked by fatigue, weakness, dark urine and jaundice, and an acute hepatitis-like elevation in serum enzymes (hepatocellular pattern). Allergic phenomena (rash, fever, eosinophilia) were uncommon and serum autoantibodies were not usually present. Liver biopsies showed acute inflammatory changes and variable degrees of necrosis, ranging from rare spotty necrosis to bridging hepatic necrosis and submassive or massive necrosis. At least two dozen cases of acute liver failure and death or need for liver transplantation were reported to the FDA before troglitazone was withdrawn from use in 2000.
Likelihood score: A (well recognized cause of clinically apparent liver injury).

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Protein Binding
> 99% (primarily to serum albumin)

[1]. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000 Feb 24;43(4):527-50.

[2]. In vitro and in vivo cytotoxicity of troglitazone in pancreatic cancer. J Exp Clin Cancer Res. 2017 Jul 3;36(1):91.

[3]. PPARγ activation by troglitazone enhances human lung cancer cells to TRAIL-induced apoptosis via autophagy flux. Oncotarget. 2017 Apr 18;8(16):26819-26831.

[4]. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes. 2005 Apr;54(4):1150-6.

Troglitazone is a member of chromanes and a thiazolidinone. It has a role as a hypoglycemic agent, an antioxidant, a vasodilator agent, an anticonvulsant, an anticoagulant, a platelet aggregation inhibitor, an antineoplastic agent, an EC 6.2.1.3 (long-chain-fatty-acid--CoA ligase) inhibitor and a ferroptosis inhibitor.
Troglitazone was withdrawn in 2000 due to risk of hepatotoxicity. It was superseded by [pioglitazone] and [rosiglitazone].
Troglitazone was the first thiazolidinedione approved for use in the United States and was licensed for use in type 2 diabetes in 1997, but withdrawn 3 years later because of the frequency of liver injury including acute liver failure associated with its use.
Troglitazone is an orally-active thiazolidinedione with antidiabetic and hepatotoxic properties and potential antineoplastic activity. Troglitazone activates peroxisome proliferator-activated receptor gamma (PPAR-gamma), a ligand-activated transcription factor, thereby inducing cell differentiation and inhibiting cell growth and angiogenesis. This agent also modulates the transcription of insulin-responsive genes, inhibits macrophage and monocyte activation, and stimulates adipocyte differentiation. (NCI04)
Troglitazone was withdrawn in 2000 due to risk of hepatotoxicity. It was superseded by pioglitazone and rosiglitazone.
A chroman and thiazolidinedione derivative that acts as a PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPAR) agonist. It was formerly used in the treatment of TYPE 2 DIABETES MELLITUS, but has been withdrawn due to hepatotoxicity.

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Drug Indication
For the treatment of Type II diabetes mellitus. It is used alone or in combination with a sulfonylurea, metformin, or insulin as an adjunct to diet and exercise.
FDA Label

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Mechanism of Action
Troglitazone is a thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin. It has a unique mechanism of action that is dependent on the presence of insulin for activity. Troglitazone decreases hepatic glucose output and increases insulin dependent glucose disposal in skeletal muscle. Its mechanism of action is thought to involve binding to nuclear receptors (PPAR) that regulate the transcription of a number of insulin responsive genes critical for the control of glucose and lipid metabolism. Troglitazone is a ligand to both PPARα and PPARγ, with a highter affinity for PPARγ. The drug also contains an α-tocopheroyl moiety, potentially giving it vitamin E-like activity. Troglitazone has been shown to reduce inflammation, and is associated with a decrase in nuclear factor kappa-B (NF-κB) and a concomitant increase in its inhibitor (IκB). Unlike sulfonylureas, troglitazone is not an insulin secretagogue.

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Pharmacodynamics
Troglitazone is an oral antihyperglycemic agent which acts primarily by decreasing insulin resistance. Troglitazone is used in the management of type II diabetes (noninsulin-dependent diabetes mellitus (NIDDM) also known as adult-onset diabetes). It improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Troglitazone is not chemically or functionally related to either the sulfonylureas, the biguanides, or the g-glucosidase inhibitors. Troglitazone may be used concomitantly with a sulfonylurea or insulin to improve glycemic control.

C24H27NO5S

441.54

441.16

97322-87-7

Troglitazone-d4;2749370-85-0

5591

White to off-white solid powder

1.3±0.1 g/cm3

657.0±55.0 °C at 760 mmHg

184-186°C

351.2±31.5 °C

0.0±2.1 mmHg at 25°C

1.608

4.99

2

6

5

31

681

0

GXPHKUHSUJUWKP-UHFFFAOYSA-N

InChI=1S/C24H27NO5S/c1-13-14(2)21-18(15(3)20(13)26)9-10-24(4,30-21)12-29-17-7-5-16(6-8-17)11-19-22(27)25-23(28)31-19/h5-8,19,26H,9-12H2,1-4H3,(H,25,27,28)

5-[[4-[(6-hydroxy-2,5,7,8-tetramethyl-3,4-dihydrochromen-2-yl)methoxy]phenyl]methyl]-1,3-thiazolidine-2,4-dione

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.66 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.71 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 10 mg/mL (22.65 mM) in 0.5% CMC-Na 0.5% Tween-80 (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)