Disposition and Metabolism of the Oral Antidiabetic Drug Troglitazone in Monkeys.

Kawai, Kenji; Tsuruta, Fujiko; Iwabuchi, Haruo; Ishikawa, Minoru; Haruyama, Hideyuki; Ikenaga, Hideki; Ikeda, Toshihiko; Nakamura, Kenji

doi:10.2133/dmpk.15.89

Cited by 47 publications

(88 citation statements)

References 3 publications

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“…Flow cytometric detection of ROS applied in both the previous toxicologic study on hepatocytes 31 and the present study has been shown to be efficient to reveal the functional influences of potential toxicants, such as troglitazone, which have hitherto been not detected by con- ventional premarketing screening, including any animal experiments. 40,41 In this study, the OUMS-29 cells showed a gradual, but significant, decrease in unit ⌬⌿ m after long exposure to troglitazone, although not resulting in clear cell death. Lack of obvious cell death in troglitazone-treated hepatocytes has also been reported, 31 suggesting that the troglitazone-induced ⌬⌿ m attenuation was not a critical inducer, but a possible priming, for hepatocyte death.…”

Section: Discussionmentioning

confidence: 47%

Hydrogen peroxide overproduction in megamitochondria of troglitazone-treated human hepatocytes

Shishido

2003

Hepatology

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Troglitazone has been withdrawn from therapeutic options for diabetes mellitus because of its severe hepatocyte toxicity of unknown pathogenesis. The aim of the present study was to assess both morphologic and functional alterations in the mitochondria of troglitazonetreated hepatocytes. A polarized human hepatocyte cell line, OUMS-29, was used in this study. The mitochondrial volume and the mitochondrial transmembrane potential (⌬⌿ m ) were examined using flow cytometry with nonylacridine orange (NAO) and rhodamine-123, respectively. An ultrastructural examination of the troglitazone-treated OUMS-29 cells was performed using transmission electron microscopy (TEM). Reactive oxygen species (ROS) production was assessed using flow cytometry with dihydroethidium and 2 ,7 -dichlorodihydrofluorescein diacetate. A significant increase in the mitochondrial volume of the troglitazone-treated cells was found by the NAO analysis, in comparison with pioglitazone-treated and ciglitazone-treated cells. The increase in volume was due to a marked enlargement in the mitochondria. The markedly enlarged mitochondria with intramitochondrial electrondense deposits were confirmed on TEM, which showed myelin-like structures, indicating degraded membrane constituents. The troglitazone-treated cells showed a significant decline in the ⌬⌿ m per unit mitochondrial volume but resulted in no clear cell death. ROS analysis revealed a significant production of hydrogen peroxide in the troglitazone-treated hepatocytes. This production was attenuated using an antioxidant, N-acetyl-L-cysteine. In conclusion, troglitazone caused overproduction of hydrogen peroxide, which deteriorated both mitochondrial membrane structures and mitochondrial function, leading to a possible priming for the severe hepatocyte toxicity. (HEPATOLOGY 2003;37:136-147.) T roglitazone, a ligand for peroxisome proliferatoractivated receptor ␥ (PPAR␥), used to be administered as an antidiabetic drug until it was discovered to be associated with hepatotoxicity and withdrawn from the market after reports of several dozens of deaths or cases of severe hepatic failure requiring liver transplantation. 1,2 In contrast to troglitazone, 2 other glitazones, pioglitazone and rosiglitazone, are still on the market; however, several cautionary reports have suggested that the latter 2 drugs show hepatotoxicity as a class effect of glitazones. [2][3][4][5][6][7][8][9] Although the troglitazone-associated hepatotoxicity has been considered idiosyncratic direct hepatocyte toxicity, 10 the precise mechanism has remained unclear. In our recent study, mitochondrial damage was ultrastructurally demonstrated in troglitazone-treated human hepatoma cells, 11 allowing us to first focus on alterations in the mitochondrial structure and the function in the troglitazone-treated human hepatocytes. Troglitazone is known

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Section: Discussionmentioning

confidence: 47%

Hydrogen peroxide overproduction in megamitochondria of troglitazone-treated human hepatocytes

Shishido

2003

Hepatology

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“…We allowed 1 h between the administration of thiazolidinedione drugs and the beginning of ischaemia or levcromakalim infusion. At 1 h following intravenous administration of troglitazone or rosiglitazone, pharmacokinetics are similar to those observed after oral administration of an equal dose [47,48].…”

Section: Discussionmentioning

confidence: 55%

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Reiter

et al. 2008

Diabetologia

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Aims/hypothesis Opening of ATP-sensitive potassium (K ATP ) channels during myocardial ischaemia shortens action potential duration and is believed to be an adaptive, energy-sparing response. Thiazolidinedione drugs block K ATP channels in non-cardiac cells in vitro. This study determined whether thiazolidinedione drugs block cardiac K ATP channels in vivo. Methods Experiments in 68 anaesthetised pigs determined: (1) effects of inert vehicle, troglitazone (10 mg/kg i.v.) or rosiglitazone (0.1 or 1.0 mg/kg i.v.) on epicardial monophasic action potential (MAP) during 90 min low-flow ischaemia; (2) effects of troglitazone, rosiglitazone or pioglitazone (1 mg/kg i.v.) on response of MAP to intracoronary infusion of a K ATP channel opener, levcromakalim; and (3) effects of inert vehicle, rosiglitazone (1 mg/kg i.v.) or the sarcolemmal K ATP blocker HMR-1098 on time to onset of ventricular fibrillation following complete coronary occlusion. Results With vehicle, epicardial MAP shortened by 44±9 ms during ischaemia. This effect was attenuated to 12±8 ms with troglitazone and 6±6 ms with rosiglitazone (p<0.01 for both vs vehicle), suggesting K ATP blockade. Intracoronary levcromakalim shortened MAP by 38±10 ms, an effect attenuated to 12±8, 13±4 and 9±5 ms during co-treatment with troglitazone, rosiglitazone or pioglitazone (p<0.05 for each), confirming K ATP blockade. During coronary occlusion, median time to ventricular fibrillation was 29 min in pigs treated with vehicle and 6 min in pigs treated with rosiglitazone or HMR-1098 (p<0.05 for both vs vehicle), indicating that K ATP blockade promotes ischaemic ventricular fibrillation in this model. Conclusions/interpretation Thiazolidinedione drugs block cardiac K ATP channels at clinically relevant doses and promote onset of ventricular fibrillation during severe ischaemia.

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“…The other 2 PPARγ ligands also exhibited similar dose responses. According to the pharmacokinetics of troglitazone (Ploskar and Faulds, 1999) and due to a higher tissue distribution in liver (Kawai et al, 1997), a daily dose of 600 to 800 mg troglitazone may attain an effective drug level in vivo. Similarly, 30 to 60 mg daily dose of pioglitazone would result in an effective drug level.…”

Section: Discussionmentioning

confidence: 99%

“…A dose ranging from 0.1 to 50 µM troglitazone was selected for this in vitro study according to the pharmacokinetics (Plosker and Faulds, 1999) and tissue distribution of the drug (Kawai et al, 1997). For comparison of the dose effect, the 2 other PPARγ ligands, pioglitazone and 15d-PGJ2 were also applied to cells at the same dosages.…”

Section: Experimental Drugsmentioning

confidence: 99%

Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

et al. 2001

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Summary Peroxisome proliferator-activated receptor γ (PPARγ) ligands have been implicated in the growth inhibition and differentiation of certain human cancers with diverse tissue origin. In this study, expression of PPARγ in human hepatocellular carcinoma (HCC) and the effect of PPARγ ligands on HCC cells were investigated in vitro using Hep G2, HuH-7, KYN-1 and KYN-2 cell lines. All cell lines were found to express functionally active PPARγ and a marked growth inhibition was induced by thiazolidinedione ligands troglitazone, and pioglitazone as well as with its natural ligand 15-deoxy-∆ 12,14 -prostaglandin J 2 . The growth inhibitory effect was associated with a dose-dependent inhibition of DNA synthesis, cell cycle progression and α fetoprotein expression.

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Disposition and Metabolism of the Oral Antidiabetic Drug Troglitazone in Monkeys.

Cited by 47 publications

References 3 publications

Hydrogen peroxide overproduction in megamitochondria of troglitazone-treated human hepatocytes

Hydrogen peroxide overproduction in megamitochondria of troglitazone-treated human hepatocytes

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma

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