Altered pharmacokinetics of rosiglitazone in a mouse model of non-alcoholic fatty liver disease

Kulkarni, Nagaraj M.; Malampati, Sandeep; Mahat, Mahamad Yunnus A.; Chandrasekaran, S.; Raghul, J.; Khan, Ansar A.; Krishnan, Uma Maheswari; Narayanan, Shridhar

doi:10.1515/dmpt-2016-0008

Cited by 10 publications

(8 citation statements)

References 21 publications

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“…1 D,E). Notably, the doses used compare well with daily human recommended doses, given the differences in the pharmacokinetics of the three drugs in the mouse and human systems [ 41 – 43 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of first-line diabetes therapy with biguanides, sulphonylurea and thiazolidinediones on the differentiation, proliferation and apoptosis of islet cell populations

Sarnobat

Moffett

Flatt

et al. 2021

J Endocrinol Invest

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Aims Metformin, rosiglitazone and sulfonylureas enhance either insulin action or secretion and thus have been used extensively as early stage anti-diabetic medication, independently of the aetiology of the disease. When administered to newly diagnosed diabetes patients, these drugs produce variable results. Here, we examined the effects of the three early stage oral hypoglycaemic agents in mice with diabetes induced by multiple low doses of streptozotocin, focusing specifically on the developmental biology of pancreatic islets. Methods Streptozotocin-treated diabetic mice expressing a fluorescent reporter specifically in pancreatic islet α-cells were administered the biguanide metformin (100 mg/kg), thiazolidinedione rosiglitazone (10 mg/kg), or sulfonylurea tolbutamide (20 mg/kg) for 10 days. We assessed the impact of the treatment on metabolic status of the animals as well as on the morphology, proliferative potential and transdifferentiation of pancreatic islet cells, using immunofluorescence. Results The effect of the therapy on the islet cells varied depending on the drug and included enhanced pancreatic islet β-cell proliferation, in case of metformin and rosiglitazone; de-differentiation of α-cells and β-cell apoptosis with tolbutamide; increased relative number of β-cells and bi-hormonal insulin + glucagon + cells with metformin. These effects were accompanied by normalisation of food and fluid intake with only minor effects on glycaemia at the low doses of the agents employed. Conclusions Our data suggest that metformin and rosiglitazone attenuate the depletion of the β-cell pool in the streptozotocin-induced diabetes, whereas tolbutamide exacerbates the β-cell apoptosis, but is likely to protect β-cells from chronic hyperglycaemia by directly elevating insulin secretion.

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Section: Discussionmentioning

confidence: 99%

Effects of first-line diabetes therapy with biguanides, sulphonylurea and thiazolidinediones on the differentiation, proliferation and apoptosis of islet cell populations

Sarnobat

Moffett

Flatt

et al. 2021

J Endocrinol Invest

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“…However, the direction of change is not clear as both increasing and decreasing trends have been observed (Fisher et al , 2009, Li et al , 2016). The AUC of rosiglitazone, an insulin sensitizer and a substrate of CYP2C8 and CYP2C9 (Baldwin et al , 1999), was found to be significantly increased in male mice after high fat and high fructose NAFLD induction (Kulkarni et al , 2016). Nevertheless, it is not clear whether this increase was mediated through down-regulation of the CYP2C8/9 or alteration in transport mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Non-alcoholic fatty liver disease (NAFLD) – pathogenesis, classification, and effect on drug metabolizing enzymes and transporters

Cobbina

Akhlaghi

2017

Drug Metabolism Reviews

479

351

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Non-alcoholic fatty liver disease (NAFLD) is a spectrum of liver disorders. It is defined by the presence of steatosis in more than 5 % of hepatocytes with little or no alcohol consumption. Insulin resistance, the metabolic syndrome or type 2 diabetes and genetic variants of PNPLA3 or TM6SF2 seem to play a role in the pathogenesis of NAFLD. The pathological progression of NAFLD follows tentatively a ‘three-hit’ process namely steatosis, lipotoxicity and inflammation. The presence of steatosis, oxidative stress and inflammatory mediators like TNF-α and IL-6 have been implicated in the alterations of nuclear factors such as CAR, PXR, PPAR-α in NAFLD. These factors may results in altered expression and activity of drug metabolizing enzymes (DMEs) or transporters. Existing evidence suggests that the effect of NAFLD on CYP3A4, CYP2E1 and MRP3 are more consistent across rodent and human studies. CYP3A4 activity is down-regulated in NASH whereas the activity of CYP2E1 and the efflux transporter MRP3 are up-regulated. However, it is not clear how the majority of CYPs, UGTs, SULTs and transporters are influenced by NAFLD either in vivo or in vitro. The alterations associated with NAFLD could be a potential source of drug variability in patients and could have serious implications for the safety and efficacy of xenobiotics. In this review, we summarize the effects of NAFLD on the regulation, expression and activity of major drug metabolizing enzymes and transporters. We also discuss the potential mechanisms underlying these alterations.

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“…Greater hepatotoxicity of rosiglitazone in some obese patients might also be secondary to an alteration in its pharmacokinetics, which might favor higher plasma concentrations and PPARγ overactivation in the liver. In keeping with this hypothesis, the plasma halflife of rosiglitazone was nearly tripled in a mouse model of diet-induced obesity [91]. Rosiglitazone mainly undergoes CYP2C8-mediated p-hydroxylation and N-demethylation, followed by sulfate and glucuronide conjugation [92], metabolic pathways that might be affected in obesity.…”

Section: Thiazolidinedionesmentioning

confidence: 83%

Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease

Massart¹,

Begriche²,

Corlu³

et al. 2022

IJMS

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Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals. The mechanisms whereby xenobiotics can aggravate MAFLD are still poorly understood and are currently under deep investigations. Nevertheless, previous studies pointed to the role of different metabolic pathways and cellular events such as activation of de novo lipogenesis and mitochondrial dysfunction, mostly associated with reactive oxygen species overproduction. This review presents the available data gathered with some prototypic compounds with a focus on corticosteroids and rosiglitazone for pharmaceuticals as well as bisphenol A and perfluorooctanoic acid for endocrine disruptors. Although not typically considered as a xenobiotic, ethanol is also discussed because its abuse has dire consequences on obese liver.

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Altered pharmacokinetics of rosiglitazone in a mouse model of non-alcoholic fatty liver disease

Cited by 10 publications

References 21 publications

Effects of first-line diabetes therapy with biguanides, sulphonylurea and thiazolidinediones on the differentiation, proliferation and apoptosis of islet cell populations

Effects of first-line diabetes therapy with biguanides, sulphonylurea and thiazolidinediones on the differentiation, proliferation and apoptosis of islet cell populations

Non-alcoholic fatty liver disease (NAFLD) – pathogenesis, classification, and effect on drug metabolizing enzymes and transporters

Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease

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