Influence of the pharmacokinetic profile on the plasma glucose lowering effect of the PPARγ agonist pioglitazone in Wistar fatty rats

Goto, Akihiko; Tagawa, Yoshihiko; Kimura, Yukio; Kogame, Akifumi; Moriya, Yuu; Amano, Nobuyuki

doi:10.1002/bdd.2076

Cited by 2 publications

(2 citation statements)

References 19 publications

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“…Recently, population PK-PD models have been used to describe the exposure-response relationship between plasma rifampicin and 4β-hydroxycholesterol, an endogenous product of CYP3A [ 84 , 85 ]. Similarly, an indirect PK/PD response model has been built for the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone in vivo [ 86 ]. In the NONMEM model, a plasma glucose lowering effect was selected as a surrogate for an anti-diabetic effect of the drug.…”

Section: Mathematical Models Of Pxr Activation and Pxr-induced Genmentioning

confidence: 99%

Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction

Tebbens

Azar

Friedmann

et al. 2018

IJMS

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The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drug–drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression.

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Section: Mathematical Models Of Pxr Activation and Pxr-induced Genmentioning

confidence: 99%

Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction

Tebbens

Azar

Friedmann

et al. 2018

IJMS

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“…Ligand binding with PPAR- γ receptor acts as a switch leading to the transcription complexes mediating repression or activation of transcription on specific target genes [ 2 ]. Moreover, PPAR- γ possesses beneficial pleotropic effects including anti-inflammatory and neuroprotective actions [ 3 , 4 ] and antidiabetic [ 5 – 7 ], antineoplastic [ 8 ], and renoprotective effects [ 9 ]. PPAR- γ is expressed in normal human anterior pituitary as well as in adrenocorticotropic hormone- (ACTH-) secreting pituitary adenomas.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effects of a Novel PPAR-γAgonist MEKT1 onPomcExpression/ACTH Secretion in AtT20 Cells

et al. 2018

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Although therapeutic effects of the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists rosiglitazone and pioglitazone against Cushing's disease have been reported, their effects are still controversial and inconsistent. We therefore examined the effects of a novel PPAR-γ agonist, MEKT1, on Pomc expression/ACTH secretion using murine corticotroph-derived AtT20 cells and compared its effects with those of rosiglitazone and pioglitazone. AtT20 cells were treated with either 1 nM~10 μM MEKT1, rosiglitazone, or pioglitazone for 24 hours. Thereafter, their effects on proopiomelanocortin gene (Pomc) mRNA expression were studied by qPCR and the Pomc promoter (−703/+58) activity was demonstrated by luciferase assay. Pomc mRNA expression and promoter activity were significantly inhibited by MEKT1 at 10 μM compared to rosiglitazone and pioglitazone. SiRNA-mediated PPAR-γ knockdown significantly abrogated MEKT1-mediated Pomc mRNA suppression. ACTH secretion from AtT20 cells was also significantly inhibited by MEKT1. Deletion/point mutant analyses of Pomc promoter indicated that the MEKT1-mediated suppression was mediated via NurRE, TpitRE, and NBRE at −404/−383, −316/−309, and −69/−63, respectively. Moreover, MEKT1 significantly suppressed Nur77, Nurr1, and Tpit mRNA expression. MEKT1 also was demonstrated to inhibit the protein-DNA interaction of Nur77/Nurr1-NurRE, Tpit-TpitRE, and Nur77-NBRE by ChIP assay. Taken together, it is suggested that MEKT1 could be a novel therapeutic medication for Cushing's disease.

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Influence of the pharmacokinetic profile on the plasma glucose lowering effect of the PPARγ agonist pioglitazone in Wistar fatty rats

Cited by 2 publications

References 19 publications

Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction

Mathematical Models in the Description of Pregnane X Receptor (PXR)-Regulated Cytochrome P450 Enzyme Induction

Inhibitory Effects of a Novel PPAR-γAgonist MEKT1 onPomcExpression/ACTH Secretion in AtT20 Cells

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