Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats

Hazra, Anasuya; Pyszczynski, Nancy A.; DuBois, Debra C.; Almon, Richard R.; Jusko, William J.

doi:10.1007/s11095-007-9371-8

Cited by 32 publications

(41 citation statements)

References 40 publications

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“…This steady state was limited by the concentrations of free GR receptor. The estimate for synthesis of GR in inflamed tissue was 0.1054 h Ϫ1 compared with 0.54 h Ϫ1 in liver tissue reported previously (Schindler et al, 1990;Ramakrishnan et al, 2002;Hazra et al, 2007bHazra et al, , 2008.…”

supporting

confidence: 48%

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis II: Mechanistic Pharmacodynamic Model for Dexamethasone Effects in Lewis Rats with Collagen-Induced Arthritis

Earp¹,

DuBois²,

Molano³

et al. 2008

J Pharmacol Exp Ther

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A mechanism-based model for pharmacodynamic effects of dexamethasone (DEX) was incorporated into our model for arthritis disease progression in the rat to aid in identification of the primary factors responsible for edema and bone loss. Collagen-induced arthritis was produced in male Lewis rats after injection of type II porcine collagen. DEX was given subcutaneously in single doses of 0.225 or 2.25 mg/kg or 7-day multiple doses of 0.045 or 0.225 mg/kg at 21 days postdisease induction. Effects on disease progression were measured by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST), and tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Lumbar and femur BMD was determined by PIXImus II dual-energy X-ray absorptiometry. Plasma CST was assayed by high-performance liquid chromatography. Cytokine and GR mRNA were assayed by quantitative real-time polymerase chain reaction. Indirect response models, drug interaction models, transduction processes, and the fifth-generation model of corticosteroid dynamics were integrated and applied using S-ADAPT software to describe how dexamethasone binding to GR can regulate diverse processes. Cytokine mRNA, GR mRNA, plasma CST, and paw edema were suppressed after DEX administration. TNF-␣ mRNA expression and BMD seemed to increase immediately after dosing but were ultimately reduced. Model parameters indicated that IL-6 and IL-1␤ were most sensitive to inhibition by DEX. TNF-␣ seemed to primarily influence edema, whereas IL-6 contributed the most to bone loss. Lower doses of corticosteroids may be sufficient to suppress the cytokines most relevant to bone erosion.

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supporting

confidence: 48%

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis II: Mechanistic Pharmacodynamic Model for Dexamethasone Effects in Lewis Rats with Collagen-Induced Arthritis

Earp¹,

DuBois²,

Molano³

et al. 2008

J Pharmacol Exp Ther

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“…[16] Transient down-regulation of LDL receptors in rats followed methylprednisolone admini stration, accounting for elevated LDL and TC. [17] Overall, animal models illustrate marked effects on HDL and some adverse effects on LDL, as well as differences between the drugs.…”

Section: Animal Studies Of Lipid Changes In Steroid Usementioning

confidence: 99%

The influence of glucocorticoids on lipid and lipoprotein metabolism and atherosclerosis

Ross

Marais

2014

S Afr Med J

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Lipoproteins transport lipids in the circulation in four major pathways: (i) a postprandial (exogenous) pathway for chylomicrons; (ii) an endogenous pathway involving very-low-density lipoprotein (VLDL) for triglyceride (TG) transport from the liver; (iii) a lowdensity lipoprotein (LDL) pathway from a proportion of VLDL as a source of cholesterol for cells; and (iv) a reverse cholesterol transport pathway by high-density lipoprotein (HDL).[1] These pathways and the reported effects of glucocorticoids are shown in Fig. 1. Exogenous TG pathwayChylomicrons, comprising 85 -90% TG and containing apolipoprotein B (apo B)-48 (apoB48), apolipoprotein Ai (apoAi) and apolipoprotein Aiv (apoAiv), are produced in enterocytes, traverse the thoracic duct and ultimately reach the systemic circulation. Lipoprotein lipase anchored on cells by heparan sulphate proteoglycans hydrolyses TG at the vascular endothelium, yielding non-esterified fatty acids (NEFAs) and remnants, proportionately richer in cholesterol esters. Chylomicron remnants are rapidly cleared by liver remnant receptors, [2] as a result of apolipoprotein E (apoE) acquired in the circulation. Dietary fat restriction will have a significant impact on severe hypertriglyceridaemia.

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“…An extensive description of these animal experiments has been published previously (Yao et al, 2006;Hazra et al, 2008). In brief, both experiments consisted of male Wistar rats that were acclimatized for 2 to 3 weeks in environments with constant temperature (22°C) and humidity (72%) equipped with 12-h light/dark cycles with free access to standard chow and drinking water.…”

Section: Animalsmentioning

confidence: 99%

“…A two-compartment model with two absorption components from the injection site was used to describe the PK of MPL (Hazra et al, 2008). The PK parameters were fixed with estimates obtained from our previous study as given in Table 1.…”

Section: Pharmacokinetic and Pharmacodynamic Modelmentioning

confidence: 99%

Mechanistic Modeling of the Effects of Glucocorticoids and Circadian Rhythms on Adipokine Expression

Sukumaran

Jusko²,

DuBois³

et al. 2011

J Pharmacol Exp Ther

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A mechanism-based model was developed to describe the effects of methylprednisolone (MPL), circadian rhythms, and the glucose/free fatty acid (FFA)/insulin system on leptin and adiponectin expression in white adipose tissue in rats. Fiftyfour normal Wistar rats received 50 mg/kg MPL intramuscularly and were sacrificed at various times. An additional set of 54 normal Wistar rats were sacrificed at 18 time points across the 24-h light/dark cycle and served as controls. Measurements included plasma MPL, glucocorticoid receptor (GR) mRNA, leptin mRNA, adiponectin mRNA, plasma leptin, adiponectin, glucose, FFA, and insulin. MPL pharmacokinetics was described by a two-compartment model with two absorption components. All measured plasma markers and mRNA expression exhibited circadian patterns except for adiponectin and were described by Fourier harmonic functions. MPL caused significant down-regulation in GR mRNA with the nadir occurring at 5 h. MPL disrupted the circadian patterns in plasma glucose and FFA by stimulating their production. Plasma glucose and FFA subsequently caused an increase in plasma insulin. Furthermore, MPL disrupted the circadian patterns in leptin mRNA expression by stimulating its production. This rise was closely followed by an increase in plasma leptin. Both leptin mRNA and plasma leptin peaked at 12 h after MPL and eventually returned back to their circadian baselines. MPL and insulin had opposing effects on adiponectin mRNA expression and plasma adiponectin, which resulted in biphasic pharmacodynamic profiles. This small systems model quantitatively describes, integrates, and provides additional insights into various factors controlling adipokine gene expression.

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Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats

Abstract: Our PK/PD model was able to satisfactorily capture the MPL effects on hepatic LDLR, its relationship to various plasma cholesterols, and builds the foundation to explore this area in the future.

Cited by 32 publications

References 40 publications

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis II: Mechanistic Pharmacodynamic Model for Dexamethasone Effects in Lewis Rats with Collagen-Induced Arthritis

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis II: Mechanistic Pharmacodynamic Model for Dexamethasone Effects in Lewis Rats with Collagen-Induced Arthritis

The influence of glucocorticoids on lipid and lipoprotein metabolism and atherosclerosis

Mechanistic Modeling of the Effects of Glucocorticoids and Circadian Rhythms on Adipokine Expression

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