Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

Abstract

Receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase (TAT) were evaluated in normal rats. A group of normal male Wistar rats were injected with 50 mg/kg methylprednisolone (MPL) intramuscularly at the nadir of their plasma corticosterone (CST) rhythm (early light cycle) and sacrificed at various time points up to 96 h post-treatment. Blood and livers were collected to measure plasma MPL, CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density, TAT mRNA, and TAT activity. The pharmacokinetics of MPL showed bi-exponential disposition with two first-order absorption components from the injection NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript site and bioavailability was 21%. Plasma CST was reduced after MPL dosing, but resumed its daily circadian pattern within 36 h. Cytosolic receptor density was significantly suppressed (90%) and returned to baseline by 72 h resuming its biphasic pattern. Hepatic GR mRNA follows a circadian pattern which was disrupted by MPL and did not return during the study. MPL caused significant down-regulation (50%) in GR mRNA which was followed by a delayed rebound phase (60-70 h). Hepatic TAT mRNA and activity showed up-regulation as a consequence of MPL, and returned to their circadian baseline within 72 and 24 h of treatment. A mechanistic receptor/genemediated pharmacokinetic/pharmacodynamic model was able to satisfactorily describe the complex interplay of exogenous and endogenous corticosteroid effects on hepatic GR mRNA, cytosolic free GR, TAT mRNA, and TAT activity in normal rats.

Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism

“…Approximately 100 proteins related to various aspects of energy metabolism (amino acid metabolism, carbohydrate metabolism, lipid/fatty acid metabolism, and the Krebs cycle) were identified as differentially regulated by MPL (Figure 10; bottom right). Our observations of MPL-induced up-regulation in amino acid degrading enzymes such as TAT are consistent with previous findings at the mRNA level [13, 108]. Furthermore, the time-course of TAT protein expression strongly complemented that of TAT activity measured using a colorimetric assay [108] in livers obtained from the same animals (Supplementary Figure S2 in the SI).…”

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

“…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.…”

On the analysis of complex biological supply chains: From process systems engineering to quantitative systems pharmacology

“…As the complexity of a pharmacodynamic model increases and becomes mechanistically-based, many parallels can be drawn from the methodology and concepts associated with systems biology models (Danhof et al, 2008). In that context, the examples of indirect effect, transduction and transit models, tolerance models, and feedback mechanisms (Fang et al, 2013; Hazra et al, 2007; Jin et al, 2003; Jin & Jusko, 2009; Sukumaran et al, 2011) adapt basic elements of reaction kinetics towards revealing the exposure-response relationship of a drug.…”