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1.  Modeling of Corticosteroid Effects on Hepatic Low-Density Lipoprotein Receptors and Plasma Lipid Dynamics in Rats 
Pharmaceutical research  2007;25(4):769-780.
Purpose
This study examines methylprednisolone (MPL) effects on the dynamics of hepatic low-density lipoprotein receptor (LDLR) mRNA and plasma lipids associated with increased risks for atherosclerosis.
Materials and methods
Normal male Wistar rats were given 50 mg/kg MPL intramuscularly (IM) and sacrificed at various times. Measurements included plasma MPL and CST, hepatic glucocorticoid receptor (GR) mRNA, cytosolic GR density and hepatic LDLR mRNA, and plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), and triglycerides (TG).
Results
MPL showed bi-exponential disposition with two first-order absorption components. Hepatic GR and LDLR mRNA exhibited circadian patterns which were disrupted by MPL. Down-regulation in GR mRNA (40–50%) was followed by a delayed rebound phase. LDLR mRNA exhibited transient down-regulation (60–70%). Cytosolic GR density was significantly suppressed but returned to baseline by 72 h. Plasma TC and LDLC showed increases (55 and 142%) at 12 h. A mechanistic receptor/gene pharmacokinetic/pharmacodynamic model was developed to describe CS effects on hepatic LDLR mRNA and plasma cholesterols.
Conclusions
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.
doi:10.1007/s11095-007-9371-8
PMCID: PMC4196440  PMID: 17674160
cholesterol; corticosteroids; glucocorticoid receptors; LDL receptors; lipids; pharmacodynamics
2.  Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling1 
A retrospective analysis was performed to modify our fourth-generation pharmacodynamic model for glucocorticoid receptor (GR) dynamics with incorporation of more physiological features. This modified model was developed by integrating previously reported free cytosolic GR and GR mRNA data following single (10, 50 mg/kg) and dual (50 mg/kg at 0 and 24 hr) intravenous doses of methylprednisolone (MPL) in adrenalectomized (ADX) male Wistar rats with several in vitro studies describing real-time kinetics of the transfer of rat steroid-receptor complex from the cell cytosol to the nucleus. Additionally, free hepatic cytosolic GR and its mRNA data from a chronic infusion dosing study of MPL (0.1 and 0.3 mg/kg/hr) in male ADX Wistar rats were used to verify the predictability of the model. Incorporation of information regarding in vitro receptor kinetics allowed us to describe the receptor-mediated pharmacogenomic effects of MPL for a larger variety of genes in rat liver from microarray studies. These included early responsive gene like CCAAT/enhancer binding protein-β (CEBP-β), a transcription factor, as well as the later responsive gene for tyrosine aminotransferase (TAT), a classical biomarker of glucocorticoid (GC) genomic effects. This more mechanistic model of GR dynamics can be applied to characterize profiles for a greater number of genes in liver.
doi:10.1007/s10928-007-9049-1
PMCID: PMC4184272  PMID: 17285360
glucocorticoids; glucocorticoid receptor; nuclear localization; pharmacodynamics; methylprednisolone; pharmacogenomics
3.  Pharmacokinetics of Methylprednisolone after Intravenous and Intramuscular Administration in Rats 
Methylprednisolone (MPL) pharmacokinetics was examined in adrenalectomized (ADX) and normal rats to assess the feasibility of intramuscular (i.m.) dosing for use in pharmacodynamic studies. Several study phases were pursued. Parallel group studies were performed in normal and ADX rats given 50 mg/kg MPL (i.v. or i.m.) and blood samples were collected up to 6 h. Data from studies where normal rats were dosed with 50 mg/kg MPL i.m. and killed over either 6 or 96 h were combined to determine muscle site and plasma MPL concentrations. Lastly, ADX rats were dosed with 50 mg/kg MPL i.m. and killed over 18 h to assess hepatic tyrosine aminotransferase (TAT) dynamics. MPL exhibited bi-exponential kinetics after i.v. dosing with a terminal slope of 2.1 h−1. The i.m. drug was absorbed slowly with two first-order absorption rate constants, 1.26 and 0.219 h−1 indicating flip-flop kinetics with overall 50% bioavailability. The kinetics of MPL at the injection site exhibited slow, dual absorption rates. Although i.m. MPL showed lower bioavailability compared with other corticosteroids in rats, TAT dynamics revealed similar i.m. and i.v. response profiles. The more convenient intramuscular dosing can replace the i.v. route without causing marked differences in pharmacodynamics.
doi:10.1002/bdd.551
PMCID: PMC4181331  PMID: 17569107
methylprednisolone; corticosteroids; pharmacokinetics; intramuscular injection; tyrosine aminotransferase
4.  Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids 
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 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/gene-mediated 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.
doi:10.1007/s10928-007-9063-3
PMCID: PMC4180077  PMID: 17593325
Methylprednisolone; Corticosteroids; Pharmacokinetics; Pharmacodynamics; Tyrosine aminotransferase; Glucocorticoid receptors
5.  Pharmacodynamic Modeling of Acute and Chronic Effects of Methylprednisolone on Hepatic Urea Cycle Genes in Rats* 
Corticosteroids (CS) regulate many enzymes at both mRNA and protein levels. This study used microarrays to broadly assess regulation of various genes related to the greater urea cycle and employs pharmacokinetic/pharmacodynamic (PK/PD) modeling to quantitatively analyze and compare the temporal profiles of these genes during acute and chronic exposure to methylprednisolone (MPL). One group of adrenalectomized male Wistar rats received an intravenous bolus dose (50 mg/kg) of MPL, whereas a second group received MPL by a subcutaneous infusion (Alzet osmotic pumps) at a rate of 0.3 mg/kg/hr for seven days. The rats were sacrificed at various time points over 72 hours (acute) or 168 hours (chronic) and livers were harvested. Total RNA was extracted and Affymetrix® gene chips (RG_U34A for acute and RAE 230A for chronic) were used to identify genes regulated by CS. Besides five primary urea cycle enzymes, many other genes related to the urea cycle showed substantial changes in mRNA expression. Some genes that were simply up- or down-regulated after acute MPL showed complex biphasic patterns upon chronic infusion indicating involvement of secondary regulation. For the simplest patterns, indirect response models were used to describe the nuclear steroid-bound receptor mediated increase or decrease in gene transcription (e.g. tyrosine aminotransferase, glucocorticoid receptor). For the biphasic profiles, involvement of a secondary biosignal was assumed (e.g. ornithine decarboxylase, CCAAT/enhancer binding protein) and more complex models were derived. Microarrays were used successfully to explore CS effects on various urea cycle enzyme genes. PD models presented in this report describe testable hypotheses regarding molecular mechanisms and quantitatively characterize the direct or indirect regulation of various genes by CS.
PMCID: PMC2733100  PMID: 19787073
urea cycle; corticosteroids; methylprednisolone; pharmacodynamics; genomics

Results 1-5 (5)