Analysis of methylprednisolone, methylprednisone and corticosterone for assessment of methylprednisolone disposition in the rat

Haughey, David B.; Jusko, William J.

doi:10.1016/s0378-4347(00)83159-x

Cited by 47 publications

(35 citation statements)

References 13 publications

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“…Thus for simplicity we used basic bi-exponentials as forcing functions to describe the PK after various doses of MPL. Determination of MPL in plasma (22) measures total plasma drug concentration, whereas only the free drug can enter the cell and bind to the receptor. In the previous studies (12,20), total MPL in the plasma was allowed to interact with the intracellular receptors, which perhaps resulted in an apparent binding constant, k on , which is somewhat lower (since the amount of cytosolic receptors are fixed) than the true value.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling

Hazra

DuBois

Almon

et al. 2007

J Pharmacokinet Pharmacodyn

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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.

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Section: Discussionmentioning

confidence: 99%

“…Plasma concentrations of MPL were determined by a normal phase high-performance liquid chromatography (HPLC) method (22). The lower limit of quantification is 10 ng/ml with inter-and intra-day assay variability less than 10%.…”

Section: Assaysmentioning

confidence: 99%

Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling

Hazra

DuBois

Almon

et al. 2007

J Pharmacokinet Pharmacodyn

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“…The CST and MPL concentrations were determined by a normal phase high-performance liquid chromatography (HPLC) method [16]. The lower limits of quantification for both of these steroids are 10 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

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

Hazra

Pyszczynski

DuBois

et al. 2007

J Pharmacokinet Pharmacodyn

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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.

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“…The NaOH phase was removed after centrifugation, and the MeCl 2 phase was washed twice with 0.5 ml of water, discarding the water after each wash. MeCl 2 was evaporated off with purified air, leaving a residue that was reconstituted in 110 l of mobile phase. Chromatography conditions involved a mobile phase of 600 ml of MeCl 2 , 350 ml of heptane, 10 ml of glacial acetic acid, and 54 ml of ethanol; a Zorbax normal phase column (Agilent Technologies, Santa Clara, CA); Waters model 1515 isocratic pump; and Waters model 2487 dual-wavelength absorbance detector (Waters, Milford, MA) (Haughey and Jusko, 1988). The lower limit of quantification was 5 ng/ml with an intraday coefficient of variation of less than 10%.…”

Section: Quantitative Disease Progression Model Of Arthritis In Rats 533mentioning

confidence: 99%

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis I: Mechanistic Disease Progression Model for the Time Course of Collagen-Induced Arthritis in Lewis Rats

Earp¹,

DuBois²,

Molano³

et al. 2008

J Pharmacol Exp Ther

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A mechanism-based model was developed to describe the time course of arthritis progression in the rat. Arthritis was induced in male Lewis rats with type II porcine collagen into the base of the tail. Disease progression was monitored by paw swelling, bone mineral density (BMD), body weights, plasma corticosterone (CST) concentrations, and tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, IL-6, and glucocorticoid receptor (GR) mRNA expression in paw tissue. Bone mineral density was determined by PIXImus II dual energy X-ray densitometry. Plasma CST was assayed by high-performance liquid chromatography. Cytokine and GR mRNA were determined by quantitative real-time polymerase chain reaction. Disease progression models were constructed from transduction and indirect response models and applied using S-ADAPT software. A delay in the onset of increased paw TNF-␣ and IL-6 mRNA concentrations was successfully characterized by simple transduction. This rise was closely followed by an up-regulation of GR mRNA and CST concentrations. Paw swelling and body weight responses peaked approximately 21 days after induction, whereas bone mineral density changes were greatest at 23 days after induction. After peak response, the time course in IL-1␤, IL-6 mRNA, and paw edema slowly declined toward a disease steady state. Model parameters indicate TNF-␣ and IL-1␤ mRNA most significantly induce paw edema, whereas IL-6 mRNA exerted the most influence on BMD. The model for bone mineral density captures rates of turnover of cancellous and cortical bone and the fraction of each in the different regions analyzed. This small systems model integrates and quantitates multiple factors contributing to arthritis in rats.

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Analysis of methylprednisolone, methylprednisone and corticosterone for assessment of methylprednisolone disposition in the rat

Cited by 47 publications

References 13 publications

Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling

Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling

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

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis I: Mechanistic Disease Progression Model for the Time Course of Collagen-Induced Arthritis in Lewis Rats

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