Mathematical Modeling of Corticosteroid Pharmacogenomics in Rat Muscle following Acute and Chronic Methylprednisolone Dosing

Abstract

The pharmacogenomic effects of a corticosteroid (CS) were assessed in rat skeletal muscle using microarrays. Adrenalectomized (ADX) rats were treated with methylprednisolone (MPL) by either 50 mg/kg intravenous injection or 7-day 0.3 mg/kg/h infusion through subcutaneously implanted pumps. RNAs extracted from individual rat muscles were hybridized to Affymetrix Rat Genome Genechips. Data mining yielded 653 and 2316 CS-responsive probe sets following MPL bolus and infusion treatments. Of these, 196 genes were controlled by MPL under both dosing conditions. Cluster analysis revealed that 124 probe sets exhibited three typical expression dynamic profiles following acute dosing. Cluster A consisted of up-regulated probe sets which were grouped into five subclusters each exhibiting unique temporal patterns during the infusion. Cluster B comprised down-regulated probe sets which were divided into two subclusters with distinct dynamics during the infusion. Cluster C probe sets exhibited delayed down-regulation under both bolus and infusion conditions. Among those, 104 probe sets were further grouped into subclusters based on their profiles following chronic MPL dosing. Several mathematical models were proposed and adequately captured the temporal patterns for each subcluster. Multiple types of dosing regimens are needed to resolve common determinants of gene regulation as chronic exposure results in unexpected differences in gene expression compared to acute dosing. Pharmacokinetic/ pharmacodynamic (PK/PD) modeling provides a quantitative tool for elucidating the complexities of CS pharmacogenomics in skeletal muscle.

Translational Biomarkers: from Preclinical to Clinical a Report of 2009 AAPS/ACCP Biomarker Workshop

“…Studies in the Jusko Laboratory have utilized Affymetrix gene arrays to monitor gene expression under controlled baseline conditions in normal rats as well as after administration of large doses of methylprednisolone (16). These studies have shown that normal rats often exhibit circadian rhythms in gene expression in liver and muscle, but the rhythms may peak at various times of the day.…”

“…The latter is a severe complication in use of mRNA as a biomarker. Adding further complexity is that single-dose changes in gene expression are not predictive of responses during chronic infusions (16).…”

Inference of Gene Regulatory Networks Incorporating Multi-Source Biological Knowledge via a State Space Model with L1 Regularization

“…The first two observational datasets are generated by two simulation models representing pharmacogenomic pathways [37], [38], including drug kinetics/dynamics, described by difference and differential equations, respectively. These pathways are initiated by the drug stimulation and observational data are obtained as non-equally spaced time-course data.…”

Modeling TGF-β signaling pathway in epithelial-mesenchymal transition

“…As we will clarify in the forthcoming sections, the model parameters have been adjusted so to reproduce hmga2 gene expression data. This fitting procedure is customarily adopted in pharmacogenomics 10,11 and yields to reliable estimates for the a priori unknown kinetic rates, providing in turn a viable strategy to reconstruct the underlying genetic networks.…”