Modeling Pathway Dynamics of the Skeletal Muscle Response to Intravenous Methylprednisolone (MPL) Administration in Rats: Dosing and Tissue Effects

Abstract

A model-based approach for the assessment of pathway dynamics is explored to characterize metabolic and signaling pathway activity changes characteristic of the dosing-dependent differences in response to methylprednisolone in muscle. To consistently compare dosing-induced changes we extend the principles of pharmacokinetics and pharmacodynamics and introduce a novel representation of pathway-level dynamic models of activity regulation. We hypothesize the emergence of dosing-dependent regulatory interactions is critical to understanding the mechanistic implications of MPL dosing in muscle. Our results indicate that key pathways, including amino acid and lipid metabolism, signal transduction, endocrine regulation, regulation of cellular functions including growth, death, motility, transport, protein degradation, and catabolism are dependent on dosing, exhibiting diverse dynamics depending on whether the drug is administered acutely of continuously. Therefore, the dynamics of drug presentation offer the possibility for the emergence of dosing-dependent models of regulation. Finally, we compared acute and chronic MPL response in muscle with liver. The comparison revealed systematic response differences between the two tissues, notably that muscle appears more prone to adapt to MPL.