Pharmacological time-series data, from comparative dosing studies, are critical
to characterizing drug effects. Reconciling the data from multiple studies is
inevitably difficult; multiple in vivo high-throughput -omics studies are
necessary to capture the global and temporal effects of the drug, but these
experiments, though analogous, differ in (microarray or other) platforms,
time-scales, and dosing regimens and thus cannot be directly combined or
compared. This investigation addresses this reconciliation issue with a
meta-analysis technique aimed at assessing the intrinsic activity at the pathway
level. The purpose of this is to characterize the dosing effects of
methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive
corticosteroid (CS), within the liver. A multivariate decomposition approach is
applied to analyze acute and chronic MPL dosing in male adrenalectomized rats
and characterize the dosing-dependent differences in the dynamic response of
MPL-responsive signaling and metabolic pathways. We demonstrate how to
deconstruct signaling and metabolic pathways into their constituent pathway
activities, activities which are scored for intrinsic pathway activity.
Dosing-induced changes in the dynamics of pathway activities are compared using
a model-based assessment of pathway dynamics, extending the principles of
pharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. The
model-based approach enabled us to hypothesize on the likely emergence (or
disappearance) of indirect dosing-dependent regulatory interactions, pointing to
likely mechanistic implications of dosing of MPL transcriptional regulation.
Both acute and chronic MPL administration induced a strong core of activity
within pathway families including the following: lipid metabolism, amino acid
metabolism, carbohydrate metabolism, metabolism of cofactors and vitamins,
regulation of essential organelles, and xenobiotic metabolism pathway families.
Pathway activities alter between acute and chronic dosing, indicating that MPL
response is dosing dependent. Furthermore, because multiple pathway activities
are dominant within a single pathway, we observe that pathways cannot be defined
by a single response. Instead, pathways are defined by multiple, complex, and
temporally related activities corresponding to different subgroups of genes
within each pathway.