Pharmacodynamics and pharmacogenomics of methylprednisolone on glucose regulation.

摘要

The major goal of this dissertation is to investigate the pharmacodynamics and pharmacogenomics of corticosteroids (CS) on glucose regulation using methylprednisolone (MPL) as a model drug. The major concern of CS therapy is the occurrence of metabolic side effects. Impairment of glucose homeostasis represents one of the common metabolic disorders associated with CS treatment. This dissertation extensively examines the effect of MPL on glucose metabolism at the molecular, cellular, and systemic levels, and seeks mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) models to capture the major components and their interactions.; The effects of MPL on plasma glucose and insulin concentrations were investigated in adrenalectomized (ADX) rats and normal rats. Temporary increases in glucose and insulin concentrations were observed after single-doses of MPL. Chronic drug infusion provoked continuous hyperglycemia and hyperinsulinemia, as well as sustained damage of glucose homeostasis. A disease progression model incorporating reduced endogenous glucose disposition was used as a factor altering glucose and insulin dynamics for all treatments. Suppression of endogenous corticosterone and competitive interaction between endogenous and exogenous CS were added for the normal animals.; The molecular and cellular mechanism of MPL action on glucose metabolism was further studied in ADX rats under various treatments using hepatic cyclic adenosine monophosphate (cAMP), phosphoenolpyruvate carboxykinase (PEPCK) mRNA and activity as the PD markers. A mechanism-based PK/PD model was proposed to describe the receptor-mediated effects of MPL on enhancing PEPCK mRNA synthesis and degradation, as well as the translational stimulation by MPL-induced cAMP. Based on the first study, the model was extended to capture the MPL-induced glucose profiles via PEPCK and cAMP actions on gluconeogenesis and glycogen breakdown.; Similar to PEPCK, tyrosine aminotransferase (TAT) in liver is also regulated by multiple controlling factors including CS, cAMP, and insulin. A sixth-generation model of receptor/gene-mediated CS effects was developed based on results from acute and chronic dosing of MPL in ADX rats. The transcriptional induction of TAT by CS as well as the translational stimulations by CS-enhanced cAMP and insulin were nicely captured.; The pharmacogenomics of CS were studied using gene microarrays in rat liver after a single-dose of MPL. Cluster analysis (GeneSpring) of 8000 genes revealed 6 temporal patterns consisting of 197 CS-responsive probes representing 143 genes. Mechanism-based PD models were proposed to explain the time courses of all the CS-responsive genes observed in our study.; In summary, this dissertation extends the understanding of mechanisms of CS action and the internal controls of the glucose metabolic system. The sophisticated PK/PD models exemplify quantitative approaches which are feasible for signaling networks of biological systems.