Pharmacodynamics and pharmacogenomics of corticosteroids in rat skeletal muscle

Abstract

Glucocorticoids represent a class of drugs that are commonly debated between their potent anti-inflammatory and immunosuppressive functions and strong adverse effects. This thesis aims at using a mechanism based modeling approach to assist in the characterization of corticosteroid actions, with a focus on the detrimental effects in skeletal muscle. The common adverse effects including muscle atrophy and insulin resistance were evaluated at the molecular and genomic levels. Integrated pharmacokinetic/pharmacodynamic/pharmacogenomic (PK/PD/PG) models were applied extensively throughout the thesis to examine corticosteroid drug performance and molecular and genomic dynamics and seeking the opportunities in designing optimal dosing strategies to minimize adverse effects. Corticosteroid-induced muscle atrophy was studied in both adrenalectomized (ADX) and normal rats using glutamine synthetase (GS) and myostatin as PD biomarkers. Temporary increases of both biomarkers were observed following treatment of various corticosteroids including methylprednisolone (MPL), dexamethasone and hydrocortisone. In addition, physiological circadian rhythm was present for GS with dependency on plasma corticosterone (CST) concentrations. An integrated model extended from the 5 th -generation model was established. Simulations of various dosing times provide insights for future studies of corticosteroid dosing optimization. An optimal dosing strategy necessitates the studies not only on detrimental effects but also on beneficial actions of corticosteroids, with the prerequisite of maintaining desired effects within therapeutic window. In this dissertation, lymphocytopenia was tested as a biomarker component of anti-inflammatory and immunosuppressive effects. A mechanism based PK/PD model incorporating cell trafficking and apoptosis was proposed and assessed the pharmacological differences between humans and rats in response to MPL. The global pharmacogenomic actions of MPL in ADX rat skeletal muscle were evaluated using a microarray technique. Diverse gene dynamic profiles were observed indicating various complex regulatory mechanisms involved in corticosteroid actions. Genes regulated by MPL were also studied according to their functions. Dynamics of six insulin resistance related genes were closely examined and testable hypotheses of the regulatory cascades were proposed. In summary, this dissertation allows for better understanding of the physiologic, pharmacological, and genomic mechanisms involved in glucocorticoid actions on skeletal muscle including muscle atrophy and insulin resistance. Sophisticated PK/PD models integrating drug exposure with biological signaling events may assist minimization of steroid-induced side effects.