Pharmacodynamics and Pharmacogenomics of Methylprednisolone during 7-Day Infusions in Rats

摘要

An array of adverse steroid efffects was examined on a whole body, tissue and molecular leverl. Groups of male adrenalectomozed Wistar rats were subcutaneously implanted with Alzet mini-pumps giving ziro-order release rates of 0,0.1,and 0.3 mg/kg/h methylperdnisolone for 7 days. The rats tere sacrificed at various times during the 7-days infusion period. A twocompartment model with a zero order input could adequately describe the characterized by the cell trafficking model. The time coursde of changes in body and orang (liver spleen, thymus, gastrocnermium muscle, and lungs) weithrs was described using indirect response models. Markers of gene-mediated steroid effects included hepatic cytosolic frdee receptor density, receptor mRNA, tyrosine aminotranferase (ATA) mRNA, and TAT levels. Our fifth-generation model acute corticosteroid pharmacodynamics was used to predict the time courso of receptor/gene-mediated effects. An excellent agreement between the expected and observed receptor dynamics suggested that receptor events and mRNA autoregulation are not altered upon 7-day methylprednisolone dosing . However, the nodel indicated a decoupling between the receptor and TAT dynamics with this infusionl The strong tolerance seen in TAT mRNA induction could be partly accounted for by receptor down-regulation . An amplification of translation of TAT mRNA to TAT and/or a reduction in the enzyme degradation rate could account for the obsered exaggerated TAT activity . Our results exemplity the improtance of biological signal transduction variables in controlling receptor/gene-mediated steroid resoses during chronic dosing