Third-generation model for corticosteroid pharmacodynamics: Roles of glucocorticoid receptor mRNA and tyrosine aminotransferase mRNA in rat liver

摘要: A third-generation pharmacokinetic/pharmacodynamic model was proposed for receptor/genemediated corticosteroid effects. The roles of the messenger RNA (mRNA) glucocorticoid receptor (GR) in hepatic GR down-regulation and mRNA tyrosine aminotransferase (TAT) induction by methylprednisolone (MPL) were examined. Male adrenalectomized Wistar rats received 50 mg/kg MPL iv. Blood liver samples collected at various time points a period 18 hr. Plasma concentrations MPL, free cytosolic densities, mRNA, TAT activities determined. profile biexponential with terminal t1/2 0.57 Free density rapidly disappeared from cytoplasm after dose then slowly returned to about 60% starting level 16 Meanwhile, fell 45% baseline within 2 hr postdosing, remained that least protein turnover rate modeled. began increase hr, reached maximum 5 declined 14 followed similar pattern, except delayed 0.5 Pharmacodynamic parameters obtained fitting seven differential equations piecewise fashion. cascade steps modeled series inductions steroid-receptor-DNA complex, two intermediate transit compartments, activity. Results indicate are major controlling factors receptor/gene-mediated effects corticosteroids.