Dose-dependence and repeated-dose studies for receptor/gene-mediated pharmacodynamics of methylprednisolone on glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver

Dose-dependent and repeated-dose effects of methylprednisolone (MPL) on dow n-regulation of glucocorticoid receptor messenger RNA (GR mRNA) and GR dens ity, as well as thyrosine amino-transferase (TAT) mRNA and TAT induction by receptor/gene-mediated mechanisms in rat liver were examined. A previously developed pharmacokinetic/pharmacodynamic (PK/PD) model was used to design these studies which sought to challenge the model. Three groups of male ad renalectomized Wistar rats received MPL by iv injection: low-dose (10 mg/kg at Time 0), high-dose (50 mg/kg at Time 0), and dual-dose (50 mg/kg at Tim e 0 and 24 hr). Plasma concentrations of MPL, and hepatic content of free G R, GA mRNA, TAT mRNA, and TAT activity were determined. The P-Pharm program was applied for population analysis of MPL PK repealing low interindividua l variation in CL and V-c values (3-14%). Two indirect response models were applied to test two competing hypotheses for GR mRNA dynamics. Indirect Ph armacodynamic Response Model I(Model A) where the complex in the nucleus de creases the transcription rate of GR mRNA better described GR mRNA/GR down- regulation. Levels of TAT, mRNA began to increase at 1-2 hr, reached a maxi mum at 5-6 hr, and declined to the baseline at 12-14 hr after MPL dosing. T he induction of TAT activity followed a similar pattern with a delay of abo ut 1-2 hr. The low-dose group had 50-60% of the TA T mRNA and TAT induction compared to the high-dose group. Since the GR density returned to about 70 % of the baseline level before the second 50 mg/kg dose at 24 hr, tolerance was found for TAT mRNA/TAT induction where only 50-60% of the initial resp onses were produced Our fourth-generation,model describes the dose dependen ce and tolerance effects of TAT mRNA/TAT induction by MPL involving multipl e-step signal transduction controlled by the steroid regimen, free GR densi ty, and GR occupancy. This model,may, provide the foundation for similar pi ng other induced proteins or enzymes mediated by the similar; receptor/nucl ear events.