Fourth-generation model for corticosteroid pharmacodynamics: A model for methylprednisolone effects on receptor/gene-mediated glucocorticoid receptordown-regulation and tyrosine aminotransferase induction in rat liver

A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for recep tor/gene-mediated effects of corticosteroids was developed. Male adrenalect omized Wistar rats received a 50 mg/kg iv bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) m essenger RNA (mRNA) and GR density tyrosine aminotransferase (TAT) mRNA, an d TAT activity in liver were determined at various rime points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45-50% of the baseline in 8-10 hr, and slowly ret urned to predose level in about 3 days; GR density fell to 0 soon after dos ing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was p arallel to the GR mRNA recovery phase. Two indirect response models were ap plied for GR mRNA dynamics regulated by activated steroid-receptor complex A full PK/PD model for GR mRNA/GR dawn-regulation was proposed, including G R recycling theory. TAT mRNA began to increase at about 1.5 AT, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1-2 hr. A transcription compartment was applied as one of the cascade even ts leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were o btained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down -regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.