3RD-GENERATION MODEL FOR CORTICOSTEROID PHARMACODYNAMICS - ROLES OF GLUCOCORTICOID RECEPTOR MESSENGER-RNA AND TYROSINE AMINOTRANSFERASE MESSENGER-RNA IN RAT-LIVER

A third-generation pharmacokinetic/pharmacodynamic model was proposed for receptor/genemediated corticosteroid effects. The roles of the mes senger RNA (mRNA) for the glucocorticoid receptor (GR) in hepatic GR d own-regulation and the MRNA for hepatic tyrosine aminotransferase (TAT ) induction by methylprednisolone (MPL) were examined. Male adrenalect omized Wistar rats received 50 mg/kg MPL iv. Blood and liver samples w ere collected at various time points for a period of 18 hr. Plasma con centrations of MPL, free hepatic cytosolic GR densities, GR mRNA, TAT mRNA, and tat activities in liver were determined. Plasma MPL profile was biexponential with a terminal T-1/2 of 0.57 hr. Free hepatic GR de nsity rapidly disappeared from cytoplasm after the MPL dose and then s lowly returned to about 60% of starting level after 16 hr. Meanwhile, GR mRNA level fell to 45% of baseline within 2 hr, reached a maximum a t about 5 hr, and declined to baseline by 14 hr. TAT induction followe d a similar pattern, except the induction was delayed about 0.5 hr. Ph armacodynamic parameters were obtained by fitting seven differential e quations in a piecewise fashion. The cascade of corticosteroid steps w ere modeled by a series of inductions for steroid-receptor-DNA complex , two intermediate transit compartments, TAT mRNA, and TAT activity. R esults indicate that GR mRNA and TAT mRNA are major controlling factor s for the receptor/gene-mediated effects of corticosteroids.