Receptor-mediated pharmacodynamics of prednisolone in the rat

Abstract

A pharmacokinetic/pharmacodynamic model describing receptor-mediated effects of prednisolone is presented. The basis of the model is the generally accepted mechanism of action of steroid hormones in which corticosteroids bind to cytosolic receptors forming steroid-receptor complexes, which are activated and translocated into the nucleus. There the complexes associate with specific DNA sequences and modulate the rate of transcription of DNA into specific RNAs that code for the synthesis of proteins that elicit biological responses. Prednisolone, 5 or 50 mg/kg, was administered intravenously to adrenalectomized rats. Total plasma, free plasma, CBG-free plasma, and liver prednisolone concentrations were measured simultaneously with free hepatic cytosolic glucocorticoid receptor concentrations and tyrosine aminotransferase (TAT) activity of the liver as a function of time. The association/dissociation kinetics of prednisolone binding to the glucocorticoid receptor were measured separately in vitro at 37 degrees C. Total plasma, free plasma, and CBG-free plasma prednisolone concentrations could be used equally well in the model to account for the time course of receptor concentrations and TAT activity. However, use of liver steroid concentrations resulted in an overestimation of receptor depletion. Steroid concentrations in plasma increased 20 to 30-fold with a tenfold increase in dose, but receptor occupancy and TAT activity over time increased about threefold. While prednisolone pharmacokinetics were dose-dependent, parameters describing receptor kinetics and TAT activity were constant at each prednisolone dose. The major determinants of receptor-mediated glucocorticoid activity are confirmed to be the availability of the receptor, drug-receptor dissociation rate, and corticosteroid persistence in the biophase.

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

“…Glucocorticoid receptors-A previously developed [10,17] radio-ligand binding assay was used to quantify the hepatic free cytosolic GR density with some modifications. Liver tissues stored at −80°C were ground in liquid nitrogen chilled mortars and pestles.…”

“…The down-regulation followed by rebound in GR mRNA caused by MPL was described by DR(N)-mediated inhibition of k s,GRm (t) and subsequent inhibition of k d,GRm by a transduction signal generated from DR(N), (15) (16) (17) where TC 1 and TC 2 are two transit compartments, τ DR(N) is the mean transit time for signal transduction from DR(N), IC 50,DR(N) is the concentration of DR(N) at which the synthesis rate of GR mRNA is reduced to 50% of its baseline, and IC 50,TC2 is the concentration of TC 2 responsible for 50% inhibition of the loss rate for GR mRNA. Because stationarity was not assumed for normal rats, the k s,GR parameter was estimated with other parameters.…”

Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling

“…A well-established radio-ligand binding assay was used to quantify the hepatic free cytosolic GR density. The total (D T ) and nonspecific (D NS ) binding of radio-labeled DEX were measured (12,23). The receptor density or B max at any given time point was calculated by simultaneously solving Eqs.…”

Physiologically based pharmacokinetic modelling: a sound mechanistic basis is needed

“…It is now time that these two methods came together, so that PBPKPD models can be put on a firm mechanistic basis. Again, some very nice semimechanistic work has appeared, particularly from Jusko and colleagues in Buffalo [17], who in this issue of the Journal describe a semi-mechanistic pharmacokineticpharmacodynamic model of the antimalarial effect of artemisinin [18]. The pharmacokinetic model incorporates autoinduction and saturable metabolism and is linked to a pharmacodynamic model reflecting different stages of the parasite's life-cycle.…”