Pharmacokinetics/pharmacodynamics of glucocorticoids: modeling the glucocorticoid receptor dynamics and dose/response of commonly prescribed glucocorticoids

Abstract

Background and purpose: The main features of the dynamics of the glucocorticoid receptor (GR) have been known for 50 years: 1) in the absence of glucocorticoid (G), the receptor is localized entirely in the cytoplasm; 2) upon G binding, GR is converted into a tightly bound G form and is rapidly imported into the nucleus where it can bind DNA and modulate transcription; 3) nuclear export of GR is very slow; and 4) the nuclear form of GR can recycle through an unbound form, back to the bound transcription modulating form without leaving the nucleus.

Experimental approach: A kinetic model that captures these features is presented, a set of model parameters for dexamethasone is derived, and the clinical implication for the commonly used glucocorticoids is discussed.

Key results: At the high concentrations normally used to describe G pharmacodynamics, the model reduces to the standard Michaelis-Menten equation with a K _m that is a function of 4 model parameters. At very low concentrations, it reduces to another Michaelis-Menten equation with about a 1000-fold greater affinity, eg. at the nadir human endogenous cortisol concentration, the full model GR activity is 2.6 times greater than that predicted by extrapolation of the high concentration results.

Conclusion: The model is used to relate normal human 24-hour endogenous plasma cortisol levels to transcriptional activity and is applied to the commonly prescribed glucocorticoids (dexamethasone, methylprednisolone, prednisone) in an attempt to provide a pharmacological rationale for the very large therapeutic dosage range that has been traditionally used.

Keywords: Dexamethasone; cortisol; methylprednisolone; prednisolone; prednisone; transcription.

Figure 1.

Glucocorticoid receptor kinetic model. The receptor cycles through 7 states: unbound in the cytoplasm (Rc) and the nucleus (Rn), a loose equilibrium G bound form in the cytoplasm (RcG) and nucleus (RnG), a tightly bound form in the cytoplasm (RcGt) and nucleus (RnGt), and the form that can bind DNA (RnGN), modifying transcription. The model is characterized by two equilibrium binding constants (Kc and Kn) and 6 rate constants (k1 to k6)

Figure 2.

Fraction of receptor that is located in the nucleus as a function of glucocorticoid concentration using the dexamethasone parameters in Table 1

Figure 3.

Steady state glucocorticoid concentration dependence of the fraction of receptor that is in the state RnGN (see Figure 1) that can potentially modify the transcription rate for the high-affinity dexamethasone (Table 1) with its apparent experimental transcriptional KmT of 5 nM. Three different concentration ranges are shown: very low (a), intermediate (b) and high concentration (c). The black line is the exact solution (Equation 2), the red line is the high concentration approximation (Equation 3) and the blue line is the low concentration approximation (Equation 4)

Figure 4.

Steady state glucocorticoid concentration (nM) dependence of the fraction of receptor that is in the state RnGN (see Figure 1) that can potentially modify the transcription rate for the low-affinity cortisol (Table 1) with its apparent experimental transcriptional KmT of 50 nM. Three different concentration ranges are shown: very low (a), intermediate (b) and high (c). The black line is the exact solution (Equation 2), the red line is the high concentration approximation (Equation 3) and the blue line is the low concentration approximation (Equation 4)

Figure 5.

Time course of the fraction of GR in the transcriptional modifying state RnGN as a function of time after the addition of varying concentrations of DEX

Figure 6.

Time course of labeled [³H]dexamethasone tightly bound to nuclear GR receptor following a cold chase with a 200-fold excess of unlabeled dexamethasone. At time 0, 100 nM [³H]dexamethasone is added. At time of 100 minutes, 20 mM unlabeled dexamethasone is added. The fraction of [³H]dexamethasone labeled nuclear receptor (RnG*t + RnG*N) is plotted as a function of time. The solid circles are the experimental data of Meijsing et. al. [17]

Figure 7.

Daily endogenous human free plasma cortisol

Figure 8.

Endogenous human cortisol nuclear transcription activity as fraction of maximum possible. The free plasma cortisol concentration (green line) is indicated on right Y axis, and the GR transcriptional activity for three different approximations (red, black and blue lines) is indicated on left Y axis

Figure 9.

DEX GR activity following a -3 q.d. and b.i.d. and b – 3 oral g.d. doses per day

Figure 10.

Methylprednisolone GR activity

Figure 11.

Prednisone GR activity