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

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 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.