Abstract
Our previous report examined the pharmacokinetics (PK) of methylprednisolone (MPL) and adrenal suppression following a 50 mg/kg intramuscular bolus in male and female rats. The development of a minimal physiologically-based pharmacokinetic/pharmacodynamic (mPBPK/PD) model was described. In continuation of such assessments, we investigated sex differences in genomic MPL responses. Message expression of the glucocorticoid-induced leucine zipper (GILZ) was chosen as a multi-tissue biomarker of glucocorticoid receptor (GR)-mediated drug response. Potential time-dependent interplay between sex hormone and glucocorticoid signaling in vivo was assessed by comparing the PD enhancement of GILZ by MPL in uterus [high estrogen receptor (ER) density], and in liver (lower ER density) from males and females dosed within the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the rodent estrous cycle. An expanded systems PD model of MPL considering circadian rhythms, multi-receptor (ER and GR) control, and estrous variations was developed to delineate the determinants controlling receptor/gene-mediated steroid responses. Hepatic GILZ response was ~3-fold higher in females, regardless of estrous stage, compared to males, driven predominantly by increased MPL exposure in females and a negligible influence of estrogen interaction. In contrast, GILZ response in uterus during proestrus in females was 60% of that observed in estrus-phased females, despite no PK or receptor differences, providing in vivo support to the hypothesis of an estrogen-mediated antagonism of glucocorticoid signaling. The developed model offered a mechanistic platform to assess the determinants of sex- and tissue-specificity in corticosteroid actions and, in turn, reveal a unique PD drug-hormone interaction occurring in vivo.
SIGNIFICANCE STATEMENT Mechanisms relating to sex-based pharmacodynamic variability in genomic responses to corticosteroids have been unclear. Using combined experimental and systems pharmacology modeling approaches, sex differences in both pharmacokinetic and pharmacodynamic mechanisms controlling the enhancement of a sensitive corticosteroid-regulated biomarker, the glucocorticoid-induced leucine zipper (GILZ), were clarified in vivo. The multiscale minimal PBPK/PD model successfully captured the experimental observations and quantitatively discerned the roles of the rodent estrous cycle (hormonal variation) and tissue specificity in mediating the antagonistic co-regulation of GILZ gene synthesis. These findings collectively support the hypothesis that estrogens antagonize pharmacodynamic signaling of genomic corticosteroid actions in vivo in a time- and estrogen receptor-dependent manner.
- The American Society for Pharmacology and Experimental Therapeutics
In this issue
Modeling Corticosteroid Pharmacokinetics & Pharmacodynamics - III: Estrous Cycle- and Estrogen Receptor-Dependent Antagonism of GILZ Enhancement by Corticosteroids
