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Methylprednisolone, a corticosteroid of intermediate potency, remains an important immunomodulatory agent for autoimmune diseases. Although sex differences in corticosteroid pharmacokinetics/ pharmacodynamics (PK/PD) have been documented in humans, comprehensive preclinical assessments of such differences have not been conducted. Limited  evidence indicates possible sex differences in corticosteroid PK and PD. Therefore, it is hypothesized that comparative PK/PD assessments of methylprednisolone disposition and selected PD actions in both sexes will provide insights into factors controlling sex differences in steroid responses. This report focused on the plasma and tissue pharmacokinetics of methylprednisolone and its adrenal suppressive effects. Since time-dependent (estrous) regulation of sex hormones in females can influence drug responses, female rats were studied in the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the reproductive cycle. Cohorts of male and female rats were given a 50 mg/kg bolus dose of methylprednisolone intramuscularly. Plasma and liver concentrations of methylprednisolone as well as plasma corticosterone concentrations were assayed using high performance liquid chromatography. An enhanced minimal physiologically-based pharmacokinetic/pharmacodynamic (mPBPK/PD) model was developed to characterize methylprednisolone kinetics and corticosterone dynamics. The clearance of MPL was ~3-fold higher in males compared to females, regardless of estrous phase, likely attributable to sex-specific hepatic metabolism in males. Strong inhibitory effects on adrenal suppression was observed in all animals. These temporal steroid profiles in plasma and tissues will be used to drive receptor/gene-mediated PD effects of MPL in both sexes as described in a companion article (Part-III). SIGNIFICANCE STATEMENT: Sex is a relevant factor influencing the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs. Few preclinical PK/PD studies, however, include sex as a variable. Sex differences in the PK and adrenal suppressive effects of the synthetic corticosteroid, methylprednisolone, were assessed in male and female rats as a function of the four-day rodent reproductive cycle. Drug exposure was three-fold higher in females, regardless of estrous stage, compared to males. An extended minimal physiologically-based PK/PD (mPBPK/PD) model utilizing in vitro and in vivo measurements was developed and applied. These studies provide a framework to account for sex-dependent variability in drug and endogenous agonist (corticosterone) exposures, serving as a prelude to more intricate assessments of sex-related variability in receptor/gene-mediated corticosteroid actions.

the journal of pharmacology and experimental therapeutics/the journal of pharmacology and experimental therapeutics

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part II: Sex Differences in Methylprednisolone Pharmacokinetics and Corticosterone Suppression