Drug Interaction Report

MONITOR: Estrogens may enhance the systemic effects of both endogenous and exogenous corticosteroids. The proposed mechanism is an increase in serum cortisol-binding globulin (transcortin) induced by estrogens, resulting in a decreased rate of corticosteroid metabolic clearance. The interaction has been reported with estrogens or estrogen-containing oral contraceptives (OCs) and hydrocortisone, prednisone, and prednisolone. In one pharmacokinetic study, the mean plasma clearance of total prednisolone (40 mg IV) in eight female OC users was less than half that of five healthy female non-OC users and eight healthy males, and the prednisolone half-life and mean residence time were longer. There was also a 2-fold increase in the area under the plasma concentration-time curve for unbound prednisolone compared to controls.

MANAGEMENT: Patients treated concomitantly with an estrogen-containing drug may require lower dosages of corticosteroids or adrenocorticotropic agents. Pharmacologic response to these agents should be monitored more closely whenever an estrogen is added to or withdrawn from therapy in patients stabilized on their existing corticosteroid or adrenocorticotropic regimen, and the dosage(s) adjusted as necessary.

Coadministration with grapefruit juice may increase the bioavailability of oral estrogens. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruits. In a small, randomized, crossover study, the administration of ethinyl estradiol with grapefruit juice (compared to herbal tea) increased peak plasma drug concentration (Cmax) by 37% and area under the concentration-time curve (AUC) by 28%. Based on these findings, grapefruit juice is unlikely to affect the overall safety profile of ethinyl estradiol. However, as with other drug interactions involving grapefruit juice, the pharmacokinetic alterations are subject to a high degree of interpatient variability. Also, the effect on other estrogens has not been studied.