Drug Interaction Report

MONITOR: Estrogen therapy may reduce the response to metyrapone test. The mechanism is related to an increase in serum cortisol-binding globulin (transcortin) induced by estrogens, resulting in decreased cortisol clearance. The increase in circulating cortisol may directly interfere with test results, since the pharmacologic effect of metyrapone is to inhibit adrenal production of cortisol and corticosterone in order to elicit an increase in ACTH production by the pituitary.

MANAGEMENT: Clinicians should recognize the potential for a diminished response to metyrapone test in patients treated with estrogens.

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.