Drug Interaction Report

MONITOR: Based on in vitro inhibition data, coadministration with mibefradil may increase the plasma concentrations of drugs that are substrates of CYP450 2D6 and/or 3A4. The mechanism is decreased clearance due to inhibition of these isoenzymes by mibefradil.

MANAGEMENT: Caution is advised when mibefradil is used concomitantly with drugs that undergo metabolism by CYP450 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever mibefradil is added to or withdrawn from therapy.

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.