Drug Interaction Report

MONITOR: Coadministration of sirolimus or tacrolimus with other drugs that are also metabolized by CYP450 3A4 may result in elevated plasma concentrations of the macrolide immunosuppressant and/or the coadministered drug(s). The mechanism is decreased drug clearance due to competitive inhibition of CYP450 3A4 activity. Although clinical data are lacking, the possibility of prolonged and/or increased pharmacologic effects of the drugs should be considered.

MANAGEMENT: Pharmacologic responses and/or plasma drug levels should be monitored more closely whenever a macrolide immunosuppressant or another substrate of CYP450 3A4 is added to or withdrawn from therapy, and the dosage(s) adjusted as necessary.

ADJUST DOSING INTERVAL: Consumption of food has led to a 27% decrease in the bioavailability of orally administered tacrolimus.

MANAGEMENT: Tacrolimus should be administered at least one hour before or two hours after meals.

GENERALLY AVOID: Grapefruit juice has been reported to increase tacrolimus trough concentrations. Data are limited, but inhibition of the CYP450 enzyme system appears to be involved.

MANAGEMENT: The clinician may want to recommend that the patient avoid ingesting large amounts of grapefruit juice while taking tacrolimus.

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.