Juice of the Seville orange is known to inhibit intestinal CYP3A4 (48,49) and has been used for this purpose experimentally (50). This effect is similar to that observed with grapefruit juice in that it only affects intestinal CYP3A4 and has no effect on hepatic CYP3A4. Many drugs may be potentially affected by coadministration with Seville orange juice, including antifungals (ketoconazole, itraconazole), calcium channel blockers (diltiazem, nicardipine, verapamil), chemotherapeutic agents (etoposide, paclitaxel, vinblastine, vincristine, vindesine), dextromethorphan, felodipine, fexofenadine, glucocorticoids, losartan, midazolam, and others (7). The effects of Seville orange juice on cyclosporine disposition has been evaluated in several studies with mixed results. In one study, the Cmax of cyclosporine was increased by 64% after ingestion of C. aurantium (51). Another study demonstrated no effect of C. aurantium on cyclosporine concentrations (52). A third study looked at the effect of long-term administration of C. aurantium extract on CYP3A4 activity (53). The study found no effect of the extract on CYP3A4 activity. The authors proposed a novel explanation for the discrepancy in results from that of Seville orange juice. They suggest that although juice retains the poorly soluble furanocoumarins, most hot-water prepared extracts (including those used in the study) do not.

There are theoretical drug interactions with caffeine and monoamine oxidase inhibitors. Caffeine could increase risk of cardiovascular events when taken with C. aurantium (54). The case report of MI (45) and several of the Canadian reported adverse events included caffeine (46). Synephrine, tyramine, and octopamine are all substrates of monoamine oxidase (55). Taking a monoamine oxidase inhibitor with C. aurantium could increase concentrations of these sympathomimetics, and thus should be avoided.

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