Drug Interactions between cisapride and itraconazole

CONTRAINDICATED: Coadministration with grapefruit juice may increase the plasma concentrations of cisapride. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In a study of 14 healthy volunteers, administration with 250 mL of grapefruit juice increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of cisapride (10 mg single dose) by 34% and 39%, respectively, compared to water. A second single-dose study involving 12 healthy volunteers demonstrated an increase of 68% and 51% in cisapride Cmax and AUC, respectively, compared to water. In another 10 healthy volunteers, repeated ingestion of double-strength grapefruit juice (200 mL three times a day for 2 days, then with a 10 mg dose of cisapride and at 0.5 and 1.5 hours afterwards) resulted in an 81% and 144% increase in mean cisapride Cmax and AUC, respectively, compared to water. A high degree of intersubject variability in the grapefruit juice effect was observed in all three studies, but no patient experienced any changes in heart rate, blood pressure, or QT interval. However, high plasma levels of cisapride have been associated with prolongation of the QT interval on the ECG; ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes; cardiac arrest; and sudden death.

GENERALLY AVOID: Coadministration with red wine may increase the plasma concentrations of cisapride in susceptible individuals. The exact mechanism of interaction is unknown but is believed to involve inhibition of CYP450 3A4 in the gut wall similar to grapefruit juice. In 12 healthy volunteers, administration with 250 mL of red wine (cabernet sauvignon) produced only minor and statistically insignificant changes in cisapride pharmacokinetics compared to water. However, one subject had a doubling in cisapride AUC and Cmax with red wine. The same subject also had the largest interaction with grapefruit juice, which suggests that a significant interaction may occur in certain individuals, perhaps those with a preexisting high intestinal CYP450 3A4 content.

MANAGEMENT: Patients receiving cisapride therapy should avoid the consumption of grapefruits and grapefruit juice. Because a significant interaction may occur with red wine in the occasional patient, red wine should preferably be avoided also during cisapride therapy.

ADJUST DOSING INTERVAL: Food increases the absorption of itraconazole capsules but decreases the absorption of itraconazole oral solution. Cola beverages may increase the bioavailability of itraconazole capsules. Itraconazole capsules require an acidic gastric pH for adequate dissolution and subsequent absorption. Cola beverages help lower gastric pH and improve absorption.

GENERALLY AVOID: Grapefruit juice may impair the absorption of itraconazole capsules, resulting in decreased antifungal effects. In a small, randomized, crossover study, the administration of itraconazole capsules with double-strength grapefruit juice (compared to water) was associated with significantly decreased (43%) plasma concentrations of itraconazole and its pharmacologically active hydroxy metabolite, as well as delayed times to reach peak concentrations of both. The exact mechanism of interaction is unknown but may involve reduced absorption of itraconazole secondary to enhanced activity of intestinal P-glycoprotein drug efflux pumps and delayed gastric emptying induced by certain compounds present in grapefruits. Another study reported no pharmacokinetic changes with single-strength grapefruit juice. Whether or not these observations apply to itraconazole oral solution is unknown.

MANAGEMENT: The manufacturer recommends that the capsules be taken immediately after a full meal and the solution be taken on an empty stomach to ensure maximal absorption. Cola beverages may help increase the bioavailability of itraconazole capsules, particularly in patients with hypochlorhydria or those treated concomitantly with gastric acid suppressants. Until more information is available, it may be advisable to avoid the consumption of grapefruits and grapefruit juice during itraconazole therapy.