Repeated consumption of grapefruit juice considerably increases plasma concentrations of cisapride

Background: Grapefruit juice increases the bioavailability of several drugs that are metabolized during first pass by CYP3A4, In this study, the effect of grapefruit juice on the pharmacokinetics of orally administered cisapride was investigated. Methods: In a randomized, two-phase crossover study, 10 healthy volunteers took either 200 mL double-strength grapefruit juice or water three times a day for 2 days. On day 3, each subject ingested 10 mg cisapride with either 200 mt grapefruit juice or water, and an additional 200 mt was ingested 1/2 hour and 11/2 hours after cisapride administration. Timed blood samples were collected for 32 hours after cisapride intake, and a standard 12-lead ECG was recorded before the administration of cisapride and 2, 5, 8, and 12 hours later. Results: The mean peak plasma concentration of cisapride was increased by 81% (range, 38% to 138%; P < .01) and the total area under the plasma cisapride concentration-time curve by 144% (range, 65% to 244%; P < .01) by grapefruit juice. The time of the peak concentration of cisapride was prolonged from 1.5 to 2.5 hours (P < .05) and the elimination half-life from 6.8 to 8.4 hours (P < .05) by grapefruit juice. ECG tracings did not show any significant differences in the QTc interval between the grapefruit juice and control phases. Conclusions: Grapefruit juice significantly increases plasma concentrations of cisapride, probably by inhibition of the CYP3A4-mediated first-pass metabolism of cisapride in. the small intestine. Concomitant use of high amounts of grapefruit juice and cisapride should be avoided, at least in patients with risk factors for cardiac arrhythmia.