Influence of grapefruit juice on cisapride pharmacokinetics

Objective: Grapefruit juice increases the oral bioavailability of several d rugs metabolized by cytochrome P450 3A4. This study investigated the influe nce of grapefruit juice on the pharmacokinetics of oral cisapride, a substr ate of CYP3A4. Methods: Fourteen healthy volunteers received in random order 10 mg cisapri de (Prepulsid) with 250 mL water or grapefruit juice after an overnight fas t. Blood samples were taken for 25 hours and urine was collected for 36 hou rs after dosing. Plasma concentrations of cisapride and urinary norcisaprid e were measured by HPLC, The influence of grapefruit juice on pharmacokinet ic parameters (mean +/- SD) was assessed with the Wilcoxon matched pairs te st for 13 subjects (1 subject did not fast as instructed). Results: Grapefruit juice increased cisapride maximum measured plasma conce ntration (C-max; water, 65 +/- 398 ng/mL; grapefruit juice, 87 +/- 40 ng/mL ; P = .009) and area under the plasma concentration-time curve from 0 to 25 hours [AUC(0-25); water, 418 +/- 280 h.ng/mL; grapefruit juice, 580 +/- 28 9 h.ng/mL; P = .005] and prolonged the time to reach C-max (water, 1.26 +/- 0.36 hours; grapefruit juice, 1.72 +/- 0.55 hours; P = .02). Half-life was not affected, Urinary norcisapride recovery was similar and thus the parti al apparent metabolic clearance to norcisapride was lower (P = .046) after grapefruit juice (89.5 +/- 41.2 mL/min) than after water (121.5 +/- 54.7 mL /min). There was considerable interindividual variation in the grapefruit j uice effect [range of AUC(0-25) grapefruit juice/water ratio, 0.90 to 2.65] . Conclusions: Grapefruit juice increases the oral bioavailability of cisapri de, with large interindividual variation in the change in C-max and AUC. Be cause cisapride has a wide therapeutic index, the interaction may not be of major clinical significance for efficacy, but further studies are necessar y at steady state to rule out the possibility of side effects in susceptibl e individuals.