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.