Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: 6/5/2003
Publication Date: N/A
Citation: Interpretive Summary:
Technical Abstract: Grapefruit juice (GFJ) enhances the systemic exposure of several CYP3A substrates, including felodipine, by inhibiting intestinal (but not hepatic) first-pass metabolism. In vitro data indicate that furanocoumarins (FCs) are the major active CYP3A inhibitors. Using food grade solvents and adsorption resins, FCs were removed (>98%) from whole GFJ while other major ingredients (e.g., flavonoids) were retained. The effects of this 'FC-free' juice were tested against orange juice (OJ) (control) and the original GFJ on the pharmacokinetics of felodipine. By three-way randomized crossover design, 18 healthy volunteers were given felodipine (10 mg) with one of the three juices. Blood (10 ml) was collected from 0-24 hours. Each juice treatment was separated by at least one week. Plasma was analyzed for felodipine by LC/MS/MS. In each of the subjects examined to date (n=13), relative to OJ, only GFJ augmented the AUC and Cmax of felodipine. GFJ significantly increased the average (±SD) AUC (149±68 nM-h) and Cmax (26±11 nM) relative to both OJ and FC-free GFJ (75±36 nM-h, 9±3 nM and 67±33 nM-h, 9±4 nM, respectively) (p<0.001). Neither the average Tmax (2.8±0.8 vs. 2.7±0.6 vs. 2.7±0.9 h) nor terminal elimination rate constant (0.09±0.03 vs. 0.10±0.03 vs. 0.10±0.03 h-1) differed among the three juices (GFJ vs. OJ vs. FC-free GFJ). These results strongly indicate that FCs are indeed the active ingredients responsible for enhancing the systemic exposure of felodipine and probably other CYP3A substrates that undergo extensive intestinal first-pass metabolism.